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.

Microbial Source Module (MSM): Documenting the Science and Software for Discovery, Evaluation, and Integration

EPA Science Inventory

The Microbial Source Module (MSM) estimates microbial loading rates to land surfaces from non-point sources, and to streams from point sources for each subwatershed within a watershed. A subwatershed, the smallest modeling unit, represents the common basis for information consume...

Monitoring Growth of Hard Corals as Performance Indicators for Coral Reefs

ERIC Educational Resources Information Center

Crabbe, M. James; Karaviotis, Sarah; Smith, David J.

2004-01-01

Digital videophotography, computer image analysis and physical measurements have been used to monitor sedimentation rates, coral cover, genera richness, rugosity, and estimated recruitment dates of massive corals at three different sites in the Wakatobi Marine National Park, Indonesia, and on the reefs around Discovery Bay, Jamaica.…

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

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

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

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.

Optimal False Discovery Rate Control for Dependent Data

PubMed Central

Xie, Jichun; Cai, T. Tony; Maris, John; Li, Hongzhe

2013-01-01

This paper considers the problem of optimal false discovery rate control when the test statistics are dependent. An optimal joint oracle procedure, which minimizes the false non-discovery rate subject to a constraint on the false discovery rate is developed. A data-driven marginal plug-in procedure is then proposed to approximate the optimal joint procedure for multivariate normal data. It is shown that the marginal procedure is asymptotically optimal for multivariate normal data with a short-range dependent covariance structure. Numerical results show that the marginal procedure controls false discovery rate and leads to a smaller false non-discovery rate than several commonly used p-value based false discovery rate controlling methods. The procedure is illustrated by an application to a genome-wide association study of neuroblastoma and it identifies a few more genetic variants that are potentially associated with neuroblastoma than several p-value-based false discovery rate controlling procedures. PMID:23378870

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

Cratering time scales for the Galilean satellites

NASA Technical Reports Server (NTRS)

Shoemaker, E. M.; Wolfe, R. F.

1982-01-01

An attempt is made to estimate the present cratering rate for each Galilean satellite within the correct order of magnitude and to extend the cratering rates back into the geologic past on the basis of evidence from the earth-moon system. For collisions with long and short period comets, the magnitudes and size distributions of the comet nuclei, the distribution of their perihelion distances, and the completeness of discovery are addressed. The diameters and masses of cometary nuclei are assessed, as are crater diameters and cratering rates. The dynamical relations between long period and short period comets are discussed, and the population of Jupiter-crossing asteroids is assessed. Estimated present cratering rates on the Galilean satellites are compared and variations of cratering rate with time are considered. Finally, the consistency of derived cratering time scales with the cratering record of the icy Galilean satellites is discussed.

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.

Estimating usable resources from historical industry data.

USGS Publications Warehouse

Cargill, S.M.; Root, D.H.; Bailey, E.H.

1981-01-01

The commodities considered are mercury, copper and its byproducts gold and silver, and petroleum; the production and discovery data are for the US. The results indicate that the cumulative return per unit of effort, herein measured as grade of metal ores and discovery rate of recoverable petroleum, is proportional to a negative power of total effort expended, herein measured as total ore mined and total exploratory wells or footage drilled. This power relationship can be extended to some limiting point (a lower ore grade or a maximum number of exploratory wells or footage), and the apparent quantity of available remaining resource at that limit can be calculated. -from Authors

Constraints on the FRB rate at 700-900 MHz

NASA Astrophysics Data System (ADS)

Connor, Liam; Lin, Hsiu-Hsien; Masui, Kiyoshi; Oppermann, Niels; Pen, Ue-Li; Peterson, Jeffrey B.; Roman, Alexander; Sievers, Jonathan

2016-07-01

Estimating the all-sky rate of fast radio bursts (FRBs) has been difficult due to small-number statistics and the fact that they are seen by disparate surveys in different regions of the sky. In this paper we provide limits for the FRB rate at 800 MHz based on the only burst detected at frequencies below 1.4 GHz, FRB 110523. We discuss the difficulties in rate estimation, particularly in providing an all-sky rate above a single fluence threshold. We find an implied rate between 700 and 900 MHz that is consistent with the rate at 1.4 GHz, scaling to 6.4^{+29.5}_{-5.0} × 10^3 sky-1 d-1 for an HTRU-like survey. This is promising for upcoming experiments below a GHz like CHIME and UTMOST, for which we forecast detection rates. Given 110523's discovery at 32σ with nothing weaker detected, down to the threshold of 8σ, we find consistency with a Euclidean flux distribution but disfavour steep distributions, ruling out γ > 2.2.

Exploring Site-Specific N-Glycosylation Microheterogeneity of Haptoglobin using Glycopeptide CID Tandem Mass Spectra and Glycan Database Search

PubMed Central

Chandler, Kevin Brown; Pompach, Petr; Goldman, Radoslav

2013-01-01

Glycosylation is a common protein modification with a significant role in many vital cellular processes and human diseases, making the characterization of protein-attached glycan structures important for understanding cell biology and disease processes. Direct analysis of protein N-glycosylation by tandem mass spectrometry of glycopeptides promises site-specific elucidation of N-glycan microheterogeneity, something which detached N-glycan and de-glycosylated peptide analyses cannot provide. However, successful implementation of direct N-glycopeptide analysis by tandem mass spectrometry remains a challenge. In this work, we consider algorithmic techniques for the analysis of LC-MS/MS data acquired from glycopeptide-enriched fractions of enzymatic digests of purified proteins. We implement a computational strategy which takes advantage of the properties of CID fragmentation spectra of N-glycopeptides, matching the MS/MS spectra to peptide-glycan pairs from protein sequences and glycan structure databases. Significantly, we also propose a novel false-discovery-rate estimation technique to estimate and manage the number of false identifications. We use a human glycoprotein standard, haptoglobin, digested with trypsin and GluC, enriched for glycopeptides using HILIC chromatography, and analyzed by LC-MS/MS to demonstrate our algorithmic strategy and evaluate its performance. Our software, GlycoPeptideSearch (GPS), assigned glycopeptide identifications to 246 of the spectra at false-discovery-rate 5.58%, identifying 42 distinct haptoglobin peptide-glycan pairs at each of the four haptoglobin N-linked glycosylation sites. We further demonstrate the effectiveness of this approach by analyzing plasma-derived haptoglobin, identifying 136 N-linked glycopeptide spectra at false-discovery-rate 0.4%, representing 15 distinct glycopeptides on at least three of the four N-linked glycosylation sites. The software, GlycoPeptideSearch, is available for download from http://edwardslab.bmcb.georgetown.edu/GPS. PMID:23829323

Computational methods for a three-dimensional model of the petroleum-discovery process

USGS Publications Warehouse

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

1980-01-01

A discovery-process model devised by Drew, Schuenemeyer, and Root can be used to predict the amount of petroleum to be discovered in a basin from some future level of exploratory effort: the predictions are based on historical drilling and discovery data. Because marginal costs of discovery and production are a function of field size, the model can be used to make estimates of future discoveries within deposit size classes. The modeling approach is a geometric one in which the area searched is a function of the size and shape of the targets being sought. A high correlation is assumed between the surface-projection area of the fields and the volume of petroleum. To predict how much oil remains to be found, the area searched must be computed, and the basin size and discovery efficiency must be estimated. The basin is assumed to be explored randomly rather than by pattern drilling. The model may be used to compute independent estimates of future oil at different depth intervals for a play involving multiple producing horizons. We have written FORTRAN computer programs that are used with Drew, Schuenemeyer, and Root's model to merge the discovery and drilling information and perform the necessary computations to estimate undiscovered petroleum. These program may be modified easily for the estimation of remaining quantities of commodities other than petroleum. ?? 1980.

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.

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

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

Quantifying condition-dependent intracellular protein levels enables high-precision fitness estimates.

PubMed

Geiler-Samerotte, Kerry A; Hashimoto, Tatsunori; Dion, Michael F; Budnik, Bogdan A; Airoldi, Edoardo M; Drummond, D Allan

2013-01-01

Countless studies monitor the growth rate of microbial populations as a measure of fitness. However, an enormous gap separates growth-rate differences measurable in the laboratory from those that natural selection can distinguish efficiently. Taking advantage of the recent discovery that transcript and protein levels in budding yeast closely track growth rate, we explore the possibility that growth rate can be more sensitively inferred by monitoring the proteomic response to growth, rather than growth itself. We find a set of proteins whose levels, in aggregate, enable prediction of growth rate to a higher precision than direct measurements. However, we find little overlap between these proteins and those that closely track growth rate in other studies. These results suggest that, in yeast, the pathways that set the pace of cell division can differ depending on the growth-altering stimulus. Still, with proper validation, protein measurements can provide high-precision growth estimates that allow extension of phenotypic growth-based assays closer to the limits of evolutionary selection.

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.

Fast radio burst event rate counts - I. Interpreting the observations

NASA Astrophysics Data System (ADS)

Macquart, J.-P.; Ekers, R. D.

2018-02-01

The fluence distribution of the fast radio burst (FRB) population (the `source count' distribution, N (>F) ∝Fα), is a crucial diagnostic of its distance distribution, and hence the progenitor evolutionary history. We critically reanalyse current estimates of the FRB source count distribution. We demonstrate that the Lorimer burst (FRB 010724) is subject to discovery bias, and should be excluded from all statistical studies of the population. We re-examine the evidence for flat, α > -1, source count estimates based on the ratio of single-beam to multiple-beam detections with the Parkes multibeam receiver, and show that current data imply only a very weak constraint of α ≲ -1.3. A maximum-likelihood analysis applied to the portion of the Parkes FRB population detected above the observational completeness fluence of 2 Jy ms yields α = -2.6_{-1.3}^{+0.7 }. Uncertainties in the location of each FRB within the Parkes beam render estimates of the Parkes event rate uncertain in both normalizing survey area and the estimated post-beam-corrected completeness fluence; this uncertainty needs to be accounted for when comparing the event rate against event rates measured at other telescopes.

A Bayesian nonparametric method for prediction in EST analysis

PubMed Central

Lijoi, Antonio; Mena, Ramsés H; Prünster, Igor

2007-01-01

Background Expressed sequence tags (ESTs) analyses are a fundamental tool for gene identification in organisms. Given a preliminary EST sample from a certain library, several statistical prediction problems arise. In particular, it is of interest to estimate how many new genes can be detected in a future EST sample of given size and also to determine the gene discovery rate: these estimates represent the basis for deciding whether to proceed sequencing the library and, in case of a positive decision, a guideline for selecting the size of the new sample. Such information is also useful for establishing sequencing efficiency in experimental design and for measuring the degree of redundancy of an EST library. Results In this work we propose a Bayesian nonparametric approach for tackling statistical problems related to EST surveys. In particular, we provide estimates for: a) the coverage, defined as the proportion of unique genes in the library represented in the given sample of reads; b) the number of new unique genes to be observed in a future sample; c) the discovery rate of new genes as a function of the future sample size. The Bayesian nonparametric model we adopt conveys, in a statistically rigorous way, the available information into prediction. Our proposal has appealing properties over frequentist nonparametric methods, which become unstable when prediction is required for large future samples. EST libraries, previously studied with frequentist methods, are analyzed in detail. Conclusion The Bayesian nonparametric approach we undertake yields valuable tools for gene capture and prediction in EST libraries. The estimators we obtain do not feature the kind of drawbacks associated with frequentist estimators and are reliable for any size of the additional sample. PMID:17868445

An increased estimate of the merger rate of double neutron stars from observations of a highly relativistic system.

PubMed

Burgay, M; D'Amico, N; Possenti, A; Manchester, R N; Lyne, A G; Joshi, B C; McLaughlin, M A; Kramer, M; Sarkissian, J M; Camilo, F; Kalogera, V; Kim, C; Lorimer, D R

2003-12-04

The merger of close binary systems containing two neutron stars should produce a burst of gravitational waves, as predicted by the theory of general relativity. A reliable estimate of the double-neutron-star merger rate in the Galaxy is crucial in order to predict whether current gravity wave detectors will be successful in detecting such bursts. Present estimates of this rate are rather low, because we know of only a few double-neutron-star binaries with merger times less than the age of the Universe. Here we report the discovery of a 22-ms pulsar, PSR J0737-3039, which is a member of a highly relativistic double-neutron-star binary with an orbital period of 2.4 hours. This system will merge in about 85 Myr, a time much shorter than for any other known neutron-star binary. Together with the relatively low radio luminosity of PSR J0737-3039, this timescale implies an order-of-magnitude increase in the predicted merger rate for double-neutron-star systems in our Galaxy (and in the rest of the Universe).

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

Quantitative trait Loci analysis using the false discovery rate.

PubMed

Benjamini, Yoav; Yekutieli, Daniel

2005-10-01

False discovery rate control has become an essential tool in any study that has a very large multiplicity problem. False discovery rate-controlling procedures have also been found to be very effective in QTL analysis, ensuring reproducible results with few falsely discovered linkages and offering increased power to discover QTL, although their acceptance has been slower than in microarray analysis, for example. The reason is partly because the methodological aspects of applying the false discovery rate to QTL mapping are not well developed. Our aim in this work is to lay a solid foundation for the use of the false discovery rate in QTL mapping. We review the false discovery rate criterion, the appropriate interpretation of the FDR, and alternative formulations of the FDR that appeared in the statistical and genetics literature. We discuss important features of the FDR approach, some stemming from new developments in FDR theory and methodology, which deem it especially useful in linkage analysis. We review false discovery rate-controlling procedures--the BH, the resampling procedure, and the adaptive two-stage procedure-and discuss the validity of these procedures in single- and multiple-trait QTL mapping. Finally we argue that the control of the false discovery rate has an important role in suggesting, indicating the significance of, and confirming QTL and present guidelines for its use.

Modelling Infectious Hematopoietic Necrosis Virus Dispersion from Marine Salmon Farms in the Discovery Islands, British Columbia, Canada.

PubMed

Foreman, Michael G G; Guo, Ming; Garver, Kyle A; Stucchi, Dario; Chandler, Peter; Wan, Di; Morrison, John; Tuele, Darren

2015-01-01

Finite volume ocean circulation and particle tracking models are used to simulate water-borne transmission of infectious hematopoietic necrosis virus (IHNV) among Atlantic salmon (Salmo salar) farms in the Discovery Islands region of British Columbia, Canada. Historical simulations for April and July 2010 are carried out to demonstrate the seasonal impact of river discharge, wind, ultra-violet (UV) radiation, and heat flux conditions on near-surface currents, viral dispersion and survival. Numerical particles released from infected farm fish in accordance with IHNV shedding rates estimated through laboratory experiments are dispersed by model oceanic flows. Viral particles are inactivated by ambient UV radiation levels and by the natural microbial community at rates derived through laboratory studies. Viral concentration maps showing temporal and spatial changes are produced and combined with lab-determined minimum infectious dosages to estimate the infective connectivity among farms. Results demonstrate that neighbouring naïve farms can become exposed to IHNV via water-borne transport from an IHNV diseased farm, with a higher risk in April than July, and that many events in the sequence of farm outbreaks in 2001-2002 are consistent with higher risks in our farm connectivity matrix. Applications to other diseases, transfers between farmed and wild fish, and the effect of vaccinations are also discussed.

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.

Modelling Infectious Hematopoietic Necrosis Virus Dispersion from Marine Salmon Farms in the Discovery Islands, British Columbia, Canada

PubMed Central

Foreman, Michael G. G.; Guo, Ming; Garver, Kyle A.; Stucchi, Dario; Chandler, Peter; Wan, Di; Morrison, John; Tuele, Darren

2015-01-01

Finite volume ocean circulation and particle tracking models are used to simulate water-borne transmission of infectious hematopoietic necrosis virus (IHNV) among Atlantic salmon (Salmo salar) farms in the Discovery Islands region of British Columbia, Canada. Historical simulations for April and July 2010 are carried out to demonstrate the seasonal impact of river discharge, wind, ultra-violet (UV) radiation, and heat flux conditions on near-surface currents, viral dispersion and survival. Numerical particles released from infected farm fish in accordance with IHNV shedding rates estimated through laboratory experiments are dispersed by model oceanic flows. Viral particles are inactivated by ambient UV radiation levels and by the natural microbial community at rates derived through laboratory studies. Viral concentration maps showing temporal and spatial changes are produced and combined with lab-determined minimum infectious dosages to estimate the infective connectivity among farms. Results demonstrate that neighbouring naïve farms can become exposed to IHNV via water-borne transport from an IHNV diseased farm, with a higher risk in April than July, and that many events in the sequence of farm outbreaks in 2001-2002 are consistent with higher risks in our farm connectivity matrix. Applications to other diseases, transfers between farmed and wild fish, and the effect of vaccinations are also discussed. PMID:26114643

False discovery rates in spectral identification.

PubMed

Jeong, Kyowon; Kim, Sangtae; Bandeira, Nuno

2012-01-01

Automated database search engines are one of the fundamental engines of high-throughput proteomics enabling daily identifications of hundreds of thousands of peptides and proteins from tandem mass (MS/MS) spectrometry data. Nevertheless, this automation also makes it humanly impossible to manually validate the vast lists of resulting identifications from such high-throughput searches. This challenge is usually addressed by using a Target-Decoy Approach (TDA) to impose an empirical False Discovery Rate (FDR) at a pre-determined threshold x% with the expectation that at most x% of the returned identifications would be false positives. But despite the fundamental importance of FDR estimates in ensuring the utility of large lists of identifications, there is surprisingly little consensus on exactly how TDA should be applied to minimize the chances of biased FDR estimates. In fact, since less rigorous TDA/FDR estimates tend to result in more identifications (at higher 'true' FDR), there is often little incentive to enforce strict TDA/FDR procedures in studies where the major metric of success is the size of the list of identifications and there are no follow up studies imposing hard cost constraints on the number of reported false positives. Here we address the problem of the accuracy of TDA estimates of empirical FDR. Using MS/MS spectra from samples where we were able to define a factual FDR estimator of 'true' FDR we evaluate several popular variants of the TDA procedure in a variety of database search contexts. We show that the fraction of false identifications can sometimes be over 10× higher than reported and may be unavoidably high for certain types of searches. In addition, we further report that the two-pass search strategy seems the most promising database search strategy. While unavoidably constrained by the particulars of any specific evaluation dataset, our observations support a series of recommendations towards maximizing the number of resulting identifications while controlling database searches with robust and reproducible TDA estimation of empirical FDR.

Rediscovery of Good-Turing estimators via Bayesian nonparametrics.

PubMed

Favaro, Stefano; Nipoti, Bernardo; Teh, Yee Whye

2016-03-01

The problem of estimating discovery probabilities originated in the context of statistical ecology, and in recent years it has become popular due to its frequent appearance in challenging applications arising in genetics, bioinformatics, linguistics, designs of experiments, machine learning, etc. A full range of statistical approaches, parametric and nonparametric as well as frequentist and Bayesian, has been proposed for estimating discovery probabilities. In this article, we investigate the relationships between the celebrated Good-Turing approach, which is a frequentist nonparametric approach developed in the 1940s, and a Bayesian nonparametric approach recently introduced in the literature. Specifically, under the assumption of a two parameter Poisson-Dirichlet prior, we show that Bayesian nonparametric estimators of discovery probabilities are asymptotically equivalent, for a large sample size, to suitably smoothed Good-Turing estimators. As a by-product of this result, we introduce and investigate a methodology for deriving exact and asymptotic credible intervals to be associated with the Bayesian nonparametric estimators of discovery probabilities. The proposed methodology is illustrated through a comprehensive simulation study and the analysis of Expressed Sequence Tags data generated by sequencing a benchmark complementary DNA library. © 2015, The International Biometric Society.

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 R.; Deming, Drake; Albert, Loic; Bouma, L. G.; Bean, Jacob; Lopez-Morales, Mercedes

2018-04-01

The Transiting Exoplanet Survey Satellite (TESS) will embark in 2018 on a 2 year wide-field survey mission, discovering over a thousand terrestrial, super-Earth and sub-Neptune-sized exoplanets ({R}pl}≤slant 4 {R}\\oplus ) potentially suitable for follow-up observations using the James Webb Space Telescope (JWST). This work aims to understand the suitability of anticipated TESS planet discoveries for atmospheric characterization by JWST’s Near InfraRed Imager and Slitless Spectrograph (NIRISS) by employing a simulation tool to estimate the signal-to-noise (S/N) achievable in transmission spectroscopy. We applied this tool to Monte Carlo predictions of the TESS expected planet yield and 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 several hundred anticipated TESS discoveries with radii 1.5 {R}\\oplus < {R}pl}≤slant 2.5 {R}\\oplus will produce S/N higher than currently known exoplanets in this radius regime, such as K2-3b or K2-3c. In the terrestrial planet regime, we find that only a few anticipated TESS discoveries will result in higher S/N than currently known exoplanets, such as the TRAPPIST-1 planets, GJ1132b, and LHS1140b. However, we emphasize that this outcome is based upon Kepler-derived occurrence rates, and that co-planar compact multi-planet systems (e.g., TRAPPIST-1) may be under-represented in the predicted TESS planet yield. Finally, we apply our calculations to estimate the required magnitude of a JWST follow-up program devoted to mapping the transition region between hydrogen-dominated and high molecular weight atmospheres. We find that a modest observing program of between 60 and 100 hr of charged JWST time can define the nature of that transition (e.g., step function versus a power law).

The Large Synoptic Survey Telescope as a Near-Earth Object discovery machine

NASA Astrophysics Data System (ADS)

Jones, R. Lynne; Slater, Colin T.; Moeyens, Joachim; Allen, Lori; Axelrod, Tim; Cook, Kem; Ivezić, Željko; Jurić, Mario; Myers, Jonathan; Petry, Catherine E.

2018-03-01

Using the most recent prototypes, design, and as-built system information, we test and quantify the capability of the Large Synoptic Survey Telescope (LSST) to discover Potentially Hazardous Asteroids (PHAs) and Near-Earth Objects (NEOs). We empirically estimate an expected upper limit to the false detection rate in LSST image differencing, using measurements on DECam data and prototype LSST software and find it to be about 450 deg-2. We show that this rate is already tractable with current prototype of the LSST Moving Object Processing System (MOPS) by processing a 30-day simulation consistent with measured false detection rates. We proceed to evaluate the performance of the LSST baseline survey strategy for PHAs and NEOs using a high-fidelity simulated survey pointing history. We find that LSST alone, using its baseline survey strategy, will detect 66% of the PHA and 61% of the NEO population objects brighter than H = 22 , with the uncertainty in the estimate of ± 5 percentage points. By generating and examining variations on the baseline survey strategy, we show it is possible to further improve the discovery yields. In particular, we find that extending the LSST survey by two additional years and doubling the MOPS search window increases the completeness for PHAs to 86% (including those discovered by contemporaneous surveys) without jeopardizing other LSST science goals (77% for NEOs). This equates to reducing the undiscovered population of PHAs by additional 26% (15% for NEOs), relative to the baseline survey.

Econometrics of exhaustible resource supply: a theory and an application. Final report

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

Epple, D.; Hansen, L.P.

1981-12-01

An econometric model of US oil and natural gas discoveries is developed in this study. The econometric model is explicitly derived as the solution to the problem of maximizing the expected discounted after tax present value of revenues net of exploration, development, and production costs. The model contains equations representing producers' formation of price expectations and separate equations giving producers' optimal exploration decisions contingent on expected prices. A procedure is developed for imposing resource base constraints (e.g., ultimate recovery estimates based on geological analysis) when estimating the econometric model. The model is estimated using aggregate post-war data for the Unitedmore » States. Production from a given addition to proved reserves is assumed to follow a negative exponential path, and additions of proved reserves from a given discovery are assumed to follow a negative exponential path. Annual discoveries of oil and natural gas are estimated as latent variables. These latent variables are the endogenous variables in the econometric model of oil and natural gas discoveries. The model is estimated without resource base constraints. The model is also estimated imposing the mean oil and natural gas ultimate recovery estimates of the US Geological Survey. Simulations through the year 2020 are reported for various future price regimes.« less

Use of the false discovery rate for evaluating clinical safety data.

PubMed

Mehrotra, Devan V; Heyse, Joseph F

2004-06-01

Clinical adverse experience (AE) data are routinely evaluated using between group P values for every AE encountered within each of several body systems. If the P values are reported and interpreted without multiplicity considerations, there is a potential for an excess of false positive findings. Procedures based on confidence interval estimates of treatment effects have the same potential for false positive findings as P value methods. Excess false positive findings can needlessly complicate the safety profile of a safe drug or vaccine. Accordingly, we propose a novel method for addressing multiplicity in the evaluation of adverse experience data arising in clinical trial settings. The method involves a two-step application of adjusted P values based on the Benjamini and Hochberg false discovery rate (FDR). Data from three moderate to large vaccine trials are used to illustrate our proposed 'Double FDR' approach, and to reinforce the potential impact of failing to account for multiplicity. This work was in collaboration with the late Professor John W. Tukey who coined the term 'Double FDR'.

Predictors of timing of pregnancy discovery.

PubMed

McCarthy, Molly; Upadhyay, Ushma; Biggs, M Antonia; Anthony, Renaisa; Holl, Jennifer; Roberts, Sarah Cm

2018-04-01

Earlier pregnancy discovery is important in the context of prenatal and abortion care. We evaluated characteristics associated with later pregnancy discovery among women seeking abortion care. Data come from a survey of women seeking abortion care at four family planning facilities in Utah. The participants completed a survey during the state-mandated abortion information visit they are required to complete prior to having an abortion. The outcome in this study was pregnancy discovery before versus after 6 weeks since respondents' last menstrual period (LMP). We used logistic regression to estimate the relationship between sociodemographic and health-related independent variables of interest and pregnancy discovery before versus after 6 weeks. Among the 458 women in the sample, 28% discovered their pregnancy later than 6 weeks since LMP. Most (n=366, 80%) knew the exact date of their LMP and a significant minority estimated it (n=92, 20%). Those who estimated the date of their LMP had higher odds of later pregnancy discovery than those who knew the exact date (adjusted odds ratio (aOR)=1.81[1.07-3.07]). Those who used illicit drugs weekly, daily, or almost daily had higher odds of later pregnancy discovery (aOR=6.33[2.44, 16.40]). Women who did not track their menstrual periods and those who frequently used drugs had higher odds of discovering their pregnancies later. Women who estimated the date of their LMP and who frequently used drugs may benefit from strategies to help them recognize their pregnancies earlier and link them to care when they discover their pregnancies later. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

Variability in nest survival rates and implications to nesting studies

USGS Publications Warehouse

Klett, A.T.; Johnson, D.H.

1982-01-01

We used four reasonably large samples (83-213) of Mallard (Anas platyrhynchos) and Blue-winged Teal (A. discors) nests on an interstate highway right-of-way in southcentral North Dakota to evaluate potential biases in hatch-rate estimates. Twelve consecutive, weekly searches for nests were conducted with a cable-chain drag in 1976 and 1977. Nests were revisited at weekly intervals. Four methods were used to estimate hatch rates for the four data sets: the Traditional Method, the Mayfield Method, and two modifications of the Mayfield Method that are sometimes appropriate when daily mortality rates of nests are not constant. Hatch rates and the average age of nests at discovery declined as the interval between searches decreased, suggesting that mortality rates were not constant in our samples. An analysis of variance indicated that daily mortality rates varied with the age of nests in all four samples. Mortality was generally highest during the early laying period, moderately high during the late laying period, and lowest during incubation. We speculate that this relationship of mortality to nest age might be due to the presence of hens at nests or to differences in the vulnerability of nest sites to predation. A modification of the Mayfield Method that accounts for age-related variation in nest mortality was most appropriate for our samples. We suggest methods for conducting nesting studies and estimating nest success for species possessing similar nesting habits.

The promise of disease gene discovery in South Asia

PubMed Central

Nakatsuka, Nathan; Moorjani, Priya; Rai, Niraj; Sarkar, Biswanath; Tandon, Arti; Patterson, Nick; Bhavani, Gandham SriLakshmi; Girisha, Katta Mohan; Mustak, Mohammed S; Srinivasan, Sudha; Kaushik, Amit; Vahab, Saadi Abdul; Jagadeesh, Sujatha M.; Satyamoorthy, Kapaettu; Singh, Lalji; Reich, David; Thangaraj, Kumarasamy

2017-01-01

The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population, but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identify 81 unique groups, of which 14 have estimated census sizes of more than a million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identify multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an under-appreciated opportunity for reducing disease burden among South Asians through the discovery of and testing for recessive disease genes. PMID:28714977

Integration and Analysis of Neighbor Discovery and Link Quality Estimation in Wireless Sensor Networks

PubMed Central

Radi, Marjan; Dezfouli, Behnam; Abu Bakar, Kamalrulnizam; Abd Razak, Shukor

2014-01-01

Network connectivity and link quality information are the fundamental requirements of wireless sensor network protocols to perform their desired functionality. Most of the existing discovery protocols have only focused on the neighbor discovery problem, while a few number of them provide an integrated neighbor search and link estimation. As these protocols require a careful parameter adjustment before network deployment, they cannot provide scalable and accurate network initialization in large-scale dense wireless sensor networks with random topology. Furthermore, performance of these protocols has not entirely been evaluated yet. In this paper, we perform a comprehensive simulation study on the efficiency of employing adaptive protocols compared to the existing nonadaptive protocols for initializing sensor networks with random topology. In this regard, we propose adaptive network initialization protocols which integrate the initial neighbor discovery with link quality estimation process to initialize large-scale dense wireless sensor networks without requiring any parameter adjustment before network deployment. To the best of our knowledge, this work is the first attempt to provide a detailed simulation study on the performance of integrated neighbor discovery and link quality estimation protocols for initializing sensor networks. This study can help system designers to determine the most appropriate approach for different applications. PMID:24678277

Discovery of a Detached, Eclipsing 40 Minute Period Double White Dwarf Binary and a Friend: Implications for He+CO White Dwarf Mergers

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

Brown, Warren R.; Kilic, Mukremin; Kosakowski, Alekzander

We report the discovery of two detached double white dwarf (WD) binaries, SDSS J082239.546+304857.19 and SDSS J104336.275+055149.90, with orbital periods of 40 and 46 minutes, respectively. The 40 minute system is eclipsing; it is composed of a 0.30 M {sub ⊙} and a 0.52 M {sub ⊙} WD. The 46 minute system is a likely LISA verification binary. The short 20 ± 2 Myr and ∼34 Myr gravitational-wave merger times of the two binaries imply that many more such systems have formed and merged over the age of the Milky Way. We update the estimated Milky Way He+CO WD binarymore » merger rate and affirm our previously published result: He+CO WD binaries merge at a rate at least 40 times greater than the formation rate of stable mass-transfer AM CVn binaries, and so the majority must have unstable mass-transfer. The implication is that spin–orbit coupling in He+CO WD mergers is weak, or perhaps nova-like outbursts drive He+CO WDs into merger, as proposed by Shen.« less

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

Small Near-Earth Asteroids in the Palomar Transient Factory Survey: A Real-Time Streak-detection System

NASA Astrophysics Data System (ADS)

Waszczak, Adam; Prince, Thomas A.; Laher, Russ; Masci, Frank; Bue, Brian; Rebbapragada, Umaa; Barlow, Tom; Surace, Jason; Helou, George; Kulkarni, Shrinivas

2017-03-01

Near-Earth asteroids (NEAs) in the 1-100 meter size range are estimated to be ˜1,000 times more numerous than the ˜15,000 currently cataloged NEAs, most of which are in the 0.5-10 kilometer size range. Impacts from 10-100 meter size NEAs are not statistically life-threatening, but may cause significant regional damage, while 1-10 meter size NEAs with low velocities relative to Earth are compelling targets for space missions. We describe the implementation and initial results of a real-time NEA-discovery system specialized for the detection of small, high angular rate (visually streaked) NEAs in Palomar Transient Factory (PTF) images. PTF is a 1.2-m aperture, 7.3 deg2 field of view (FOV) optical survey designed primarily for the discovery of extragalactic transients (e.g., supernovae) in 60-second exposures reaching ˜20.5 visual magnitude. Our real-time NEA discovery pipeline uses a machine-learned classifier to filter a large number of false-positive streak detections, permitting a human scanner to efficiently and remotely identify real asteroid streaks during the night. Upon recognition of a streaked NEA detection (typically within an hour of the discovery exposure), the scanner triggers follow-up with the same telescope and posts the observations to the Minor Planet Center for worldwide confirmation. We describe our 11 initial confirmed discoveries, all small NEAs that passed 0.3-15 lunar distances from Earth. Lastly, we derive useful scaling laws for comparing streaked-NEA-detection capabilities of different surveys as a function of their hardware and survey-pattern characteristics. This work most directly informs estimates of the streak-detection capabilities of the Zwicky Transient Facility (ZTF, planned to succeed PTF in 2017), which will apply PTF’s current resolution and sensitivity over a 47-deg2 FOV.

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.

Quantifying enzymatic lysis: estimating the combined effects of chemistry, physiology and physics.

PubMed

Mitchell, Gabriel J; Nelson, Daniel C; Weitz, Joshua S

2010-10-04

The number of microbial pathogens resistant to antibiotics continues to increase even as the rate of discovery and approval of new antibiotic therapeutics steadily decreases. Many researchers have begun to investigate the therapeutic potential of naturally occurring lytic enzymes as an alternative to traditional antibiotics. However, direct characterization of lytic enzymes using techniques based on synthetic substrates is often difficult because lytic enzymes bind to the complex superstructure of intact cell walls. Here we present a new standard for the analysis of lytic enzymes based on turbidity assays which allow us to probe the dynamics of lysis without preparing a synthetic substrate. The challenge in the analysis of these assays is to infer the microscopic details of lysis from macroscopic turbidity data. We propose a model of enzymatic lysis that integrates the chemistry responsible for bond cleavage with the physical mechanisms leading to cell wall failure. We then present a solution to an inverse problem in which we estimate reaction rate constants and the heterogeneous susceptibility to lysis among target cells. We validate our model given simulated and experimental turbidity assays. The ability to estimate reaction rate constants for lytic enzymes will facilitate their biochemical characterization and development as antimicrobial therapeutics.

How often should we expect to be wrong? Statistical power, P values, and the expected prevalence of false discoveries.

PubMed

Marino, Michael J

2018-05-01

There is a clear perception in the literature that there is a crisis in reproducibility in the biomedical sciences. Many underlying factors contributing to the prevalence of irreproducible results have been highlighted with a focus on poor design and execution of experiments along with the misuse of statistics. While these factors certainly contribute to irreproducibility, relatively little attention outside of the specialized statistical literature has focused on the expected prevalence of false discoveries under idealized circumstances. In other words, when everything is done correctly, how often should we expect to be wrong? Using a simple simulation of an idealized experiment, it is possible to show the central role of sample size and the related quantity of statistical power in determining the false discovery rate, and in accurate estimation of effect size. According to our calculations, based on current practice many subfields of biomedical science may expect their discoveries to be false at least 25% of the time, and the only viable course to correct this is to require the reporting of statistical power and a minimum of 80% power (1 - β = 0.80) for all studies. Copyright © 2017 Elsevier Inc. All rights reserved.

iProphet: Multi-level Integrative Analysis of Shotgun Proteomic Data Improves Peptide and Protein Identification Rates and Error Estimates*

PubMed Central

Shteynberg, David; Deutsch, Eric W.; Lam, Henry; Eng, Jimmy K.; Sun, Zhi; Tasman, Natalie; Mendoza, Luis; Moritz, Robert L.; Aebersold, Ruedi; Nesvizhskii, Alexey I.

2011-01-01

The combination of tandem mass spectrometry and sequence database searching is the method of choice for the identification of peptides and the mapping of proteomes. Over the last several years, the volume of data generated in proteomic studies has increased dramatically, which challenges the computational approaches previously developed for these data. Furthermore, a multitude of search engines have been developed that identify different, overlapping subsets of the sample peptides from a particular set of tandem mass spectrometry spectra. We present iProphet, the new addition to the widely used open-source suite of proteomic data analysis tools Trans-Proteomics Pipeline. Applied in tandem with PeptideProphet, it provides more accurate representation of the multilevel nature of shotgun proteomic data. iProphet combines the evidence from multiple identifications of the same peptide sequences across different spectra, experiments, precursor ion charge states, and modified states. It also allows accurate and effective integration of the results from multiple database search engines applied to the same data. The use of iProphet in the Trans-Proteomics Pipeline increases the number of correctly identified peptides at a constant false discovery rate as compared with both PeptideProphet and another state-of-the-art tool Percolator. As the main outcome, iProphet permits the calculation of accurate posterior probabilities and false discovery rate estimates at the level of sequence identical peptide identifications, which in turn leads to more accurate probability estimates at the protein level. Fully integrated with the Trans-Proteomics Pipeline, it supports all commonly used MS instruments, search engines, and computer platforms. The performance of iProphet is demonstrated on two publicly available data sets: data from a human whole cell lysate proteome profiling experiment representative of typical proteomic data sets, and from a set of Streptococcus pyogenes experiments more representative of organism-specific composite data sets. PMID:21876204

Identification of differentially expressed genes and false discovery rate in microarray studies.

PubMed

Gusnanto, Arief; Calza, Stefano; Pawitan, Yudi

2007-04-01

To highlight the development in microarray data analysis for the identification of differentially expressed genes, particularly via control of false discovery rate. The emergence of high-throughput technology such as microarrays raises two fundamental statistical issues: multiplicity and sensitivity. We focus on the biological problem of identifying differentially expressed genes. First, multiplicity arises due to testing tens of thousands of hypotheses, rendering the standard P value meaningless. Second, known optimal single-test procedures such as the t-test perform poorly in the context of highly multiple tests. The standard approach of dealing with multiplicity is too conservative in the microarray context. The false discovery rate concept is fast becoming the key statistical assessment tool replacing the P value. We review the false discovery rate approach and argue that it is more sensible for microarray data. We also discuss some methods to take into account additional information from the microarrays to improve the false discovery rate. There is growing consensus on how to analyse microarray data using the false discovery rate framework in place of the classical P value. Further research is needed on the preprocessing of the raw data, such as the normalization step and filtering, and on finding the most sensitive test procedure.

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.

A new estimator of the discovery probability.

PubMed

Favaro, Stefano; Lijoi, Antonio; Prünster, Igor

2012-12-01

Species sampling problems have a long history in ecological and biological studies and a number of issues, including the evaluation of species richness, the design of sampling experiments, and the estimation of rare species variety, are to be addressed. Such inferential problems have recently emerged also in genomic applications, however, exhibiting some peculiar features that make them more challenging: specifically, one has to deal with very large populations (genomic libraries) containing a huge number of distinct species (genes) and only a small portion of the library has been sampled (sequenced). These aspects motivate the Bayesian nonparametric approach we undertake, since it allows to achieve the degree of flexibility typically needed in this framework. Based on an observed sample of size n, focus will be on prediction of a key aspect of the outcome from an additional sample of size m, namely, the so-called discovery probability. In particular, conditionally on an observed basic sample of size n, we derive a novel estimator of the probability of detecting, at the (n+m+1)th observation, species that have been observed with any given frequency in the enlarged sample of size n+m. Such an estimator admits a closed-form expression that can be exactly evaluated. The result we obtain allows us to quantify both the rate at which rare species are detected and the achieved sample coverage of abundant species, as m increases. Natural applications are represented by the estimation of the probability of discovering rare genes within genomic libraries and the results are illustrated by means of two expressed sequence tags datasets. © 2012, The International Biometric Society.

The Rate of Binary Black Hole Mergers Inferred from Advanced LIGO Observations Surrounding GW150914

NASA Astrophysics Data System (ADS)

Abbott, B. P.; Abbott, R.; Abbott, T. D.; Abernathy, M. R.; Acernese, F.; Ackley, K.; Adams, C.; Adams, T.; Addesso, P.; Adhikari, R. X.; Adya, V. B.; Affeldt, C.; Agathos, M.; Agatsuma, K.; Aggarwal, N.; Aguiar, O. D.; Aiello, L.; Ain, A.; Ajith, P.; Allen, B.; Allocca, A.; Altin, P. A.; Anderson, S. B.; Anderson, W. G.; Arai, K.; Araya, M. C.; Arceneaux, C. C.; Areeda, J. S.; Arnaud, N.; Arun, K. G.; Ascenzi, S.; Ashton, G.; Ast, M.; Aston, S. M.; Astone, P.; Aufmuth, P.; Aulbert, C.; Babak, S.; Bacon, P.; Bader, M. K. M.; Baker, P. T.; Baldaccini, F.; Ballardin, G.; Ballmer, S. W.; Barayoga, J. C.; Barclay, S. E.; Barish, B. C.; Barker, D.; Barone, F.; Barr, B.; Barsotti, L.; Barsuglia, M.; Barta, D.; Bartlett, J.; Bartos, I.; Bassiri, R.; Basti, A.; Batch, J. C.; Baune, C.; Bavigadda, V.; Bazzan, M.; Behnke, B.; Bejger, M.; Bell, A. S.; Bell, C. J.; Berger, B. K.; Bergman, J.; Bergmann, G.; Berry, C. P. L.; Bersanetti, D.; Bertolini, A.; Betzwieser, J.; Bhagwat, S.; Bhandare, R.; Bilenko, I. A.; Billingsley, G.; Birch, J.; Birney, R.; Biscans, S.; Bisht, A.; Bitossi, M.; Biwer, C.; Bizouard, M. A.; Blackburn, J. K.; Blair, C. D.; Blair, D. G.; Blair, R. M.; Bloemen, S.; Bock, O.; Bodiya, T. P.; Boer, M.; Bogaert, G.; Bogan, C.; Bohe, A.; Bojtos, P.; Bond, C.; Bondu, F.; Bonnand, R.; Boom, B. A.; Bork, R.; Boschi, V.; Bose, S.; Bouffanais, Y.; Bozzi, A.; Bradaschia, C.; Brady, P. R.; Braginsky, V. B.; Branchesi, M.; Brau, J. E.; Briant, T.; Brillet, A.; Brinkmann, M.; Brisson, V.; Brockill, P.; Brooks, A. F.; Brown, D. A.; Brown, D. D.; Brown, N. M.; Buchanan, C. C.; Buikema, A.; Bulik, T.; Bulten, H. J.; Buonanno, A.; Buskulic, D.; Buy, C.; Byer, R. L.; Cadonati, L.; Cagnoli, G.; Cahillane, C.; Calderón Bustillo, J.; Callister, T.; Calloni, E.; Camp, J. B.; Cannon, K. C.; Cao, J.; Capano, C. D.; Capocasa, E.; Carbognani, F.; Caride, S.; Casanueva Diaz, J.; Casentini, C.; Caudill, S.; Cavaglià, M.; Cavalier, F.; Cavalieri, R.; Cella, G.; Cepeda, C. B.; Cerboni Baiardi, L.; Cerretani, G.; Cesarini, E.; Chakraborty, R.; Chalermsongsak, T.; Chamberlin, S. J.; Chan, M.; Chao, S.; Charlton, P.; Chassande-Mottin, E.; Chen, H. Y.; Chen, Y.; Cheng, C.; Chincarini, A.; Chiummo, A.; Cho, H. S.; Cho, M.; Chow, J. H.; Christensen, N.; Chu, Q.; Chua, S.; Chung, S.; Ciani, G.; Clara, F.; Clark, J. A.; Cleva, F.; Coccia, E.; Cohadon, P.-F.; Colla, A.; Collette, C. G.; Cominsky, L.; Constancio, M., Jr.; Conte, A.; Conti, L.; Cook, D.; Corbitt, T. R.; Cornish, N.; Corsi, A.; Cortese, S.; Costa, C. A.; Coughlin, M. W.; Coughlin, S. B.; Coulon, J.-P.; Countryman, S. T.; Couvares, P.; Cowan, E. E.; Coward, D. M.; Cowart, M. J.; Coyne, D. C.; Coyne, R.; Craig, K.; Creighton, J. D. E.; Cripe, J.; Crowder, S. G.; Cumming, A.; Cunningham, L.; Cuoco, E.; Dal Canton, T.; Danilishin, S. L.; D'Antonio, S.; Danzmann, K.; Darman, N. S.; Dattilo, V.; Dave, I.; Daveloza, H. P.; Davier, M.; Davies, G. S.; Daw, E. J.; Day, R.; De, S.; DeBra, D.; Debreczeni, G.; Degallaix, J.; De Laurentis, M.; Deléglise, S.; Del Pozzo, W.; Denker, T.; Dent, T.; Dereli, H.; Dergachev, V.; De Rosa, R.; DeRosa, R. T.; DeSalvo, R.; Dhurandhar, S.; Díaz, M. C.; Di Fiore, L.; Di Giovanni, M.; Di Lieto, A.; Di Pace, S.; Di Palma, I.; Di Virgilio, A.; Dojcinoski, G.; Dolique, V.; Donovan, F.; Dooley, K. L.; Doravari, S.; Douglas, R.; Downes, T. P.; Drago, M.; Drever, R. W. P.; Driggers, J. C.; Du, Z.; Ducrot, M.; Dwyer, S. E.; Edo, T. B.; Edwards, M. C.; Effler, A.; Eggenstein, H.-B.; Ehrens, P.; Eichholz, J.; Eikenberry, S. S.; Engels, W.; Essick, R. C.; Etzel, T.; Evans, M.; Evans, T. M.; Everett, R.; Factourovich, M.; Fafone, V.; Fair, H.; Fairhurst, S.; Fan, X.; Fang, Q.; Farinon, S.; Farr, B.; Farr, W. M.; Favata, M.; Fays, M.; Fehrmann, H.; Fejer, M. M.; Ferrante, I.; Ferreira, E. C.; Ferrini, F.; Fidecaro, F.; Fiori, I.; Fiorucci, D.; Fisher, R. P.; Flaminio, R.; Fletcher, M.; Fong, H.; Fournier, J.-D.; Franco, S.; Frasca, S.; Frasconi, F.; Frei, Z.; Freise, A.; Frey, R.; Frey, V.; Fricke, T. T.; Fritschel, P.; Frolov, V. V.; Fulda, P.; Fyffe, M.; Gabbard, H. A. G.; Gair, J. R.; Gammaitoni, L.; Gaonkar, S. G.; Garufi, F.; Gatto, A.; Gaur, G.; Gehrels, N.; Gemme, G.; Gendre, B.; Genin, E.; Gennai, A.; George, J.; Gergely, L.; Germain, V.; Ghosh, Archisman; Ghosh, S.; Giaime, J. A.; Giardina, K. D.; Giazotto, A.; Gill, K.; Glaefke, A.; Goetz, E.; Goetz, R.; Gondan, L.; González, G.; Gonzalez Castro, J. M.; Gopakumar, A.; Gordon, N. A.; Gorodetsky, M. L.; Gossan, S. E.; Gosselin, M.; Gouaty, R.; Graef, C.; Graff, P. B.; Granata, M.; Grant, A.; Gras, S.; Gray, C.; Greco, G.; Green, A. C.; Groot, P.; Grote, H.; Grunewald, S.; Guidi, G. M.; Guo, X.; Gupta, A.; Gupta, M. K.; Gushwa, K. E.; Gustafson, E. K.; Gustafson, R.; Hacker, J. J.; Hall, B. R.; Hall, E. D.; Hammond, G.; Haney, M.; Hanke, M. M.; Hanks, J.; Hanna, C.; Hannam, M. D.; Hanson, J.; Hardwick, T.; Harms, J.; Harry, G. M.; Harry, I. W.; Hart, M. J.; Hartman, M. T.; Haster, C.-J.; Haughian, K.; Heidmann, A.; Heintze, M. C.; Heitmann, H.; Hello, P.; Hemming, G.; Hendry, M.; Heng, I. S.; Hennig, J.; Heptonstall, A. W.; Heurs, M.; Hild, S.; Hoak, D.; Hodge, K. A.; Hofman, D.; Hollitt, S. E.; Holt, K.; Holz, D. E.; Hopkins, P.; Hosken, D. J.; Hough, J.; Houston, E. A.; Howell, E. J.; Hu, Y. M.; Huang, S.; Huerta, E. A.; Huet, D.; Hughey, B.; Husa, S.; Huttner, S. H.; Huynh-Dinh, T.; Idrisy, A.; Indik, N.; Ingram, D. R.; Inta, R.; Isa, H. N.; Isac, J.-M.; Isi, M.; Islas, G.; Isogai, T.; Iyer, B. R.; Izumi, K.; Jacqmin, T.; Jang, H.; Jani, K.; Jaranowski, P.; Jawahar, S.; Jiménez-Forteza, F.; Johnson, W. W.; Jones, D. I.; Jones, R.; Jonker, R. J. G.; Ju, L.; K, Haris; Kalaghatgi, C. V.; Kalogera, V.; Kandhasamy, S.; Kang, G.; Kanner, J. B.; Karki, S.; Kasprzack, M.; Katsavounidis, E.; Katzman, W.; Kaufer, S.; Kaur, T.; Kawabe, K.; Kawazoe, F.; Kéfélian, F.; Kehl, M. S.; Keitel, D.; Kelley, D. B.; Kells, W.; Kennedy, R.; Key, J. S.; Khalaidovski, A.; Khalili, F. Y.; Khan, I.; Khan, S.; Khan, Z.; Khazanov, E. A.; Kijbunchoo, N.; Kim, C.; Kim, J.; Kim, K.; Kim, Nam-Gyu; Kim, Namjun; Kim, Y.-M.; King, E. J.; King, P. J.; Kinzel, D. L.; Kissel, J. S.; Kleybolte, L.; Klimenko, S.; Koehlenbeck, S. M.; Kokeyama, K.; Koley, S.; Kondrashov, V.; Kontos, A.; Korobko, M.; Korth, W. Z.; Kowalska, I.; Kozak, D. B.; Kringel, V.; Krishnan, B.; Królak, A.; Krueger, C.; Kuehn, G.; Kumar, P.; Kuo, L.; Kutynia, A.; Lackey, B. D.; Landry, M.; Lange, J.; Lantz, B.; Lasky, P. D.; Lazzarini, A.; Lazzaro, C.; Leaci, P.; Leavey, S.; Lebigot, E. O.; Lee, C. H.; Lee, H. K.; Lee, H. M.; Lee, K.; Lenon, A.; Leonardi, M.; Leong, J. R.; Leroy, N.; Letendre, N.; Levin, Y.; Levine, B. M.; Li, T. G. F.; Libson, A.; Littenberg, T. B.; Lockerbie, N. A.; Logue, J.; Lombardi, A. L.; Lord, J. E.; Lorenzini, M.; Loriette, V.; Lormand, M.; Losurdo, G.; Lough, J. D.; Lück, H.; Lundgren, A. P.; Luo, J.; Lynch, R.; Ma, Y.; MacDonald, T.; Machenschalk, B.; MacInnis, M.; Macleod, D. M.; Magaña-Sandoval, F.; Magee, R. M.; Mageswaran, M.; Majorana, E.; Maksimovic, I.; Malvezzi, V.; Man, N.; Mandel, I.; Mandic, V.; Mangano, V.; Mansell, G. L.; Manske, M.; Mantovani, M.; Marchesoni, F.; Marion, F.; Márka, S.; Márka, Z.; Markosyan, A. S.; Maros, E.; Martelli, F.; Martellini, L.; Martin, I. W.; Martin, R. M.; Martynov, D. V.; Marx, J. N.; Mason, K.; Masserot, A.; Massinger, T. J.; Masso-Reid, M.; Matichard, F.; Matone, L.; Mavalvala, N.; Mazumder, N.; Mazzolo, G.; McCarthy, R.; McClelland, D. E.; McCormick, S.; McGuire, S. C.; McIntyre, G.; McIver, J.; McManus, D. J.; McWilliams, S. T.; Meacher, D.; Meadors, G. D.; Meidam, J.; Melatos, A.; Mendell, G.; Mendoza-Gandara, D.; Mercer, R. A.; Merilh, E.; Merzougui, M.; Meshkov, S.; Messenger, C.; Messick, C.; Meyers, P. M.; Mezzani, F.; Miao, H.; Michel, C.; Middleton, H.; Mikhailov, E. E.; Milano, L.; Miller, J.; Millhouse, M.; Minenkov, Y.; Ming, J.; Mirshekari, S.; Mishra, C.; Mitra, S.; Mitrofanov, V. P.; Mitselmakher, G.; Mittleman, R.; Moggi, A.; Mohan, M.; Mohapatra, S. R. P.; Montani, M.; Moore, B. C.; Moore, C. J.; Moraru, D.; Moreno, G.; Morriss, S. R.; Mossavi, K.; Mours, B.; Mow-Lowry, C. M.; Mueller, C. L.; Mueller, G.; Muir, A. W.; Mukherjee, Arunava; Mukherjee, D.; Mukherjee, S.; Mukund, N.; Mullavey, A.; Munch, J.; Murphy, D. J.; Murray, P. G.; Mytidis, A.; Nardecchia, I.; Naticchioni, L.; Nayak, R. K.; Necula, V.; Nedkova, K.; Nelemans, G.; Neri, M.; Neunzert, A.; Newton, G.; Nguyen, T. T.; Nielsen, A. B.; Nissanke, S.; Nitz, A.; Nocera, F.; Nolting, D.; Normandin, M. E.; Nuttall, L. K.; Oberling, J.; Ochsner, E.; O'Dell, J.; Oelker, E.; Ogin, G. H.; Oh, J. J.; Oh, S. H.; Ohme, F.; Oliver, M.; Oppermann, P.; Oram, Richard J.; O'Reilly, B.; O'Shaughnessy, R.; Ottaway, D. J.; Ottens, R. S.; Overmier, H.; Owen, B. J.; Pai, A.; Pai, S. A.; Palamos, J. R.; Palashov, O.; Palomba, C.; Pal-Singh, A.; Pan, H.; Pankow, C.; Pannarale, F.; Pant, B. C.; Paoletti, F.; Paoli, A.; Papa, M. A.; Paris, H. R.; Parker, W.; Pascucci, D.; Pasqualetti, A.; Passaquieti, R.; Passuello, D.; Patricelli, B.; Patrick, Z.; Pearlstone, B. L.; Pedraza, M.; Pedurand, R.; Pekowsky, L.; Pele, A.; Penn, S.; Perreca, A.; Phelps, M.; Piccinni, O.; Pichot, M.; Piergiovanni, F.; Pierro, V.; Pillant, G.; Pinard, L.; Pinto, I. M.; Pitkin, M.; Poggiani, R.; Popolizio, P.; Porter, E. K.; Post, A.; Powell, J.; Prasad, J.; Predoi, V.; Premachandra, S. S.; Prestegard, T.; Price, L. R.; Prijatelj, M.; Principe, M.; Privitera, S.; Prodi, G. A.; Prokhorov, L.; Puncken, O.; Punturo, M.; Puppo, P.; Pürrer, M.; Qi, H.; Qin, J.; Quetschke, V.; Quintero, E. A.; Quitzow-James, R.; Raab, F. J.; Rabeling, D. S.; Radkins, H.; Raffai, P.; Raja, S.; Rakhmanov, M.; Rapagnani, P.; Raymond, V.; Razzano, M.; Re, V.; Read, J.; Reed, C. M.; Regimbau, T.; Rei, L.; Reid, S.; Reitze, D. H.; Rew, H.; Reyes, S. D.; Ricci, F.; Riles, K.; Robertson, N. A.; Robie, R.; Robinet, F.; Rocchi, A.; Rolland, L.; Rollins, J. G.; Roma, V. J.; Romano, R.; Romanov, G.; Romie, J. H.; Rosińska, D.; Rowan, S.; Rüdiger, A.; Ruggi, P.; Ryan, K.; Sachdev, S.; Sadecki, T.; Sadeghian, L.; Salconi, L.; Saleem, M.; Salemi, F.; Samajdar, A.; Sammut, L.; Sampson, L.; Sanchez, E. J.; Sandberg, V.; Sandeen, B.; Sanders, J. R.; Sassolas, B.; Sathyaprakash, B. S.; Saulson, P. R.; Sauter, O.; Savage, R. L.; Sawadsky, A.; Schale, P.; Schilling, R.; Schmidt, J.; Schmidt, P.; Schnabel, R.; Schofield, R. M. S.; Schönbeck, A.; Schreiber, E.; Schuette, D.; Schutz, B. F.; Scott, J.; Scott, S. M.; Sellers, D.; Sengupta, A. S.; Sentenac, D.; Sequino, V.; Sergeev, A.; Serna, G.; Setyawati, Y.; Sevigny, A.; Shaddock, D. A.; Shah, S.; Shahriar, M. S.; Shaltev, M.; Shao, Z.; Shapiro, B.; Shawhan, P.; Sheperd, A.; Shoemaker, D. H.; Shoemaker, D. M.; Siellez, K.; Siemens, X.; Sigg, D.; Silva, A. D.; Simakov, D.; Singer, A.; Singer, L. P.; Singh, A.; Singh, R.; Singhal, A.; Sintes, A. M.; Slagmolen, B. J. J.; Smith, J. R.; Smith, N. D.; Smith, R. J. E.; Son, E. J.; Sorazu, B.; Sorrentino, F.; Souradeep, T.; Srivastava, A. K.; Staley, A.; Steinke, M.; Steinlechner, J.; Steinlechner, S.; Steinmeyer, D.; Stephens, B. C.; Stevenson, S.; Stone, R.; Strain, K. A.; Straniero, N.; Stratta, G.; Strauss, N. A.; Strigin, S.; Sturani, R.; Stuver, A. L.; Summerscales, T. Z.; Sun, L.; Sutton, P. J.; Swinkels, B. L.; Szczepańczyk, M. J.; Tacca, M.; Talukder, D.; Tanner, D. B.; Tápai, M.; Tarabrin, S. P.; Taracchini, A.; Taylor, R.; Theeg, T.; Thirugnanasambandam, M. P.; Thomas, E. G.; Thomas, M.; Thomas, P.; Thorne, K. A.; Thorne, K. S.; Thrane, E.; Tiwari, S.; Tiwari, V.; Tokmakov, K. V.; Tomlinson, C.; Tonelli, M.; Torres, C. V.; Torrie, C. I.; Töyrä, D.; Travasso, F.; Traylor, G.; Trifirò, D.; Tringali, M. C.; Trozzo, L.; Tse, M.; Turconi, M.; Tuyenbayev, D.; Ugolini, D.; Unnikrishnan, C. S.; Urban, A. L.; Usman, S. A.; Vahlbruch, H.; Vajente, G.; Valdes, G.; Vallisneri, M.; van Bakel, N.; van Beuzekom, M.; van den Brand, J. F. J.; Van Den Broeck, C.; Vander-Hyde, D. C.; van der Schaaf, L.; van Heijningen, J. V.; van Veggel, A. A.; Vardaro, M.; Vass, S.; Vasúth, M.; Vaulin, R.; Vecchio, A.; Vedovato, G.; Veitch, J.; Veitch, P. J.; Venkateswara, K.; Verkindt, D.; Vetrano, F.; Viceré, A.; Vinciguerra, S.; Vine, D. J.; Vinet, J.-Y.; Vitale, S.; Vo, T.; Vocca, H.; Vorvick, C.; Voss, D.; Vousden, W. D.; Vyatchanin, S. P.; Wade, A. R.; Wade, L. E.; Wade, M.; Walker, M.; Wallace, L.; Walsh, S.; Wang, G.; Wang, H.; Wang, M.; Wang, X.; Wang, Y.; Ward, R. L.; Warner, J.; Was, M.; Weaver, B.; Wei, L.-W.; Weinert, M.; Weinstein, A. J.; Weiss, R.; Welborn, T.; Wen, L.; Weßels, P.; Westphal, T.; Wette, K.; Whelan, J. T.; White, D. J.; Whiting, B. F.; Williams, R. D.; Williamson, A. R.; Willis, J. L.; Willke, B.; Wimmer, M. H.; Winkler, W.; Wipf, C. C.; Wittel, H.; Woan, G.; Worden, J.; Wright, J. L.; Wu, G.; Yablon, J.; Yam, W.; Yamamoto, H.; Yancey, C. C.; Yap, M. J.; Yu, H.; Yvert, M.; Zadrożny, A.; Zangrando, L.; Zanolin, M.; Zendri, J.-P.; Zevin, M.; Zhang, F.; Zhang, L.; Zhang, M.; Zhang, Y.; Zhao, C.; Zhou, M.; Zhou, Z.; Zhu, X. J.; Zucker, M. E.; Zuraw, S. E.; Zweizig, J.; LIGO Scientific Collaboration; Virgo Collaboration

2016-12-01

A transient gravitational-wave signal, GW150914, was identified in the twin Advanced LIGO detectors on 2015 September 2015 at 09:50:45 UTC. To assess the implications of this discovery, the detectors remained in operation with unchanged configurations over a period of 39 days around the time of the signal. At the detection statistic threshold corresponding to that observed for GW150914, our search of the 16 days of simultaneous two-detector observational data is estimated to have a false-alarm rate (FAR) of \\lt 4.9× {10}-6 {{yr}}-1, yielding a p-value for GW150914 of \\lt 2× {10}-7. Parameter estimation follow-up on this trigger identifies its source as a binary black hole (BBH) merger with component masses ({m}1,{m}2)=({36}-4+5,{29}-4+4) {M}⊙ at redshift z={0.09}-0.04+0.03 (median and 90% credible range). Here, we report on the constraints these observations place on the rate of BBH coalescences. Considering only GW150914, assuming that all BBHs in the universe have the same masses and spins as this event, imposing a search FAR threshold of 1 per 100 years, and assuming that the BBH merger rate is constant in the comoving frame, we infer a 90% credible range of merger rates between 2{--}53 {{Gpc}}-3 {{yr}}-1 (comoving frame). Incorporating all search triggers that pass a much lower threshold while accounting for the uncertainty in the astrophysical origin of each trigger, we estimate a higher rate, ranging from 13{--}600 {{Gpc}}-3 {{yr}}-1 depending on assumptions about the BBH mass distribution. All together, our various rate estimates fall in the conservative range 2{--}600 {{Gpc}}-3 {{yr}}-1.

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.

cn.MOPS: mixture of Poissons for discovering copy number variations in next-generation sequencing data with a low false discovery rate

PubMed Central

Klambauer, Günter; Schwarzbauer, Karin; Mayr, Andreas; Clevert, Djork-Arné; Mitterecker, Andreas; Bodenhofer, Ulrich; Hochreiter, Sepp

2012-01-01

Quantitative analyses of next-generation sequencing (NGS) data, such as the detection of copy number variations (CNVs), remain challenging. Current methods detect CNVs as changes in the depth of coverage along chromosomes. Technological or genomic variations in the depth of coverage thus lead to a high false discovery rate (FDR), even upon correction for GC content. In the context of association studies between CNVs and disease, a high FDR means many false CNVs, thereby decreasing the discovery power of the study after correction for multiple testing. We propose ‘Copy Number estimation by a Mixture Of PoissonS’ (cn.MOPS), a data processing pipeline for CNV detection in NGS data. In contrast to previous approaches, cn.MOPS incorporates modeling of depths of coverage across samples at each genomic position. Therefore, cn.MOPS is not affected by read count variations along chromosomes. Using a Bayesian approach, cn.MOPS decomposes variations in the depth of coverage across samples into integer copy numbers and noise by means of its mixture components and Poisson distributions, respectively. The noise estimate allows for reducing the FDR by filtering out detections having high noise that are likely to be false detections. We compared cn.MOPS with the five most popular methods for CNV detection in NGS data using four benchmark datasets: (i) simulated data, (ii) NGS data from a male HapMap individual with implanted CNVs from the X chromosome, (iii) data from HapMap individuals with known CNVs, (iv) high coverage data from the 1000 Genomes Project. cn.MOPS outperformed its five competitors in terms of precision (1–FDR) and recall for both gains and losses in all benchmark data sets. The software cn.MOPS is publicly available as an R package at http://www.bioinf.jku.at/software/cnmops/ and at Bioconductor. PMID:22302147

cn.MOPS: mixture of Poissons for discovering copy number variations in next-generation sequencing data with a low false discovery rate.

PubMed

Klambauer, Günter; Schwarzbauer, Karin; Mayr, Andreas; Clevert, Djork-Arné; Mitterecker, Andreas; Bodenhofer, Ulrich; Hochreiter, Sepp

2012-05-01

Quantitative analyses of next-generation sequencing (NGS) data, such as the detection of copy number variations (CNVs), remain challenging. Current methods detect CNVs as changes in the depth of coverage along chromosomes. Technological or genomic variations in the depth of coverage thus lead to a high false discovery rate (FDR), even upon correction for GC content. In the context of association studies between CNVs and disease, a high FDR means many false CNVs, thereby decreasing the discovery power of the study after correction for multiple testing. We propose 'Copy Number estimation by a Mixture Of PoissonS' (cn.MOPS), a data processing pipeline for CNV detection in NGS data. In contrast to previous approaches, cn.MOPS incorporates modeling of depths of coverage across samples at each genomic position. Therefore, cn.MOPS is not affected by read count variations along chromosomes. Using a Bayesian approach, cn.MOPS decomposes variations in the depth of coverage across samples into integer copy numbers and noise by means of its mixture components and Poisson distributions, respectively. The noise estimate allows for reducing the FDR by filtering out detections having high noise that are likely to be false detections. We compared cn.MOPS with the five most popular methods for CNV detection in NGS data using four benchmark datasets: (i) simulated data, (ii) NGS data from a male HapMap individual with implanted CNVs from the X chromosome, (iii) data from HapMap individuals with known CNVs, (iv) high coverage data from the 1000 Genomes Project. cn.MOPS outperformed its five competitors in terms of precision (1-FDR) and recall for both gains and losses in all benchmark data sets. The software cn.MOPS is publicly available as an R package at http://www.bioinf.jku.at/software/cnmops/ and at Bioconductor.

Estimation of the prevalence of adverse drug reactions from social media.

PubMed

Nguyen, Thin; Larsen, Mark E; O'Dea, Bridianne; Phung, Dinh; Venkatesh, Svetha; Christensen, Helen

2017-06-01

This work aims to estimate the degree of adverse drug reactions (ADR) for psychiatric medications from social media, including Twitter, Reddit, and LiveJournal. Advances in lightning-fast cluster computing was employed to process large scale data, consisting of 6.4 terabytes of data containing 3.8 billion records from all the media. Rates of ADR were quantified using the SIDER database of drugs and side-effects, and an estimated ADR rate was based on the prevalence of discussion in the social media corpora. Agreement between these measures for a sample of ten popular psychiatric drugs was evaluated using the Pearson correlation coefficient, r, with values between 0.08 and 0.50. Word2vec, a novel neural learning framework, was utilized to improve the coverage of variants of ADR terms in the unstructured text by identifying syntactically or semantically similar terms. Improved correlation coefficients, between 0.29 and 0.59, demonstrates the capability of advanced techniques in machine learning to aid in the discovery of meaningful patterns from medical data, and social media data, at scale. Copyright © 2017 Elsevier B.V. All rights reserved.

Assessment of Metabolome Annotation Quality: A Method for Evaluating the False Discovery Rate of Elemental Composition Searches

PubMed Central

Matsuda, Fumio; Shinbo, Yoko; Oikawa, Akira; Hirai, Masami Yokota; Fiehn, Oliver; Kanaya, Shigehiko; Saito, Kazuki

2009-01-01

Background In metabolomics researches using mass spectrometry (MS), systematic searching of high-resolution mass data against compound databases is often the first step of metabolite annotation to determine elemental compositions possessing similar theoretical mass numbers. However, incorrect hits derived from errors in mass analyses will be included in the results of elemental composition searches. To assess the quality of peak annotation information, a novel methodology for false discovery rates (FDR) evaluation is presented in this study. Based on the FDR analyses, several aspects of an elemental composition search, including setting a threshold, estimating FDR, and the types of elemental composition databases most reliable for searching are discussed. Methodology/Principal Findings The FDR can be determined from one measured value (i.e., the hit rate for search queries) and four parameters determined by Monte Carlo simulation. The results indicate that relatively high FDR values (30–50%) were obtained when searching time-of-flight (TOF)/MS data using the KNApSAcK and KEGG databases. In addition, searches against large all-in-one databases (e.g., PubChem) always produced unacceptable results (FDR >70%). The estimated FDRs suggest that the quality of search results can be improved not only by performing more accurate mass analysis but also by modifying the properties of the compound database. A theoretical analysis indicates that FDR could be improved by using compound database with smaller but higher completeness entries. Conclusions/Significance High accuracy mass analysis, such as Fourier transform (FT)-MS, is needed for reliable annotation (FDR <10%). In addition, a small, customized compound database is preferable for high-quality annotation of metabolome data. PMID:19847304

A continuation of base-line studies for environmentally monitoring Space Transportation Systems (STS) at John F. Kennedy Space Center. Volume 4: Threatened and endangered species of the Kennedy Space Center. Part 1: Marine turtle studies

NASA Technical Reports Server (NTRS)

Ehrhart, L. M.

1980-01-01

The status of marine turtle populations in the KSC area was studied using data from previous results from ground and aerial surveillance conducted from 1976 to April 1979. During ground surveillance, various data were recorded on emergent turtles such as: species, weight, tag number (if previously tagged), time discovered, activity at discovery and the location of discovery. Observations were also made on nesting and reproductive characteristics, population estimates, immigration and emigration and growth rate of the turtles. Mortality studies were additionally made and autopsies performed on dead turtles found in the area. It is concluded that further mortality documentation should be done just prior to and just after a future space launch operation in order to accurately assess the cause and effect relationship of such a launch on the turtle population.

Reserve growth in oil fields of the North Sea

USGS Publications Warehouse

Klett, T.R.; Gautier, D.L.

2005-01-01

The assessment of petroleum resources of the North Sea, as well as other areas of the world, requires a viable means to forecast the amount of growth of reserve estimates (reserve growth) for discovered fields and to predict the potential fully developed sizes of undiscovered fields. This study investigates the utility of North Sea oil field data to construct reserve-growth models. Oil fields of the North Sea provide an excellent dataset in which to examine the mechanisms, characteristics, rates and quantities of reserve growth because of the high level of capital investments, implementation of sophisticated technologies and careful data collection. Additionally, these field data are well reported and available publicly. Increases in successive annual estimat es of recoverable crude oil volumes indicate that oil fields in the North Sea, collectively and in each country, experience reserve growth. Specific patterns of reserve growth are observed among countries and primary producing reservoir-rock types. Since 1985, Norwegian oil fields had the greatest volume increase; Danish oil fields increased by the greatest percentage relative to 1985 estimates; and British oil fields experienced an increase in recoverable oil estimates for the first ten years since 1985, followed by a slight reduction. Fields producing primarily from clastic reservoirs account for the majority of the estimated recoverable oil and, therefore, these fields had the largest volumetric increase. Fields producing primarily from chalk (limestone) reservoirs increased by a greater percentage relative to 1985 estimates than did fields producing primarily from clastic reservoirs. Additionally, the largest oil fields had the greatest volumetric increases. Although different reserve-growth patterns are observed among oil fields located in different countries, the small number of fields in Denmark precludes construction of reserve-growth models for that country. However, differences in reserve-growth patterns among oil fields that produce from primarily clastic and primarily chalk reservoirs, in addition to a greater number of fields in each of the two categories, allow separate reserve-growth models to be constructed based on reservoir-rock type. Reserve-growth models referenced to the date of discovery and to the date of first production may be constructed from North Sea field data. Years since discovery or years since first production are used as surrogates for, or measures of, field-development effort that is applied to promote reserve growth. Better estimates of recoverable oil are made as fields are developed. Because much of the field development occurs some time later than the field discovery date, reserve-growth models referenced to the date of first production may provide a more appropriate measure of development than does date of discovery. ?? 2005 EAGE/Geological Society of London.

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.

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.

Order Under Uncertainty: Robust Differential Expression Analysis Using Probabilistic Models for Pseudotime Inference

PubMed Central

Campbell, Kieran R.

2016-01-01

Single cell gene expression profiling can be used to quantify transcriptional dynamics in temporal processes, such as cell differentiation, using computational methods to label each cell with a ‘pseudotime’ where true time series experimentation is too difficult to perform. However, owing to the high variability in gene expression between individual cells, there is an inherent uncertainty in the precise temporal ordering of the cells. Pre-existing methods for pseudotime estimation have predominantly given point estimates precluding a rigorous analysis of the implications of uncertainty. We use probabilistic modelling techniques to quantify pseudotime uncertainty and propagate this into downstream differential expression analysis. We demonstrate that reliance on a point estimate of pseudotime can lead to inflated false discovery rates and that probabilistic approaches provide greater robustness and measures of the temporal resolution that can be obtained from pseudotime inference. PMID:27870852

Asymptotics of empirical eigenstructure for high dimensional spiked covariance.

PubMed

Wang, Weichen; Fan, Jianqing

2017-06-01

We derive the asymptotic distributions of the spiked eigenvalues and eigenvectors under a generalized and unified asymptotic regime, which takes into account the magnitude of spiked eigenvalues, sample size, and dimensionality. This regime allows high dimensionality and diverging eigenvalues and provides new insights into the roles that the leading eigenvalues, sample size, and dimensionality play in principal component analysis. Our results are a natural extension of those in Paul (2007) to a more general setting and solve the rates of convergence problems in Shen et al. (2013). They also reveal the biases of estimating leading eigenvalues and eigenvectors by using principal component analysis, and lead to a new covariance estimator for the approximate factor model, called shrinkage principal orthogonal complement thresholding (S-POET), that corrects the biases. Our results are successfully applied to outstanding problems in estimation of risks of large portfolios and false discovery proportions for dependent test statistics and are illustrated by simulation studies.

Asymptotics of empirical eigenstructure for high dimensional spiked covariance

PubMed Central

Wang, Weichen

2017-01-01

We derive the asymptotic distributions of the spiked eigenvalues and eigenvectors under a generalized and unified asymptotic regime, which takes into account the magnitude of spiked eigenvalues, sample size, and dimensionality. This regime allows high dimensionality and diverging eigenvalues and provides new insights into the roles that the leading eigenvalues, sample size, and dimensionality play in principal component analysis. Our results are a natural extension of those in Paul (2007) to a more general setting and solve the rates of convergence problems in Shen et al. (2013). They also reveal the biases of estimating leading eigenvalues and eigenvectors by using principal component analysis, and lead to a new covariance estimator for the approximate factor model, called shrinkage principal orthogonal complement thresholding (S-POET), that corrects the biases. Our results are successfully applied to outstanding problems in estimation of risks of large portfolios and false discovery proportions for dependent test statistics and are illustrated by simulation studies. PMID:28835726

Multiple testing with discrete data: Proportion of true null hypotheses and two adaptive FDR procedures.

PubMed

Chen, Xiongzhi; Doerge, Rebecca W; Heyse, Joseph F

2018-05-11

We consider multiple testing with false discovery rate (FDR) control when p values have discrete and heterogeneous null distributions. We propose a new estimator of the proportion of true null hypotheses and demonstrate that it is less upwardly biased than Storey's estimator and two other estimators. The new estimator induces two adaptive procedures, that is, an adaptive Benjamini-Hochberg (BH) procedure and an adaptive Benjamini-Hochberg-Heyse (BHH) procedure. We prove that the adaptive BH (aBH) procedure is conservative nonasymptotically. Through simulation studies, we show that these procedures are usually more powerful than their nonadaptive counterparts and that the adaptive BHH procedure is usually more powerful than the aBH procedure and a procedure based on randomized p-value. The adaptive procedures are applied to a study of HIV vaccine efficacy, where they identify more differentially polymorphic positions than the BH procedure at the same FDR level. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

New U.S. Geological Survey Method for the Assessment of Reserve Growth

USGS Publications Warehouse

Klett, Timothy R.; Attanasi, E.D.; Charpentier, Ronald R.; Cook, Troy A.; Freeman, P.A.; Gautier, Donald L.; Le, Phuong A.; Ryder, Robert T.; Schenk, Christopher J.; Tennyson, Marilyn E.; Verma, Mahendra K.

2011-01-01

Reserve growth is defined as the estimated increases in quantities of crude oil, natural gas, and natural gas liquids that have the potential to be added to remaining reserves in discovered accumulations through extension, revision, improved recovery efficiency, and additions of new pools or reservoirs. A new U.S. Geological Survey method was developed to assess the reserve-growth potential of technically recoverable crude oil and natural gas to be added to reserves under proven technology currently in practice within the trend or play, or which reasonably can be extrapolated from geologically similar trends or plays. This method currently is in use to assess potential additions to reserves in discovered fields of the United States. The new approach involves (1) individual analysis of selected large accumulations that contribute most to reserve growth, and (2) conventional statistical modeling of reserve growth in remaining accumulations. This report will focus on the individual accumulation analysis. In the past, the U.S. Geological Survey estimated reserve growth by statistical methods using historical recoverable-quantity data. Those statistical methods were based on growth rates averaged by the number of years since accumulation discovery. Accumulations in mature petroleum provinces with volumetrically significant reserve growth, however, bias statistical models of the data; therefore, accumulations with significant reserve growth are best analyzed separately from those with less significant reserve growth. Large (greater than 500 million barrels) and older (with respect to year of discovery) oil accumulations increase in size at greater rates late in their development history in contrast to more recently discovered accumulations that achieve most growth early in their development history. Such differences greatly affect the statistical methods commonly used to forecast reserve growth. The individual accumulation-analysis method involves estimating the in-place petroleum quantity and its uncertainty, as well as the estimated (forecasted) recoverability and its respective uncertainty. These variables are assigned probabilistic distributions and are combined statistically to provide probabilistic estimates of ultimate recoverable quantities. Cumulative production and remaining reserves are then subtracted from the estimated ultimate recoverable quantities to provide potential reserve growth. In practice, results of the two methods are aggregated to various scales, the highest of which includes an entire country or the world total. The aggregated results are reported along with the statistically appropriate uncertainties.

An extended sequential goodness-of-fit multiple testing method for discrete data.

PubMed

Castro-Conde, Irene; Döhler, Sebastian; de Uña-Álvarez, Jacobo

2017-10-01

The sequential goodness-of-fit (SGoF) multiple testing method has recently been proposed as an alternative to the familywise error rate- and the false discovery rate-controlling procedures in high-dimensional problems. For discrete data, the SGoF method may be very conservative. In this paper, we introduce an alternative SGoF-type procedure that takes into account the discreteness of the test statistics. Like the original SGoF, our new method provides weak control of the false discovery rate/familywise error rate but attains false discovery rate levels closer to the desired nominal level, and thus it is more powerful. We study the performance of this method in a simulation study and illustrate its application to a real pharmacovigilance data set.

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.

A strategy to estimate unknown viral diversity in mammals.

PubMed

Anthony, Simon J; Epstein, Jonathan H; Murray, Kris A; Navarrete-Macias, Isamara; Zambrana-Torrelio, Carlos M; Solovyov, Alexander; Ojeda-Flores, Rafael; Arrigo, Nicole C; Islam, Ariful; Ali Khan, Shahneaz; Hosseini, Parviez; Bogich, Tiffany L; Olival, Kevin J; Sanchez-Leon, Maria D; Karesh, William B; Goldstein, Tracey; Luby, Stephen P; Morse, Stephen S; Mazet, Jonna A K; Daszak, Peter; Lipkin, W Ian

2013-09-03

The majority of emerging zoonoses originate in wildlife, and many are caused by viruses. However, there are no rigorous estimates of total viral diversity (here termed "virodiversity") for any wildlife species, despite the utility of this to future surveillance and control of emerging zoonoses. In this case study, we repeatedly sampled a mammalian wildlife host known to harbor emerging zoonotic pathogens (the Indian Flying Fox, Pteropus giganteus) and used PCR with degenerate viral family-level primers to discover and analyze the occurrence patterns of 55 viruses from nine viral families. We then adapted statistical techniques used to estimate biodiversity in vertebrates and plants and estimated the total viral richness of these nine families in P. giganteus to be 58 viruses. Our analyses demonstrate proof-of-concept of a strategy for estimating viral richness and provide the first statistically supported estimate of the number of undiscovered viruses in a mammalian host. We used a simple extrapolation to estimate that there are a minimum of 320,000 mammalian viruses awaiting discovery within these nine families, assuming all species harbor a similar number of viruses, with minimal turnover between host species. We estimate the cost of discovering these viruses to be ~$6.3 billion (or ~$1.4 billion for 85% of the total diversity), which if annualized over a 10-year study time frame would represent a small fraction of the cost of many pandemic zoonoses. Recent years have seen a dramatic increase in viral discovery efforts. However, most lack rigorous systematic design, which limits our ability to understand viral diversity and its ecological drivers and reduces their value to public health intervention. Here, we present a new framework for the discovery of novel viruses in wildlife and use it to make the first-ever estimate of the number of viruses that exist in a mammalian host. As pathogens continue to emerge from wildlife, this estimate allows us to put preliminary bounds around the potential size of the total zoonotic pool and facilitates a better understanding of where best to allocate resources for the subsequent discovery of global viral diversity.

Discovery of a Detached, Eclipsing 40 Minute Period Double White Dwarf Binary and a Friend: Implications for He+CO White Dwarf Mergers

NASA Astrophysics Data System (ADS)

Brown, Warren R.; Kilic, Mukremin; Kosakowski, Alekzander; Gianninas, A.

2017-09-01

We report the discovery of two detached double white dwarf (WD) binaries, SDSS J082239.546+304857.19 and SDSS J104336.275+055149.90, with orbital periods of 40 and 46 minutes, respectively. The 40 minute system is eclipsing; it is composed of a 0.30 M ⊙ and a 0.52 M ⊙ WD. The 46 minute system is a likely LISA verification binary. The short 20 ± 2 Myr and ˜34 Myr gravitational-wave merger times of the two binaries imply that many more such systems have formed and merged over the age of the Milky Way. We update the estimated Milky Way He+CO WD binary merger rate and affirm our previously published result: He+CO WD binaries merge at a rate at least 40 times greater than the formation rate of stable mass-transfer AM CVn binaries, and so the majority must have unstable mass-transfer. The implication is that spin-orbit coupling in He+CO WD mergers is weak, or perhaps nova-like outbursts drive He+CO WDs into merger, as proposed by Shen. Based on observations obtained at the MMT Observatory, a joint facility of the Smithsonian Institution and the University of Arizona, and on observations obtained with the Apache Point Observatory 3.5 m telescope, which is owned and operated by the Astrophysical Research Consortium.

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.

NGC 4051: Black hole mass and photon index-mass accretion rate correlation

NASA Astrophysics Data System (ADS)

Seifina, Elena; Chekhtman, Alexandre; Titarchuk, Lev

2018-05-01

We present a discovery of the correlation between the X-ray spectral (photon) index and mass accretion rate observed in an active galactic nucleus, NGC 4051. We analyzed spectral transition episodes observed in NGC 4051 using XMM-Newton, Suzaku and RXTE. We applied a scaling technique for a black hole (BH) mass evaluation which uses a correlation between the photon index and normalization of the seed (disk) component, which is proportional to a mass accretion rate. We developed an analytical model that shows the spectral (photon) index of the BH emergent spectrum undergoes an evolution from lower to higher values depending on a mass accretion rate in the accretion disk. We considered Cygnus X-1 and GRO J1550-564 as reference sources for which distances, inclination angles and the BH masses are evaluated by dynamical measurements. Application of the scaling technique for the photon index-mass accretion rate correlation provides an estimate of the black hole mass in NGC 4051 to be more than 6 × 105 solar masses.

Implementation of false discovery rate for exploring novel paradigms and trait dimensions with ERPs.

PubMed

Crowley, Michael J; Wu, Jia; McCreary, Scott; Miller, Kelly; Mayes, Linda C

2012-01-01

False discovery rate (FDR) is a multiple comparison procedure that targets the expected proportion of false discoveries among the discoveries. Employing FDR methods in event-related potential (ERP) research provides an approach to explore new ERP paradigms and ERP-psychological trait/behavior relations. In Study 1, we examined neural responses to escape behavior from an aversive noise. In Study 2, we correlated a relatively unexplored trait dimension, ostracism, with neural response. In both situations we focused on the frontal cortical region, applying a channel by time plots to display statistically significant uncorrected data and FDR corrected data, controlling for multiple comparisons.

A Scalable Approach for Protein False Discovery Rate Estimation in Large Proteomic Data Sets.

PubMed

Savitski, Mikhail M; Wilhelm, Mathias; Hahne, Hannes; Kuster, Bernhard; Bantscheff, Marcus

2015-09-01

Calculating the number of confidently identified proteins and estimating false discovery rate (FDR) is a challenge when analyzing very large proteomic data sets such as entire human proteomes. Biological and technical heterogeneity in proteomic experiments further add to the challenge and there are strong differences in opinion regarding the conceptual validity of a protein FDR and no consensus regarding the methodology for protein FDR determination. There are also limitations inherent to the widely used classic target-decoy strategy that particularly show when analyzing very large data sets and that lead to a strong over-representation of decoy identifications. In this study, we investigated the merits of the classic, as well as a novel target-decoy-based protein FDR estimation approach, taking advantage of a heterogeneous data collection comprised of ∼19,000 LC-MS/MS runs deposited in ProteomicsDB (https://www.proteomicsdb.org). The "picked" protein FDR approach treats target and decoy sequences of the same protein as a pair rather than as individual entities and chooses either the target or the decoy sequence depending on which receives the highest score. We investigated the performance of this approach in combination with q-value based peptide scoring to normalize sample-, instrument-, and search engine-specific differences. The "picked" target-decoy strategy performed best when protein scoring was based on the best peptide q-value for each protein yielding a stable number of true positive protein identifications over a wide range of q-value thresholds. We show that this simple and unbiased strategy eliminates a conceptual issue in the commonly used "classic" protein FDR approach that causes overprediction of false-positive protein identification in large data sets. The approach scales from small to very large data sets without losing performance, consistently increases the number of true-positive protein identifications and is readily implemented in proteomics analysis software. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

A Scalable Approach for Protein False Discovery Rate Estimation in Large Proteomic Data Sets

PubMed Central

Savitski, Mikhail M.; Wilhelm, Mathias; Hahne, Hannes; Kuster, Bernhard; Bantscheff, Marcus

2015-01-01

Calculating the number of confidently identified proteins and estimating false discovery rate (FDR) is a challenge when analyzing very large proteomic data sets such as entire human proteomes. Biological and technical heterogeneity in proteomic experiments further add to the challenge and there are strong differences in opinion regarding the conceptual validity of a protein FDR and no consensus regarding the methodology for protein FDR determination. There are also limitations inherent to the widely used classic target–decoy strategy that particularly show when analyzing very large data sets and that lead to a strong over-representation of decoy identifications. In this study, we investigated the merits of the classic, as well as a novel target–decoy-based protein FDR estimation approach, taking advantage of a heterogeneous data collection comprised of ∼19,000 LC-MS/MS runs deposited in ProteomicsDB (https://www.proteomicsdb.org). The “picked” protein FDR approach treats target and decoy sequences of the same protein as a pair rather than as individual entities and chooses either the target or the decoy sequence depending on which receives the highest score. We investigated the performance of this approach in combination with q-value based peptide scoring to normalize sample-, instrument-, and search engine-specific differences. The “picked” target–decoy strategy performed best when protein scoring was based on the best peptide q-value for each protein yielding a stable number of true positive protein identifications over a wide range of q-value thresholds. We show that this simple and unbiased strategy eliminates a conceptual issue in the commonly used “classic” protein FDR approach that causes overprediction of false-positive protein identification in large data sets. The approach scales from small to very large data sets without losing performance, consistently increases the number of true-positive protein identifications and is readily implemented in proteomics analysis software. PMID:25987413

A Methodology for the Analysis of Programmer Productivity and Effort Estimation within the Framework of Software Conversion.

DTIC Science & Technology

1984-05-01

TEST CH~ART NAT ONAL BQREAu Or s T AADS-963-’ 82 The coefficient of KCA(programmer’s knowledge of the program) initially seemed to be an error...productivity, as expected. An interesting manifestation, supporting a discovery by Oliver, was exhibited by the rating of a programmer’s knowledge of...ACCESSION NO. 3. RECIPIENT’S CATALOG NUM13ER 10 AFIT/CI/NR 84-44D _ _ ___)___________ 4. TITLE (.,d S ..benli) PR#fQP6rV/rV S . TYPE OF REPORT A PERIOD

The Discovery of Single-Nucleotide Polymorphisms—and Inferences about Human Demographic History

PubMed Central

Wakeley, John; Nielsen, Rasmus; Liu-Cordero, Shau Neen; Ardlie, Kristin

2001-01-01

A method of historical inference that accounts for ascertainment bias is developed and applied to single-nucleotide polymorphism (SNP) data in humans. The data consist of 84 short fragments of the genome that were selected, from three recent SNP surveys, to contain at least two polymorphisms in their respective ascertainment samples and that were then fully resequenced in 47 globally distributed individuals. Ascertainment bias is the deviation, from what would be observed in a random sample, caused either by discovery of polymorphisms in small samples or by locus selection based on levels or patterns of polymorphism. The three SNP surveys from which the present data were derived differ both in their protocols for ascertainment and in the size of the samples used for discovery. We implemented a Monte Carlo maximum-likelihood method to fit a subdivided-population model that includes a possible change in effective size at some time in the past. Incorrectly assuming that ascertainment bias does not exist causes errors in inference, affecting both estimates of migration rates and historical changes in size. Migration rates are overestimated when ascertainment bias is ignored. However, the direction of error in inferences about changes in effective population size (whether the population is inferred to be shrinking or growing) depends on whether either the numbers of SNPs per fragment or the SNP-allele frequencies are analyzed. We use the abbreviation “SDL,” for “SNP-discovered locus,” in recognition of the genomic-discovery context of SNPs. When ascertainment bias is modeled fully, both the number of SNPs per SDL and their allele frequencies support a scenario of growth in effective size in the context of a subdivided population. If subdivision is ignored, however, the hypothesis of constant effective population size cannot be rejected. An important conclusion of this work is that, in demographic or other studies, SNP data are useful only to the extent that their ascertainment can be modeled. PMID:11704929

A survey of computational methods and error rate estimation procedures for peptide and protein identification in shotgun proteomics

PubMed Central

Nesvizhskii, Alexey I.

2010-01-01

This manuscript provides a comprehensive review of the peptide and protein identification process using tandem mass spectrometry (MS/MS) data generated in shotgun proteomic experiments. The commonly used methods for assigning peptide sequences to MS/MS spectra are critically discussed and compared, from basic strategies to advanced multi-stage approaches. A particular attention is paid to the problem of false-positive identifications. Existing statistical approaches for assessing the significance of peptide to spectrum matches are surveyed, ranging from single-spectrum approaches such as expectation values to global error rate estimation procedures such as false discovery rates and posterior probabilities. The importance of using auxiliary discriminant information (mass accuracy, peptide separation coordinates, digestion properties, and etc.) is discussed, and advanced computational approaches for joint modeling of multiple sources of information are presented. This review also includes a detailed analysis of the issues affecting the interpretation of data at the protein level, including the amplification of error rates when going from peptide to protein level, and the ambiguities in inferring the identifies of sample proteins in the presence of shared peptides. Commonly used methods for computing protein-level confidence scores are discussed in detail. The review concludes with a discussion of several outstanding computational issues. PMID:20816881

Hypothesis-Testing Demands Trustworthy Data—A Simulation Approach to Inferential Statistics Advocating the Research Program Strategy

PubMed Central

Krefeld-Schwalb, Antonia; Witte, Erich H.; Zenker, Frank

2018-01-01

In psychology as elsewhere, the main statistical inference strategy to establish empirical effects is null-hypothesis significance testing (NHST). The recent failure to replicate allegedly well-established NHST-results, however, implies that such results lack sufficient statistical power, and thus feature unacceptably high error-rates. Using data-simulation to estimate the error-rates of NHST-results, we advocate the research program strategy (RPS) as a superior methodology. RPS integrates Frequentist with Bayesian inference elements, and leads from a preliminary discovery against a (random) H0-hypothesis to a statistical H1-verification. Not only do RPS-results feature significantly lower error-rates than NHST-results, RPS also addresses key-deficits of a “pure” Frequentist and a standard Bayesian approach. In particular, RPS aggregates underpowered results safely. RPS therefore provides a tool to regain the trust the discipline had lost during the ongoing replicability-crisis. PMID:29740363

Hypothesis-Testing Demands Trustworthy Data-A Simulation Approach to Inferential Statistics Advocating the Research Program Strategy.

PubMed

Krefeld-Schwalb, Antonia; Witte, Erich H; Zenker, Frank

2018-01-01

In psychology as elsewhere, the main statistical inference strategy to establish empirical effects is null-hypothesis significance testing (NHST). The recent failure to replicate allegedly well-established NHST-results, however, implies that such results lack sufficient statistical power, and thus feature unacceptably high error-rates. Using data-simulation to estimate the error-rates of NHST-results, we advocate the research program strategy (RPS) as a superior methodology. RPS integrates Frequentist with Bayesian inference elements, and leads from a preliminary discovery against a (random) H 0 -hypothesis to a statistical H 1 -verification. Not only do RPS-results feature significantly lower error-rates than NHST-results, RPS also addresses key-deficits of a "pure" Frequentist and a standard Bayesian approach. In particular, RPS aggregates underpowered results safely. RPS therefore provides a tool to regain the trust the discipline had lost during the ongoing replicability-crisis.

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.

Discovery of optical flickering from the symbiotic star EF Aquilae

NASA Astrophysics Data System (ADS)

Zamanov, R. K.; Boeva, S.; Nikolov, Y. M.; Petrov, B.; Bachev, R.; Latev, G. Y.; Popov, V. A.; Stoyanov, K. A.; Bode, M. F.; Martí, J.; Tomov, T.; Antonova, A.

2017-07-01

We report optical CCD photometry of the recently identified symbiotic star EF Aql. Our observations in Johnson V and B bands clearly show the presence of stochastic light variations with an amplitude of about 0.2 mag on a time scale of minutes. The observations point toward a white dwarf (WD) as the hot component in the system. It is the 11-th object among more than 200 symbiotic stars known with detected optical flickering. Estimates of the mass accretion rate onto the WD and the mass loss rate in the wind of the Mira secondary star lead to the conclusion that less than 1 per cent of the wind is captured by the WD. Eight further candidates for the detection of flickering in similar systems are suggested.

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

PubMed Central

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

2016-01-01

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

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)

Adaptation of Decoy Fusion Strategy for Existing Multi-Stage Search Workflows

NASA Astrophysics Data System (ADS)

Ivanov, Mark V.; Levitsky, Lev I.; Gorshkov, Mikhail V.

2016-09-01

A number of proteomic database search engines implement multi-stage strategies aiming at increasing the sensitivity of proteome analysis. These approaches often employ a subset of the original database for the secondary stage of analysis. However, if target-decoy approach (TDA) is used for false discovery rate (FDR) estimation, the multi-stage strategies may violate the underlying assumption of TDA that false matches are distributed uniformly across the target and decoy databases. This violation occurs if the numbers of target and decoy proteins selected for the second search are not equal. Here, we propose a method of decoy database generation based on the previously reported decoy fusion strategy. This method allows unbiased TDA-based FDR estimation in multi-stage searches and can be easily integrated into existing workflows utilizing popular search engines and post-search algorithms.

Improving sensitivity in proteome studies by analysis of false discovery rates for multiple search engines.

PubMed

Jones, Andrew R; Siepen, Jennifer A; Hubbard, Simon J; Paton, Norman W

2009-03-01

LC-MS experiments can generate large quantities of data, for which a variety of database search engines are available to make peptide and protein identifications. Decoy databases are becoming widely used to place statistical confidence in result sets, allowing the false discovery rate (FDR) to be estimated. Different search engines produce different identification sets so employing more than one search engine could result in an increased number of peptides (and proteins) being identified, if an appropriate mechanism for combining data can be defined. We have developed a search engine independent score, based on FDR, which allows peptide identifications from different search engines to be combined, called the FDR Score. The results demonstrate that the observed FDR is significantly different when analysing the set of identifications made by all three search engines, by each pair of search engines or by a single search engine. Our algorithm assigns identifications to groups according to the set of search engines that have made the identification, and re-assigns the score (combined FDR Score). The combined FDR Score can differentiate between correct and incorrect peptide identifications with high accuracy, allowing on average 35% more peptide identifications to be made at a fixed FDR than using a single search engine.

SPIRE: Systematic protein investigative research environment.

PubMed

Kolker, Eugene; Higdon, Roger; Morgan, Phil; Sedensky, Margaret; Welch, Dean; Bauman, Andrew; Stewart, Elizabeth; Haynes, Winston; Broomall, William; Kolker, Natali

2011-12-10

The SPIRE (Systematic Protein Investigative Research Environment) provides web-based experiment-specific mass spectrometry (MS) proteomics analysis (https://www.proteinspire.org). Its emphasis is on usability and integration of the best analytic tools. SPIRE provides an easy to use web-interface and generates results in both interactive and simple data formats. In contrast to run-based approaches, SPIRE conducts the analysis based on the experimental design. It employs novel methods to generate false discovery rates and local false discovery rates (FDR, LFDR) and integrates the best and complementary open-source search and data analysis methods. The SPIRE approach of integrating X!Tandem, OMSSA and SpectraST can produce an increase in protein IDs (52-88%) over current combinations of scoring and single search engines while also providing accurate multi-faceted error estimation. One of SPIRE's primary assets is combining the results with data on protein function, pathways and protein expression from model organisms. We demonstrate some of SPIRE's capabilities by analyzing mitochondrial proteins from the wild type and 3 mutants of C. elegans. SPIRE also connects results to publically available proteomics data through its Model Organism Protein Expression Database (MOPED). SPIRE can also provide analysis and annotation for user supplied protein ID and expression data. Copyright © 2011. Published by Elsevier B.V.

Gene variants associated with ischemic stroke: the cardiovascular health study.

PubMed

Luke, May M; O'Meara, Ellen S; Rowland, Charles M; Shiffman, Dov; Bare, Lance A; Arellano, Andre R; Longstreth, W T; Lumley, Thomas; Rice, Kenneth; Tracy, Russell P; Devlin, James J; Psaty, Bruce M

2009-02-01

The purpose of this study was to determine whether 74 single nucleotide polymorphisms (SNPs), which had been associated with coronary heart disease, are associated with incident ischemic stroke. Based on antecedent studies of coronary heart disease, we prespecified the risk allele for each of the 74 SNPs. We used Cox proportional hazards models that adjusted for traditional risk factors to estimate the associations of these SNPs with incident ischemic stroke during 14 years of follow-up in a population-based study of older adults: the Cardiovascular Health Study (CHS). In white CHS participants, the prespecified risk alleles of 7 of the 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) were nominally associated with increased risk of stroke (one-sided P<0.05, false discovery rate=0.42). In black participants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were nominally associated with stroke (one-sided P<0.05, false discovery rate=0.55). The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90% CI, 1.11 to 11.6) participants of CHS. Kaplan-Meier estimates of the 10-year cumulative incidence of stroke were greater among Val allele homozygotes than among Met allele carriers in both white (10% versus 6%) and black (12% versus 3%) participants of CHS. The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS.

Empirical Validation of Pooled Whole Genome Population Re-Sequencing in Drosophila melanogaster

PubMed Central

Zhu, Yuan; Bergland, Alan O.; González, Josefa; Petrov, Dmitri A.

2012-01-01

The sequencing of pooled non-barcoded individuals is an inexpensive and efficient means of assessing genome-wide population allele frequencies, yet its accuracy has not been thoroughly tested. We assessed the accuracy of this approach on whole, complex eukaryotic genomes by resequencing pools of largely isogenic, individually sequenced Drosophila melanogaster strains. We called SNPs in the pooled data and estimated false positive and false negative rates using the SNPs called in individual strain as a reference. We also estimated allele frequency of the SNPs using “pooled” data and compared them with “true” frequencies taken from the estimates in the individual strains. We demonstrate that pooled sequencing provides a faithful estimate of population allele frequency with the error well approximated by binomial sampling, and is a reliable means of novel SNP discovery with low false positive rates. However, a sufficient number of strains should be used in the pooling because variation in the amount of DNA derived from individual strains is a substantial source of noise when the number of pooled strains is low. Our results and analysis confirm that pooled sequencing is a very powerful and cost-effective technique for assessing of patterns of sequence variation in populations on genome-wide scales, and is applicable to any dataset where sequencing individuals or individual cells is impossible, difficult, time consuming, or expensive. PMID:22848651

Targeting a Complex Transcriptome: The Construction of the Mouse Full-Length cDNA Encyclopedia

PubMed Central

Carninci, Piero; Waki, Kazunori; Shiraki, Toshiyuki; Konno, Hideaki; Shibata, Kazuhiro; Itoh, Masayoshi; Aizawa, Katsunori; Arakawa, Takahiro; Ishii, Yoshiyuki; Sasaki, Daisuke; Bono, Hidemasa; Kondo, Shinji; Sugahara, Yuichi; Saito, Rintaro; Osato, Naoki; Fukuda, Shiro; Sato, Kenjiro; Watahiki, Akira; Hirozane-Kishikawa, Tomoko; Nakamura, Mari; Shibata, Yuko; Yasunishi, Ayako; Kikuchi, Noriko; Yoshiki, Atsushi; Kusakabe, Moriaki; Gustincich, Stefano; Beisel, Kirk; Pavan, William; Aidinis, Vassilis; Nakagawara, Akira; Held, William A.; Iwata, Hiroo; Kono, Tomohiro; Nakauchi, Hiromitsu; Lyons, Paul; Wells, Christine; Hume, David A.; Fagiolini, Michela; Hensch, Takao K.; Brinkmeier, Michelle; Camper, Sally; Hirota, Junji; Mombaerts, Peter; Muramatsu, Masami; Okazaki, Yasushi; Kawai, Jun; Hayashizaki, Yoshihide

2003-01-01

We report the construction of the mouse full-length cDNA encyclopedia,the most extensive view of a complex transcriptome,on the basis of preparing and sequencing 246 libraries. Before cloning,cDNAs were enriched in full-length by Cap-Trapper,and in most cases,aggressively subtracted/normalized. We have produced 1,442,236 successful 3′-end sequences clustered into 171,144 groups, from which 60,770 clones were fully sequenced cDNAs annotated in the FANTOM-2 annotation. We have also produced 547,149 5′ end reads,which clustered into 124,258 groups. Altogether, these cDNAs were further grouped in 70,000 transcriptional units (TU),which represent the best coverage of a transcriptome so far. By monitoring the extent of normalization/subtraction, we define the tentative equivalent coverage (TEC),which was estimated to be equivalent to >12,000,000 ESTs derived from standard libraries. High coverage explains discrepancies between the very large numbers of clusters (and TUs) of this project,which also include non-protein-coding RNAs,and the lower gene number estimation of genome annotations. Altogether,5′-end clusters identify regions that are potential promoters for 8637 known genes and 5′-end clusters suggest the presence of almost 63,000 transcriptional starting points. An estimate of the frequency of polyadenylation signals suggests that at least half of the singletons in the EST set represent real mRNAs. Clones accounting for about half of the predicted TUs await further sequencing. The continued high-discovery rate suggests that the task of transcriptome discovery is not yet complete. PMID:12819125

Separate class true discovery rate degree of association sets for biomarker identification.

PubMed

Crager, Michael R; Ahmed, Murat

2014-01-01

In 2008, Efron showed that biological features in a high-dimensional study can be divided into classes and a separate false discovery rate (FDR) analysis can be conducted in each class using information from the entire set of features to assess the FDR within each class. We apply this separate class approach to true discovery rate degree of association (TDRDA) set analysis, which is used in clinical-genomic studies to identify sets of biomarkers having strong association with clinical outcome or state while controlling the FDR. Careful choice of classes based on prior information can increase the identification power of the separate class analysis relative to the overall analysis.

Pharmacovigilance data mining with methods based on false discovery rates: a comparative simulation study.

PubMed

Ahmed, I; Thiessard, F; Miremont-Salamé, G; Bégaud, B; Tubert-Bitter, P

2010-10-01

The early detection of adverse reactions caused by drugs that are already on the market is the prime concern of pharmacovigilance efforts; the methods in use for postmarketing surveillance are aimed at detecting signals pointing to potential safety concerns, on the basis of reports from health-care providers and from information available in various databases. Signal detection methods based on the estimation of false discovery rate (FDR) have recently been proposed. They address the limitation of arbitrary detection thresholds of the automatic methods in current use, including those last updated by the US Food and Drug Administration and the World Health Organization's Uppsala Monitoring Centre. We used two simulation procedures to compare the false-positive performances for three current methods: the reporting odds ratio (ROR), the information component (IC), the gamma Poisson shrinkage (GPS), and also for two FDR-based methods derived from the GPS model and Fisher's test. Large differences in FDR rates were associated with the signal-detection methods currently in use. These differences ranged from 0.01 to 12% in an analysis that was restricted to signals with at least three reports. The numbers of signals generated were also highly variable. Among fixed-size lists of signals, the FDR was lowered when the FDR-based approaches were used. Overall, the outcomes in both simulation studies suggest that improvement in effectiveness can be expected from use of the FDR-based GPS method.

Pre-discovery Observations and Orbit of Comet C/2017 K2 (PANSTARRS)

NASA Astrophysics Data System (ADS)

Hui, Man-To; Jewitt, David; Clark, David

2018-01-01

We present a study of comet C/2017 K2 (PANSTARRS) using pre-discovery archival data taken from 2013 to 2017. Our measurements show that the comet has been marginally increasing in activity since at least 2013 May (heliocentric distance of {r}{{H}}=23.7 {au} pre-perihelion). We estimate the mass-loss rate during the period 2013–2017 as \\overline{\\dot{M}}≈ (2.4+/- 1.1)× {10}2 kg s‑1, which requires a minimum active surface area of ∼10–102 km2 for sublimation of supervolatiles such as CO and CO2, by assuming a nominal cometary albedo {p}V=0.04+/- 0.02. The corresponding lower limit to the nucleus radius is a few kilometers. Our Monte Carlo dust simulations show that dust grains in the coma are ≳ 0.5 {mm} in radius, with ejection speeds from ∼1 to 3 m s‑1, and have been emitted in a protracted manner since 2013, confirming estimates by Jewitt et al. The current heliocentric orbit is hyperbolic. Our N-body backward dynamical integration of the orbit suggests that the comet is most likely (with a probability of ∼98%) from the Oort spike. The calculated median reciprocal of the semimajor axis 1 Myr ago was {a}med}-1=(3.61+/- 1.71)× {10}-5 au‑1 (in a reference system centered on the solar-system barycenter).

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

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.

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…

Pathway-based analyses.

PubMed

Kent, Jack W

2016-02-03

New technologies for acquisition of genomic data, while offering unprecedented opportunities for genetic discovery, also impose severe burdens of interpretation and penalties for multiple testing. The Pathway-based Analyses Group of the Genetic Analysis Workshop 19 (GAW19) sought reduction of multiple-testing burden through various approaches to aggregation of highdimensional data in pathways informed by prior biological knowledge. Experimental methods testedincluded the use of "synthetic pathways" (random sets of genes) to estimate power and false-positive error rate of methods applied to simulated data; data reduction via independent components analysis, single-nucleotide polymorphism (SNP)-SNP interaction, and use of gene sets to estimate genetic similarity; and general assessment of the efficacy of prior biological knowledge to reduce the dimensionality of complex genomic data. The work of this group explored several promising approaches to managing high-dimensional data, with the caveat that these methods are necessarily constrained by the quality of external bioinformatic annotation.

False Discovery Control in Large-Scale Spatial Multiple Testing

PubMed Central

Sun, Wenguang; Reich, Brian J.; Cai, T. Tony; Guindani, Michele; Schwartzman, Armin

2014-01-01

Summary This article develops a unified theoretical and computational framework for false discovery control in multiple testing of spatial signals. We consider both point-wise and cluster-wise spatial analyses, and derive oracle procedures which optimally control the false discovery rate, false discovery exceedance and false cluster rate, respectively. A data-driven finite approximation strategy is developed to mimic the oracle procedures on a continuous spatial domain. Our multiple testing procedures are asymptotically valid and can be effectively implemented using Bayesian computational algorithms for analysis of large spatial data sets. Numerical results show that the proposed procedures lead to more accurate error control and better power performance than conventional methods. We demonstrate our methods for analyzing the time trends in tropospheric ozone in eastern US. PMID:25642138

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

Comparison of Two Methods Used to Model Shape Parameters of Pareto Distributions

USGS Publications Warehouse

Liu, C.; Charpentier, R.R.; Su, J.

2011-01-01

Two methods are compared for estimating the shape parameters of Pareto field-size (or pool-size) distributions for petroleum resource assessment. Both methods assume mature exploration in which most of the larger fields have been discovered. Both methods use the sizes of larger discovered fields to estimate the numbers and sizes of smaller fields: (1) the tail-truncated method uses a plot of field size versus size rank, and (2) the log-geometric method uses data binned in field-size classes and the ratios of adjacent bin counts. Simulation experiments were conducted using discovered oil and gas pool-size distributions from four petroleum systems in Alberta, Canada and using Pareto distributions generated by Monte Carlo simulation. The estimates of the shape parameters of the Pareto distributions, calculated by both the tail-truncated and log-geometric methods, generally stabilize where discovered pool numbers are greater than 100. However, with fewer than 100 discoveries, these estimates can vary greatly with each new discovery. The estimated shape parameters of the tail-truncated method are more stable and larger than those of the log-geometric method where the number of discovered pools is more than 100. Both methods, however, tend to underestimate the shape parameter. Monte Carlo simulation was also used to create sequences of discovered pool sizes by sampling from a Pareto distribution with a discovery process model using a defined exploration efficiency (in order to show how biased the sampling was in favor of larger fields being discovered first). A higher (more biased) exploration efficiency gives better estimates of the Pareto shape parameters. ?? 2011 International Association for Mathematical Geosciences.

From computational discovery to experimental characterization of a high hole mobility organic crystal

PubMed Central

Sokolov, Anatoliy N.; Atahan-Evrenk, Sule; Mondal, Rajib; Akkerman, Hylke B.; Sánchez-Carrera, Roel S.; Granados-Focil, Sergio; Schrier, Joshua; Mannsfeld, Stefan C.B.; Zoombelt, Arjan P.; Bao, Zhenan; Aspuru-Guzik, Alán

2011-01-01

For organic semiconductors to find ubiquitous electronics applications, the development of new materials with high mobility and air stability is critical. Despite the versatility of carbon, exploratory chemical synthesis in the vast chemical space can be hindered by synthetic and characterization difficulties. Here we show that in silico screening of novel derivatives of the dinaphtho[2,3-b:2′,3′-f]thieno[3,2-b]thiophene semiconductor with high hole mobility and air stability can lead to the discovery of a new high-performance semiconductor. On the basis of estimates from the Marcus theory of charge transfer rates, we identified a novel compound expected to demonstrate a theoretic twofold improvement in mobility over the parent molecule. Synthetic and electrical characterization of the compound is reported with single-crystal field-effect transistors, showing a remarkable saturation and linear mobility of 12.3 and 16 cm2 V−1 s−1, respectively. This is one of the very few organic semiconductors with mobility greater than 10 cm2 V−1 s−1 reported to date. PMID:21847111

Discovery of Three New Millisecond Pulsars in Terzan 5

NASA Astrophysics Data System (ADS)

Cadelano, M.; Ransom, S. M.; Freire, P. C. C.; Ferraro, F. R.; Hessels, J. W. T.; Lanzoni, B.; Pallanca, C.; Stairs, I. H.

2018-03-01

We report on the discovery of three new millisecond pulsars (MSPs; namely J1748‑2446aj, J1748‑2446ak, and J1748‑2446al) in the inner regions of the dense stellar system Terzan 5. These pulsars have been discovered thanks to a method, alternative to the classical search routines, that exploited the large set of archival observations of Terzan 5 acquired with the Green Bank Telescope over five years (from 2010 to 2015). This technique allowed the analysis of stacked power spectra obtained by combining ∼206 hr of observation. J1748‑2446aj has a spin period of ∼2.96 ms, J1748‑2446ak of ∼1.89 ms (thus it is the fourth fastest pulsar in the cluster) and J1748‑2446al of ∼5.95 ms. All three MSPs are isolated, and currently we have timing solutions only for J1748‑2446aj and J1748‑2446ak. For these two systems, we evaluated the contribution to the measured spin-down rate of the acceleration due to the cluster potential field, thus estimating the intrinsic spin-down rates, which are in agreement with those typically measured for MSPs in globular clusters (GCs). Our results increase the number of pulsars known in Terzan 5 to 37, which now hosts 25% of the entire pulsar population identified, so far, in GCs.

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 Evaluation of Different Target Enrichment Methods in Pooled Sequencing Designs for Complex Disease Association Studies

PubMed Central

Day-Williams, Aaron G.; McLay, Kirsten; Drury, Eleanor; Edkins, Sarah; Coffey, Alison J.; Palotie, Aarno; Zeggini, Eleftheria

2011-01-01

Pooled sequencing can be a cost-effective approach to disease variant discovery, but its applicability in association studies remains unclear. We compare sequence enrichment methods coupled to next-generation sequencing in non-indexed pools of 1, 2, 10, 20 and 50 individuals and assess their ability to discover variants and to estimate their allele frequencies. We find that pooled resequencing is most usefully applied as a variant discovery tool due to limitations in estimating allele frequency with high enough accuracy for association studies, and that in-solution hybrid-capture performs best among the enrichment methods examined regardless of pool size. PMID:22069447

The accumulation rate of meteorite falls at the earth's surface - The view from Roosevelt County, New Mexico

NASA Technical Reports Server (NTRS)

Zolensky, Michael E.; Wells, Gordon L.; Rendell, Helen M.

1990-01-01

The discovery of 154 meteorite fragments within an 11-sq km area of wind-excavated basins in Roosevelt County, New Mexico, permits a new calculation of the accumulation rate of meteorite falls at the earth's surface. Thermoluminescence dating of the coversand unit comprising the prime recovery surface suggests the maximum terrestrial age of the meteorites to be about 16.0 ka. The 68 meteorite fragments subjected to petrological analyses represent a minimum of 49 individual falls. Collection bias has largely excluded carbonaceous chondrites and achondrites, requiring the accumulation rate derived from the recovered samples to be increased by a factor of 1.25. Terrestrial weathering destroying ordinary chondrites can be modeled as a first-order decay process with an estimated half-life of 3.5 + or - 1.9 ka on the semiarid American High Plains. Having accounted for the age of the recovery surface, area of field searches, pairing of finds, collection bias and weathering half-life, an accumulation rate of 940 falls/a per 10 to the 6th sq km is calculated for falls greater than 10 g total mass. This figure exceeds the best-constrained previous estimate by more than an order of magnitude. One possible reason for this disparity may be the extraordinary length of the fall record preserved in the surficial geology of Roosevelt County. The high accumulation rate determined for the past 16 ka may point to the existence of periods when the meteorite fall rate was significantly greater than at present.

On the asymmetric evolution of the perihelion distances of near-Earth Jupiter family comets around the discovery time

NASA Astrophysics Data System (ADS)

Sosa, A.; Fernández, J. A.; Pais, P.

2012-12-01

We study the dynamical evolution of the near-Earth Jupiter family comets (NEJFCs) that came close to or crossed the Earth's orbit at the epoch of their discovery (perihelion distances qdisc < 1.3 AU). We found a minimum in the time evolution of the mean perihelion distance bar{q} of the NEJFCs at the discovery time of each comet (taken as t = 0) and a past-future asymmetry of bar{q} in an interval -1000 yr, +1000 yr centred on t = 0, confirming previous results. The asymmetry indicates that there are more comets with greater q in the past than in the future. For comparison purposes, we also analysed the population of near-Earth asteroids in cometary orbits (defined as those with aphelion distances Q > 4.5 AU) and with absolute magnitudes H < 18. We found some remarkable differences in the dynamical evolution of both populations that argue against a common origin. To further analyse the dynamical evolution of NEJFCs, we integrated in time a large sample of fictitious comets, cloned from the observed NEJFCs, over a 20 000 yr time interval and started the integration before the comet's discovery time, when it had a perihelion distance q > 2 AU. By assuming that NEJFCs are mostly discovered when they decrease their perihelion distances below a certain threshold qthre = 1.05 AU for the first time during their evolution, we were able to reproduce the main features of the observed bar{q} evolution in the interval [-1000, 1000] yr with respect to the discovery time. Our best fits indicate that 40% of the population of NEJFCs would be composed of young, fresh comets that entered the region q < 2 AU a few hundred years before decreasing their perihelion distances below qthre, while 60% would be composed of older, more evolved comets, discovered after spending at least 3000 yr in the q < 2 AU region before their perihelion distances drop below qthre. As a byproduct, we put some constraints on the physical lifetime τphys of NEJFCs in the q < 2 AU region. We found a lower limit of a few hundreds of revolutions and an upper limit of about 10 000-12 000 yr, or about 1600-2000 revolutions, somewhat longer than some previous estimates. These constraints are consistent with other estimates of τphys, based either on mass loss (sublimation, outbursts, splittings) or on the extinction rate of Jupiter family comets (JFCs).

An optimized protocol for generation and analysis of Ion Proton sequencing reads for RNA-Seq.

PubMed

Yuan, Yongxian; Xu, Huaiqian; Leung, Ross Ka-Kit

2016-05-26

Previous studies compared running cost, time and other performance measures of popular sequencing platforms. However, comprehensive assessment of library construction and analysis protocols for Proton sequencing platform remains unexplored. Unlike Illumina sequencing platforms, Proton reads are heterogeneous in length and quality. When sequencing data from different platforms are combined, this can result in reads with various read length. Whether the performance of the commonly used software for handling such kind of data is satisfactory is unknown. By using universal human reference RNA as the initial material, RNaseIII and chemical fragmentation methods in library construction showed similar result in gene and junction discovery number and expression level estimated accuracy. In contrast, sequencing quality, read length and the choice of software affected mapping rate to a much larger extent. Unspliced aligner TMAP attained the highest mapping rate (97.27 % to genome, 86.46 % to transcriptome), though 47.83 % of mapped reads were clipped. Long reads could paradoxically reduce mapping in junctions. With reference annotation guide, the mapping rate of TopHat2 significantly increased from 75.79 to 92.09 %, especially for long (>150 bp) reads. Sailfish, a k-mer based gene expression quantifier attained highly consistent results with that of TaqMan array and highest sensitivity. We provided for the first time, the reference statistics of library preparation methods, gene detection and quantification and junction discovery for RNA-Seq by the Ion Proton platform. Chemical fragmentation performed equally well with the enzyme-based one. The optimal Ion Proton sequencing options and analysis software have been evaluated.

RnaSeqSampleSize: real data based sample size estimation for RNA sequencing.

PubMed

Zhao, Shilin; Li, Chung-I; Guo, Yan; Sheng, Quanhu; Shyr, Yu

2018-05-30

One of the most important and often neglected components of a successful RNA sequencing (RNA-Seq) experiment is sample size estimation. A few negative binomial model-based methods have been developed to estimate sample size based on the parameters of a single gene. However, thousands of genes are quantified and tested for differential expression simultaneously in RNA-Seq experiments. Thus, additional issues should be carefully addressed, including the false discovery rate for multiple statistic tests, widely distributed read counts and dispersions for different genes. To solve these issues, we developed a sample size and power estimation method named RnaSeqSampleSize, based on the distributions of gene average read counts and dispersions estimated from real RNA-seq data. Datasets from previous, similar experiments such as the Cancer Genome Atlas (TCGA) can be used as a point of reference. Read counts and their dispersions were estimated from the reference's distribution; using that information, we estimated and summarized the power and sample size. RnaSeqSampleSize is implemented in R language and can be installed from Bioconductor website. A user friendly web graphic interface is provided at http://cqs.mc.vanderbilt.edu/shiny/RnaSeqSampleSize/ . RnaSeqSampleSize provides a convenient and powerful way for power and sample size estimation for an RNAseq experiment. It is also equipped with several unique features, including estimation for interested genes or pathway, power curve visualization, and parameter optimization.

Uncovering robust patterns of microRNA co-expression across cancers using Bayesian Relevance Networks

PubMed Central

2017-01-01

Co-expression networks have long been used as a tool for investigating the molecular circuitry governing biological systems. However, most algorithms for constructing co-expression networks were developed in the microarray era, before high-throughput sequencing—with its unique statistical properties—became the norm for expression measurement. Here we develop Bayesian Relevance Networks, an algorithm that uses Bayesian reasoning about expression levels to account for the differing levels of uncertainty in expression measurements between highly- and lowly-expressed entities, and between samples with different sequencing depths. It combines data from groups of samples (e.g., replicates) to estimate group expression levels and confidence ranges. It then computes uncertainty-moderated estimates of cross-group correlations between entities, and uses permutation testing to assess their statistical significance. Using large scale miRNA data from The Cancer Genome Atlas, we show that our Bayesian update of the classical Relevance Networks algorithm provides improved reproducibility in co-expression estimates and lower false discovery rates in the resulting co-expression networks. Software is available at www.perkinslab.ca. PMID:28817636

Uncovering robust patterns of microRNA co-expression across cancers using Bayesian Relevance Networks.

PubMed

Ramachandran, Parameswaran; Sánchez-Taltavull, Daniel; Perkins, Theodore J

2017-01-01

Co-expression networks have long been used as a tool for investigating the molecular circuitry governing biological systems. However, most algorithms for constructing co-expression networks were developed in the microarray era, before high-throughput sequencing-with its unique statistical properties-became the norm for expression measurement. Here we develop Bayesian Relevance Networks, an algorithm that uses Bayesian reasoning about expression levels to account for the differing levels of uncertainty in expression measurements between highly- and lowly-expressed entities, and between samples with different sequencing depths. It combines data from groups of samples (e.g., replicates) to estimate group expression levels and confidence ranges. It then computes uncertainty-moderated estimates of cross-group correlations between entities, and uses permutation testing to assess their statistical significance. Using large scale miRNA data from The Cancer Genome Atlas, we show that our Bayesian update of the classical Relevance Networks algorithm provides improved reproducibility in co-expression estimates and lower false discovery rates in the resulting co-expression networks. Software is available at www.perkinslab.ca.

A reduced estimate of the number of kilometre-sized near-Earth asteroids.

PubMed

Rabinowitz, D; Helin, E; Lawrence, K; Pravdo, S

2000-01-13

Near-Earth asteroids are small (diameters < 10 km), rocky bodies with orbits that approach that of the Earth (they come within 1.3 AU of the Sun). Most have a chance of approximately 0.5% of colliding with the Earth in the next million years. The total number of such bodies with diameters > 1 km has been estimated to be in the range 1,000-2,000, which translates to an approximately 1% chance of a catastrophic collision with the Earth in the next millennium. These numbers are, however, poorly constrained because of the limitations of previous searches using photographic plates. (One kilometre is below the size of a body whose impact on the Earth would produce global effects.) Here we report an analysis of our survey for near-Earth asteroids that uses improved detection technologies. We find that the total number of asteroids with diameters > 1 km is about half the earlier estimates. At the current rate of discovery of near-Earth asteroids, 90% will probably have been detected within the next 20 years.

A measurement system for large, complex software programs

NASA Technical Reports Server (NTRS)

Rone, Kyle Y.; Olson, Kitty M.; Davis, Nathan E.

1994-01-01

This paper describes measurement systems required to forecast, measure, and control activities for large, complex software development and support programs. Initial software cost and quality analysis provides the foundation for meaningful management decisions as a project evolves. In modeling the cost and quality of software systems, the relationship between the functionality, quality, cost, and schedule of the product must be considered. This explicit relationship is dictated by the criticality of the software being developed. This balance between cost and quality is a viable software engineering trade-off throughout the life cycle. Therefore, the ability to accurately estimate the cost and quality of software systems is essential to providing reliable software on time and within budget. Software cost models relate the product error rate to the percent of the project labor that is required for independent verification and validation. The criticality of the software determines which cost model is used to estimate the labor required to develop the software. Software quality models yield an expected error discovery rate based on the software size, criticality, software development environment, and the level of competence of the project and developers with respect to the processes being employed.

Post-flight BET products for the 2nd discovery entry, STS-19 (51-A)

NASA Technical Reports Server (NTRS)

Kelly, G. M.; Mcconnell, J. G.; Heck, M. L.; Troutman, P. A.; Waters, L. A.; Findlay, J. T.

1985-01-01

The post-flight products for the second Discovery flight, STS-19 (51-A), are summarized. The inertial best estimate trajectory (BET), BT19D19/UN=169750N, was developed using spacecraft dynamic measurements from Inertial Measurement Unit 2 (IMU2) in conjunction with the best tracking coverage available for any of the earlier Shuttle entries. As a consequence of the latter, an anchor epoch was selected which conforms to an initial altitude of greater than a million feet. The Extended BET, ST19BET/UN=274885C, incorporated the previously mentioned inertial reconstructed state information and the Langley Atmospheric Information Retrieval System (LAIRS) atmosphere, ST19MET/UN=712662N, with some minor exceptions. Primary and back-up AEROBET reels are NK0165 and NK0201, respectively. This product was only developed over the lowermost 360 kft altitude range due to atmosphere problems but this relates to altitudes well above meaningful signal in the IMUs. Summary results generated from the AEROBET for this flight are presented with meaningful configuration and statistical comparisons from the previous thirteen flights. Modified maximum likelihood estimation (MMLE) files were generated based on IMU2 and the Rate Gyro Assembly/Accelerometer Assembly (RGA/AA), respectively. Appendices attached define spacecraft and physical constants utilized, show plots of the final tracking data residuals from the post-flight fit, list relevant parameters from the BET at a two second spacing, and retain for archival purpose all relevant input and output tapes and files generated.

The rate of meiotic gene conversion varies by sex and age

PubMed Central

Halldorsson, Bjarni V.; Hardarson, Marteinn T.; Kehr, Birte; Styrkarsdottir, Unnur; Gylfason, Arnaldur; Thorleifsson, Gudmar; Zink, Florian; Jonasdottir, Adalbjorg; Jonasdottir, Aslaug; Sulem, Patrick; Masson, Gisli; Thorsteinsdottir, Unnur; Helgason, Agnar; Kong, Augustine; Gudbjartsson, Daniel F.; Stefansson, Kari

2016-01-01

Meiotic recombination involves a combination of gene conversion and crossover events that along with mutations produce germline genetic diversity. Here, we report the discovery of 3,176 SNP and 61 indel gene conversions. Our estimate of the non-crossover (NCO) gene conversion rate (G) is 7.0 for SNPs and 5.8 for indels per Mb per generation, and the GC bias is 67.6%. For indels we demonstrate a 65.6% preference for the shorter allele. NCO gene conversions from mothers are longer than those from fathers and G is 2.17 times greater in mothers. Notably, G increases with the age of mothers, but not fathers. A disproportionate number of NCO gene conversions in older mothers occur outside double strand break (DSB) regions and in regions with relatively low GC content. This points to age-related changes in the mechanisms of meiotic gene conversions in oocytes. PMID:27643539

Marine-target craters on Mars? An assessment study

USGS Publications Warehouse

Ormo, J.; Dohm, J.M.; Ferris, J.C.; Lepinette, A.; Fairen, A.G.

2004-01-01

Observations of impact craters on Earth show that a water column at the target strongly influences lithology and morphology of the resultant crater. The degree of influence varies with the target water depth and impactor diameter. Morphological features detectable in satellite imagery include a concentric shape with an inner crater inset within a shallower outer crater, which is cut by gullies excavated by the resurge of water. In this study, we show that if oceans, large seas, and lakes existed on Mars for periods of time, marine-target craters must have formed. We make an assessment of the minimum and maximum amounts of such craters based on published data on water depths, extent, and duration of putative oceans within "contacts 1 and 2," cratering rate during the different oceanic phases, and computer modeling of minimum impactor diameters required to form long-lasting craters in the seafloor of the oceans. We also discuss the influence of erosion and sedimentation on the preservation and exposure of the craters. For an ocean within the smaller "contact 2" with a duration of 100,000 yr and the low present crater formation rate, only ???1-2 detectable marine-target craters would have formed. In a maximum estimate with a duration of 0.8 Gyr, as many as 1400 craters may have formed. An ocean within the larger "contact 1-Meridiani," with a duration of 100,000 yr, would not have received any seafloor craters despite the higher crater formation rate estimated before 3.5 Gyr. On the other hand, with a maximum duration of 0.8 Gyr, about 160 seafloor craters may have formed. However, terrestrial examples show that most marine-target craters may be covered by thick sediments. Ground penetrating radar surveys planned for the ESA Mars Express and NASA 2005 missions may reveal buried craters, though it is uncertain if the resolution will allow the detection of diagnostic features of marine-target craters. The implications regarding the discovery of marine-target craters on Mars is not without significance, as such discoveries would help address the ongoing debate of whether large water bodies occupied the northern plains of Mars and would help constrain future paleoclimatic reconstructions. ?? Meteoritical Society, 2004.

The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468.

PubMed

Treiber, Alexander; de Kanter, Ruben; Roch, Catherine; Gatfield, John; Boss, Christoph; von Raumer, Markus; Schindelholz, Benno; Muehlan, Clemens; van Gerven, Joop; Jenck, Francois

2017-09-01

The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX 1 and OX 2 ) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX 2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX 2 receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

A model for the prediction of latent errors using data obtained during the development process

NASA Technical Reports Server (NTRS)

Gaffney, J. E., Jr.; Martello, S. J.

1984-01-01

A model implemented in a program that runs on the IBM PC for estimating the latent (or post ship) content of a body of software upon its initial release to the user is presented. The model employs the count of errors discovered at one or more of the error discovery processes during development, such as a design inspection, as the input data for a process which provides estimates of the total life-time (injected) error content and of the latent (or post ship) error content--the errors remaining a delivery. The model presented presumes that these activities cover all of the opportunities during the software development process for error discovery (and removal).

Dismantling Hubble's Legacy?

NASA Astrophysics Data System (ADS)

Way, Michael J.

2014-01-01

Edwin Hubble is famous for a number of discoveries that are well known to amateur and professional astronomers, students and even the general public. The origins of three of the most well-known discoveries are examined: The distances to nearby spiral nebulae, the classification of extragalactic-nebulae and the Hubble constant. In the case of the first two a great deal of supporting evidence was already in place, but little credit was given. The Hubble Constant had already been estimated in 1927 by Georges Lemaitre with roughly the same value that Hubble obtained in 1929 using redshifts provided mostly by Vesto M. Slipher. These earlier estimates were not adopted or were forgotten by the astronomical community for complex scientific, sociological and psychological reasons.

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.

A note on the false discovery rate of novel peptides in proteogenomics.

PubMed

Zhang, Kun; Fu, Yan; Zeng, Wen-Feng; He, Kun; Chi, Hao; Liu, Chao; Li, Yan-Chang; Gao, Yuan; Xu, Ping; He, Si-Min

2015-10-15

Proteogenomics has been well accepted as a tool to discover novel genes. In most conventional proteogenomic studies, a global false discovery rate is used to filter out false positives for identifying credible novel peptides. However, it has been found that the actual level of false positives in novel peptides is often out of control and behaves differently for different genomes. To quantitatively model this problem, we theoretically analyze the subgroup false discovery rates of annotated and novel peptides. Our analysis shows that the annotation completeness ratio of a genome is the dominant factor influencing the subgroup FDR of novel peptides. Experimental results on two real datasets of Escherichia coli and Mycobacterium tuberculosis support our conjecture. yfu@amss.ac.cn or xupingghy@gmail.com or smhe@ict.ac.cn Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

Lack of Dependence of Dynamic Triggering on the Timing within the Seismic Cycle

NASA Astrophysics Data System (ADS)

Cattania, C.; McGuire, J. J.; Collins, J. A.

2009-12-01

Numerical models predict that dynamic triggering of earthquakes is more likely when faults are close to failure (e.g. late in their earthquake cycle), and laboratory experiments have supported this hypothesis. We attempted to test this idea by analysing data on three adjacent transform faults of the East Pacific Rise which have a relatively well defined, quasiperiodic seismic cycle with a median repeat time of 5 years. Moreover, the Gofar, Discovery and Quebrada transform faults share several seismicity properties with continental geothermal areas, including high geothermal gradients, high seismicity rates, and frequent earthquake swarms, that suggest they may be prone to dynamic triggering. We analyze an earthquake catalog of over 100,000 events recorded in 2008 by a network of 38 Ocean Bottom Seismometers. We extract Mw>6.3 mainshocks from the Global CMT catalog, and perform the β test for an array of time intervals covering from 5 hours before to 10 hours after the low-frequency Rayleigh wave arrival. To verify the presence of common seismicity patterns, β plots are also stacked for multiple earthquakes. We observe triggering after the May 12th Wenchuan earthquake. On the Quebrada transform a burst of seismicity starts during the wavetrain; in Gofar there is no response during the wave, but an increase in seismicity (β=5.08) starts about 2 h later; no triggering is visible on the Discovery fault. A Mw=6.0 earthquake ruptured the Gofar transform on September 18th, and triggered seismicity on Discovery: ~60 earthquakes (β=15.3), starting 1h after the wave arrival. We have no data from Quebrada for this period. Other instances of triggering are dubious. Stacked β plots suggest delayed triggering (Δt>1h) in Gofar and Discovery, but the statistical significance of these results is unclear. From a comparison of different fault segments, triggering does not appear to be more common at late stages in the seismic cycle. Instead, the events triggered by the largest dynamic stresses concentrate in the regions between rupture zones. This suggests that changes in rock composition or fluid content may make these areas act as barriers to rupture propagation as well as facilitating dynamic triggering. Using the Rate-and-State seismicity model, we estimate that the effective normal stress where triggering occurs: is extremely low (σ<0.1MPa in Quebrada and σ<0.5MPa on Discovery), implying a nearly lithostatic pore pressure.

High throughput light absorber discovery, Part 1: An algorithm for automated tauc analysis

DOE PAGES

Suram, Santosh K.; Newhouse, Paul F.; Gregoire, John M.

2016-09-23

High-throughput experimentation provides efficient mapping of composition-property relationships, and its implementation for the discovery of optical materials enables advancements in solar energy and other technologies. In a high throughput pipeline, automated data processing algorithms are often required to match experimental throughput, and we present an automated Tauc analysis algorithm for estimating band gap energies from optical spectroscopy data. The algorithm mimics the judgment of an expert scientist, which is demonstrated through its application to a variety of high throughput spectroscopy data, including the identification of indirect or direct band gaps in Fe 2O 3, Cu 2V 2O 7, and BiVOmore » 4. Here, the applicability of the algorithm to estimate a range of band gap energies for various materials is demonstrated by a comparison of direct-allowed band gaps estimated by expert scientists and by automated algorithm for 60 optical spectra.« less

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.

Quantitative estimation of pesticide-likeness for agrochemical discovery.

PubMed

Avram, Sorin; Funar-Timofei, Simona; Borota, Ana; Chennamaneni, Sridhar Rao; Manchala, Anil Kumar; Muresan, Sorel

2014-12-01

The design of chemical libraries, an early step in agrochemical discovery programs, is frequently addressed by means of qualitative physicochemical and/or topological rule-based methods. The aim of this study is to develop quantitative estimates of herbicide- (QEH), insecticide- (QEI), fungicide- (QEF), and, finally, pesticide-likeness (QEP). In the assessment of these definitions, we relied on the concept of desirability functions. We found a simple function, shared by the three classes of pesticides, parameterized particularly, for six, easy to compute, independent and interpretable, molecular properties: molecular weight, logP, number of hydrogen bond acceptors, number of hydrogen bond donors, number of rotatable bounds and number of aromatic rings. Subsequently, we describe the scoring of each pesticide class by the corresponding quantitative estimate. In a comparative study, we assessed the performance of the scoring functions using extensive datasets of patented pesticides. The hereby-established quantitative assessment has the ability to rank compounds whether they fail well-established pesticide-likeness rules or not, and offer an efficient way to prioritize (class-specific) pesticides. These findings are valuable for the efficient estimation of pesticide-likeness of vast chemical libraries in the field of agrochemical discovery. Graphical AbstractQuantitative models for pesticide-likeness were derived using the concept of desirability functions parameterized for six, easy to compute, independent and interpretable, molecular properties: molecular weight, logP, number of hydrogen bond acceptors, number of hydrogen bond donors, number of rotatable bounds and number of aromatic rings.

Predicting discovery rates of genomic features.

PubMed

Gravel, Simon

2014-06-01

Successful sequencing experiments require judicious sample selection. However, this selection must often be performed on the basis of limited preliminary data. Predicting the statistical properties of the final sample based on preliminary data can be challenging, because numerous uncertain model assumptions may be involved. Here, we ask whether we can predict "omics" variation across many samples by sequencing only a fraction of them. In the infinite-genome limit, we find that a pilot study sequencing 5% of a population is sufficient to predict the number of genetic variants in the entire population within 6% of the correct value, using an estimator agnostic to demography, selection, or population structure. To reach similar accuracy in a finite genome with millions of polymorphisms, the pilot study would require ∼15% of the population. We present computationally efficient jackknife and linear programming methods that exhibit substantially less bias than the state of the art when applied to simulated data and subsampled 1000 Genomes Project data. Extrapolating based on the National Heart, Lung, and Blood Institute Exome Sequencing Project data, we predict that 7.2% of sites in the capture region would be variable in a sample of 50,000 African Americans and 8.8% in a European sample of equal size. Finally, we show how the linear programming method can also predict discovery rates of various genomic features, such as the number of transcription factor binding sites across different cell types. Copyright © 2014 by the Genetics Society of America.

Serum metabolites are associated with all-cause mortality in chronic kidney disease.

PubMed

Hu, Jiun-Ruey; Coresh, Josef; Inker, Lesley A; Levey, Andrew S; Zheng, Zihe; Rebholz, Casey M; Tin, Adrienne; Appel, Lawrence J; Chen, Jingsha; Sarnak, Mark J; Grams, Morgan E

2018-06-02

Chronic kidney disease (CKD) involves significant metabolic abnormalities and has a high mortality rate. Because the levels of serum metabolites in patients with CKD might provide insight into subclinical disease states and risk for future mortality, we determined which serum metabolites reproducibly associate with mortality in CKD using a discovery and replication design. Metabolite levels were quantified via untargeted liquid chromatography and mass spectroscopy from serum samples of 299 patients with CKD in the Modification of Diet in Renal Disease (MDRD) study as a discovery cohort. Six among 622 metabolites were significantly associated with mortality over a median follow-up of 17 years after adjustment for demographic and clinical covariates, including urine protein and measured glomerular filtration rate. We then replicated associations with mortality in 963 patients with CKD from the African American Study of Kidney Disease and Hypertension (AASK) cohort over a median follow-up of ten years. Three of the six metabolites identified in the MDRD cohort replicated in the AASK cohort: fumarate, allantoin, and ribonate, belonging to energy, nucleotide, and carbohydrate pathways, respectively. Point estimates were similar in both studies and in meta-analysis (adjusted hazard ratios 1.63, 1.59, and 1.61, respectively, per doubling of the metabolite). Thus, selected serum metabolites were reproducibly associated with long-term mortality in CKD beyond markers of kidney function in two well characterized cohorts, providing targets for investigation. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

ALMA Detection of Bipolar Outflows: Evidence for Low-mass Star Formation within 1 pc of Sgr A*

NASA Astrophysics Data System (ADS)

Yusef-Zadeh, F.; Wardle, M.; Kunneriath, D.; Royster, M.; Wootten, A.; Roberts, D. A.

2017-12-01

We report the discovery of 11 bipolar outflows within a projected distance of 1 pc from Sgr A* based on deep ALMA observations of 13CO, H30α, and SiO (5-4) lines with subarcsecond and ˜1.3 km s-1 resolutions. These unambiguous signatures of young protostars manifest as approaching and receding lobes of dense gas swept up by the jets created during the formation and early evolution of stars. The lobe masses and momentum transfer rates are consistent with young protostellar outflows found throughout the disk of the Galaxy. The mean dynamical age of the outflow population is estimated to be {6.5}-3.6+8.1× {10}3 years. The rate of star formation is ˜5 × 10-4 {M}⊙ yr-1 assuming a mean stellar mass of ˜0.3 {M}⊙ . This discovery provides evidence that star formation is taking place within clouds surprisingly close to Sgr A*, perhaps due to events that compress the host cloud, creating condensations with sufficient self-gravity to resist tidal disruption by Sgr A*. Low-mass star formation over the past few billion years at this level would contribute significantly to the stellar mass budget in the central few parsecs of the Galaxy. The presence of many dense clumps of molecular material within 1 pc of Sgr A* suggests that star formation could take place in the immediate vicinity of supermassive black holes in the nuclei of external galaxies.

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.

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.

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.

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

Application of PBPK modelling in drug discovery and development at Pfizer.

PubMed

Jones, Hannah M; Dickins, Maurice; Youdim, Kuresh; Gosset, James R; Attkins, Neil J; Hay, Tanya L; Gurrell, Ian K; Logan, Y Raj; Bungay, Peter J; Jones, Barry C; Gardner, Iain B

2012-01-01

Early prediction of human pharmacokinetics (PK) and drug-drug interactions (DDI) in drug discovery and development allows for more informed decision making. Physiologically based pharmacokinetic (PBPK) modelling can be used to answer a number of questions throughout the process of drug discovery and development and is thus becoming a very popular tool. PBPK models provide the opportunity to integrate key input parameters from different sources to not only estimate PK parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. Using examples from the literature and our own company, we have shown how PBPK techniques can be utilized through the stages of drug discovery and development to increase efficiency, reduce the need for animal studies, replace clinical trials and to increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however, some limitations need to be addressed to realize its application and utility more broadly.

A scientometric prediction of the discovery of the first potentially habitable planet with a mass similar to Earth.

PubMed

Arbesman, Samuel; Laughlin, Gregory

2010-10-04

The search for a habitable extrasolar planet has long interested scientists, but only recently have the tools become available to search for such planets. In the past decades, the number of known extrasolar planets has ballooned into the hundreds, and with it, the expectation that the discovery of the first Earth-like extrasolar planet is not far off. Here, we develop a novel metric of habitability for discovered planets and use this to arrive at a prediction for when the first habitable planet will be discovered. Using a bootstrap analysis of currently discovered exoplanets, we predict the discovery of the first Earth-like planet to be announced in the first half of 2011, with the likeliest date being early May 2011. Our predictions, using only the properties of previously discovered exoplanets, accord well with external estimates for the discovery of the first potentially habitable extrasolar planet and highlight the the usefulness of predictive scientometric techniques to understand the pace of scientific discovery in many fields.

Novel opportunities for computational biology and sociology in drug discovery

PubMed Central

Yao, Lixia

2009-01-01

Drug discovery today is impossible without sophisticated modeling and computation. In this review we touch on previous advances in computational biology and by tracing the steps involved in pharmaceutical development, we explore a range of novel, high value opportunities for computational innovation in modeling the biological process of disease and the social process of drug discovery. These opportunities include text mining for new drug leads, modeling molecular pathways and predicting the efficacy of drug cocktails, analyzing genetic overlap between diseases and predicting alternative drug use. Computation can also be used to model research teams and innovative regions and to estimate the value of academy-industry ties for scientific and human benefit. Attention to these opportunities could promise punctuated advance, and will complement the well-established computational work on which drug discovery currently relies. PMID:19674801

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 genetic architecture of economic and political preferences

PubMed Central

Benjamin, Daniel J.; Cesarini, David; van der Loos, Matthijs J. H. M.; Dawes, Christopher T.; Koellinger, Philipp D.; Magnusson, Patrik K. E.; Chabris, Christopher F.; Conley, Dalton; Laibson, David; Johannesson, Magnus; Visscher, Peter M.

2012-01-01

Preferences are fundamental building blocks in all models of economic and political behavior. We study a new sample of comprehensively genotyped subjects with data on economic and political preferences and educational attainment. We use dense single nucleotide polymorphism (SNP) data to estimate the proportion of variation in these traits explained by common SNPs and to conduct genome-wide association study (GWAS) and prediction analyses. The pattern of results is consistent with findings for other complex traits. First, the estimated fraction of phenotypic variation that could, in principle, be explained by dense SNP arrays is around one-half of the narrow heritability estimated using twin and family samples. The molecular-genetic–based heritability estimates, therefore, partially corroborate evidence of significant heritability from behavior genetic studies. Second, our analyses suggest that these traits have a polygenic architecture, with the heritable variation explained by many genes with small effects. Our results suggest that most published genetic association studies with economic and political traits are dramatically underpowered, which implies a high false discovery rate. These results convey a cautionary message for whether, how, and how soon molecular genetic data can contribute to, and potentially transform, research in social science. We propose some constructive responses to the inferential challenges posed by the small explanatory power of individual SNPs. PMID:22566634

The genetic architecture of economic and political preferences.

PubMed

Benjamin, Daniel J; Cesarini, David; van der Loos, Matthijs J H M; Dawes, Christopher T; Koellinger, Philipp D; Magnusson, Patrik K E; Chabris, Christopher F; Conley, Dalton; Laibson, David; Johannesson, Magnus; Visscher, Peter M

2012-05-22

Preferences are fundamental building blocks in all models of economic and political behavior. We study a new sample of comprehensively genotyped subjects with data on economic and political preferences and educational attainment. We use dense single nucleotide polymorphism (SNP) data to estimate the proportion of variation in these traits explained by common SNPs and to conduct genome-wide association study (GWAS) and prediction analyses. The pattern of results is consistent with findings for other complex traits. First, the estimated fraction of phenotypic variation that could, in principle, be explained by dense SNP arrays is around one-half of the narrow heritability estimated using twin and family samples. The molecular-genetic-based heritability estimates, therefore, partially corroborate evidence of significant heritability from behavior genetic studies. Second, our analyses suggest that these traits have a polygenic architecture, with the heritable variation explained by many genes with small effects. Our results suggest that most published genetic association studies with economic and political traits are dramatically underpowered, which implies a high false discovery rate. These results convey a cautionary message for whether, how, and how soon molecular genetic data can contribute to, and potentially transform, research in social science. We propose some constructive responses to the inferential challenges posed by the small explanatory power of individual SNPs.

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.

Fossil skulls reveal that blood flow rate to the brain increased faster than brain volume during human evolution

NASA Astrophysics Data System (ADS)

Seymour, Roger S.; Bosiocic, Vanya; Snelling, Edward P.

2016-08-01

The evolution of human cognition has been inferred from anthropological discoveries and estimates of brain size from fossil skulls. A more direct measure of cognition would be cerebral metabolic rate, which is proportional to cerebral blood flow rate (perfusion). The hominin cerebrum is supplied almost exclusively by the internal carotid arteries. The sizes of the foramina that transmitted these vessels in life can be measured in hominin fossil skulls and used to calculate cerebral perfusion rate. Perfusion in 11 species of hominin ancestors, from Australopithecus to archaic Homo sapiens, increases disproportionately when scaled against brain volume (the allometric exponent is 1.41). The high exponent indicates an increase in the metabolic intensity of cerebral tissue in later Homo species, rather than remaining constant (1.0) as expected by a linear increase in neuron number, or decreasing according to Kleiber's Law (0.75). During 3 Myr of hominin evolution, cerebral tissue perfusion increased 1.7-fold, which, when multiplied by a 3.5-fold increase in brain size, indicates a 6.0-fold increase in total cerebral blood flow rate. This is probably associated with increased interneuron connectivity, synaptic activity and cognitive function, which all ultimately depend on cerebral metabolic rate.

Construction of a Calibrated Probabilistic Classification Catalog: Application to 50k Variable Sources in the All-Sky Automated Survey

NASA Astrophysics Data System (ADS)

Richards, Joseph W.; Starr, Dan L.; Miller, Adam A.; Bloom, Joshua S.; Butler, Nathaniel R.; Brink, Henrik; Crellin-Quick, Arien

2012-12-01

With growing data volumes from synoptic surveys, astronomers necessarily must become more abstracted from the discovery and introspection processes. Given the scarcity of follow-up resources, there is a particularly sharp onus on the frameworks that replace these human roles to provide accurate and well-calibrated probabilistic classification catalogs. Such catalogs inform the subsequent follow-up, allowing consumers to optimize the selection of specific sources for further study and permitting rigorous treatment of classification purities and efficiencies for population studies. Here, we describe a process to produce a probabilistic classification catalog of variability with machine learning from a multi-epoch photometric survey. In addition to producing accurate classifications, we show how to estimate calibrated class probabilities and motivate the importance of probability calibration. We also introduce a methodology for feature-based anomaly detection, which allows discovery of objects in the survey that do not fit within the predefined class taxonomy. Finally, we apply these methods to sources observed by the All-Sky Automated Survey (ASAS), and release the Machine-learned ASAS Classification Catalog (MACC), a 28 class probabilistic classification catalog of 50,124 ASAS sources in the ASAS Catalog of Variable Stars. We estimate that MACC achieves a sub-20% classification error rate and demonstrate that the class posterior probabilities are reasonably calibrated. MACC classifications compare favorably to the classifications of several previous domain-specific ASAS papers and to the ASAS Catalog of Variable Stars, which had classified only 24% of those sources into one of 12 science classes.

CONSTRUCTION OF A CALIBRATED PROBABILISTIC CLASSIFICATION CATALOG: APPLICATION TO 50k VARIABLE SOURCES IN THE ALL-SKY AUTOMATED SURVEY

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

Richards, Joseph W.; Starr, Dan L.; Miller, Adam A.

2012-12-15

With growing data volumes from synoptic surveys, astronomers necessarily must become more abstracted from the discovery and introspection processes. Given the scarcity of follow-up resources, there is a particularly sharp onus on the frameworks that replace these human roles to provide accurate and well-calibrated probabilistic classification catalogs. Such catalogs inform the subsequent follow-up, allowing consumers to optimize the selection of specific sources for further study and permitting rigorous treatment of classification purities and efficiencies for population studies. Here, we describe a process to produce a probabilistic classification catalog of variability with machine learning from a multi-epoch photometric survey. In additionmore » to producing accurate classifications, we show how to estimate calibrated class probabilities and motivate the importance of probability calibration. We also introduce a methodology for feature-based anomaly detection, which allows discovery of objects in the survey that do not fit within the predefined class taxonomy. Finally, we apply these methods to sources observed by the All-Sky Automated Survey (ASAS), and release the Machine-learned ASAS Classification Catalog (MACC), a 28 class probabilistic classification catalog of 50,124 ASAS sources in the ASAS Catalog of Variable Stars. We estimate that MACC achieves a sub-20% classification error rate and demonstrate that the class posterior probabilities are reasonably calibrated. MACC classifications compare favorably to the classifications of several previous domain-specific ASAS papers and to the ASAS Catalog of Variable Stars, which had classified only 24% of those sources into one of 12 science classes.« less

A nondestructive method to estimate the chlorophyll content of Arabidopsis seedlings

DOE PAGES

Liang, Ying; Urano, Daisuke; Liao, Kang-Ling; ...

2017-04-14

Chlorophyll content decreases in plants under stress conditions, therefore it is used commonly as an indicator of plant health. Arabidopsis thaliana offers a convenient and fast way to test physiological phenotypes of mutations and treatments. But, chlorophyll measurements with conventional solvent extraction are not applicable to Arabidopsis leaves due to their small size, especially when grown on culture dishes. We provide a nondestructive method for chlorophyll measurement whereby the red, green and blue (RGB) values of a color leaf image is used to estimate the chlorophyll content from Arabidopsis leaves. The method accommodates different profiles of digital cameras by incorporatingmore » the ColorChecker chart to make the digital negative profiles, to adjust the white balance, and to calibrate the exposure rate differences caused by the environment so that this method is applicable in any environment. We chose an exponential function model to estimate chlorophyll content from the RGB values, and fitted the model parameters with physical measurements of chlorophyll contents. As further proof of utility, this method was used to estimate chlorophyll content of G protein mutants grown on different sugar to nitrogen ratios. Our method is a simple, fast, inexpensive, and nondestructive estimation of chlorophyll content of Arabidopsis seedlings. This method lead to the discovery that G proteins are important in sensing the C/N balance to control chlorophyll content in Arabidopsis.« less

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

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.

A comprehensive database of quality-rated fossil ages for Sahul's Quaternary vertebrates.

PubMed

Rodríguez-Rey, Marta; Herrando-Pérez, Salvador; Brook, Barry W; Saltré, Frédérik; Alroy, John; Beeton, Nicholas; Bird, Michael I; Cooper, Alan; Gillespie, Richard; Jacobs, Zenobia; Johnson, Christopher N; Miller, Gifford H; Prideaux, Gavin J; Roberts, Richard G; Turney, Chris S M; Bradshaw, Corey J A

2016-07-19

The study of palaeo-chronologies using fossil data provides evidence for past ecological and evolutionary processes, and is therefore useful for predicting patterns and impacts of future environmental change. However, the robustness of inferences made from fossil ages relies heavily on both the quantity and quality of available data. We compiled Quaternary non-human vertebrate fossil ages from Sahul published up to 2013. This, the FosSahul database, includes 9,302 fossil records from 363 deposits, for a total of 478 species within 215 genera, of which 27 are from extinct and extant megafaunal species (2,559 records). We also provide a rating of reliability of individual absolute age based on the dating protocols and association between the dated materials and the fossil remains. Our proposed rating system identified 2,422 records with high-quality ages (i.e., a reduction of 74%). There are many applications of the database, including disentangling the confounding influences of hypothetical extinction drivers, better spatial distribution estimates of species relative to palaeo-climates, and potentially identifying new areas for fossil discovery.

A comprehensive database of quality-rated fossil ages for Sahul’s Quaternary vertebrates

PubMed Central

Rodríguez-Rey, Marta; Herrando-Pérez, Salvador; Brook, Barry W.; Saltré, Frédérik; Alroy, John; Beeton, Nicholas; Bird, Michael I.; Cooper, Alan; Gillespie, Richard; Jacobs, Zenobia; Johnson, Christopher N.; Miller, Gifford H.; Prideaux, Gavin J.; Roberts, Richard G.; Turney, Chris S.M.; Bradshaw, Corey J.A.

2016-01-01

The study of palaeo-chronologies using fossil data provides evidence for past ecological and evolutionary processes, and is therefore useful for predicting patterns and impacts of future environmental change. However, the robustness of inferences made from fossil ages relies heavily on both the quantity and quality of available data. We compiled Quaternary non-human vertebrate fossil ages from Sahul published up to 2013. This, the FosSahul database, includes 9,302 fossil records from 363 deposits, for a total of 478 species within 215 genera, of which 27 are from extinct and extant megafaunal species (2,559 records). We also provide a rating of reliability of individual absolute age based on the dating protocols and association between the dated materials and the fossil remains. Our proposed rating system identified 2,422 records with high-quality ages (i.e., a reduction of 74%). There are many applications of the database, including disentangling the confounding influences of hypothetical extinction drivers, better spatial distribution estimates of species relative to palaeo-climates, and potentially identifying new areas for fossil discovery. PMID:27434208

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...

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.

Discovery of a main-belt asteroid resembling ordinary chondrite meteorites.

PubMed

Binzel, R P; Xu, S; Bus, S J; Skrutskie, M F; Meyer, M R; Knezek, P; Barker, E S

1993-12-03

Although ordinary chondrite material dominates meteorite falls, the identification of a main-belt asteroid source has remained elusive. From a new survey of more than 80 small main-belt asteroids comes the discovery of one having a visible and near-infrared reflectance spectrum similar to L6 and LL6 ordinary chondrite meteorites. Asteroid 3628 BoZnemcová has an estimated diameter of 7 kilometers and is located in the vicinity of the 3:1 Jovian resonance, a predicted meteorite source region. Although the discovery of a spectral match may indicate the existence of ordinary chondrite material within the main asteroid belt, the paucity of such detections remains an unresolved problem.

Selecting superluminous supernovae in faint galaxies from the first year of the Pan-STARRS1 Medium Deep Survey

NASA Astrophysics Data System (ADS)

McCrum, M.; Smartt, S. J.; Rest, A.; Smith, K.; Kotak, R.; Rodney, S. A.; Young, D. R.; Chornock, R.; Berger, E.; Foley, R. J.; Fraser, M.; Wright, D.; Scolnic, D.; Tonry, J. L.; Urata, Y.; Huang, K.; Pastorello, A.; Botticella, M. T.; Valenti, S.; Mattila, S.; Kankare, E.; Farrow, D. J.; Huber, M. E.; Stubbs, C. W.; Kirshner, R. P.; Bresolin, F.; Burgett, W. S.; Chambers, K. C.; Draper, P. W.; Flewelling, H.; Jedicke, R.; Kaiser, N.; Magnier, E. A.; Metcalfe, N.; Morgan, J. S.; Price, P. A.; Sweeney, W.; Wainscoat, R. J.; Waters, C.

2015-04-01

The Pan-STARRS1 (PS1) survey has obtained imaging in five bands (griz yP1) over 10 Medium Deep Survey (MDS) fields covering a total of 70 square degrees. This paper describes the search for apparently hostless supernovae (SNe) within the first year of PS1 MDS data with an aim of discovering superluminous supernovae (SLSNe). A total of 249 hostless transients were discovered down to a limiting magnitude of MAB ˜ 23.5, of which 76 were classified as Type Ia supernovae (SNe Ia). There were 57 SNe with complete light curves that are likely core-collapse SNe (CCSNe) or type Ic SLSNe and 12 of these have had spectra taken. Of these 12 hostless, non-Type Ia SNe, 7 were SLSNe of type Ic at redshifts between 0.5 and 1.4. This illustrates that the discovery rate of type Ic SLSNe can be maximized by concentrating on hostless transients and removing normal SNe Ia. We present data for two possible SLSNe; PS1-10pm (z = 1.206) and PS1-10ahf (z = 1.1), and estimate the rate of type Ic SLSNe to be between 3^{+3}_{-2}× 10^{-5} and 8^{+2}_{-1}× 10^{-5} that of the CCSN rate within 0.3 ≤ z ≤ 1.4 by applying a Monte Carlo technique. The rate of slowly evolving, type Ic SLSNe (such as SN2007bi) is estimated as a factor of 10 lower than this range.

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.

Estimating the limits of adaptation from historical behaviour: Insights from the American Climate Prospectus

NASA Astrophysics Data System (ADS)

Jina, A.; Hsiang, S. M.; Kopp, R. E., III; Rasmussen, D.; Rising, J.

2014-12-01

The American Climate Prospectus (ACP), the technical analysis underlying the Risky Business project, quantitatively assessed the climate risks posed to the United States' economy in a number of economic sectors [1]. The main analysis presents projections of climate impacts with an assumption of "no adaptation". Yet, historically, when the climate imposed an economic cost upon society, adaptive responses were taken to minimise these costs. These adaptive behaviours, both autonomous and planned, can be expected to occur as climate impacts increase in the future. To understand the extent to which adaptation might decrease some of the worst impacts of climate change, we empirically estimate adaptive responses. We do this in three sectors considered in the analysis - crop yield, crime, and mortality - and estimate adaptive capacity in two steps. First, looking at changes in climate impacts through time, we identify a historical rate of adaptation. Second, spatial differences in climate impacts are then used to stratify regions into more adapted or less adapted based on climate averages. As these averages change across counties in the US, we allow each to become more adapted at the rate identified in step one. We are then able to estimate the residual damages, assuming that only the historical adaptive behaviours have taken place (fig 1). Importantly, we are unable to estimate any costs associated with these adaptations, nor are we able to estimate more novel (for example, new technological discoveries) or more disruptive (for example, migration) adaptive behaviours. However, an important insight is that historical adaptive behaviours may not be capable of reducing the worst impacts of climate change. The persistence of impacts in even the most exposed areas indicates that there are non-trivial costs associated with adaptation that will need to be met from other sources or through novel behavioural changes. References: [1] T. Houser et al. (2014), American Climate Prospectus, www.climateprospectus.org.

A renaissance of neural networks in drug discovery.

PubMed

Baskin, Igor I; Winkler, David; Tetko, Igor V

2016-08-01

Neural networks are becoming a very popular method for solving machine learning and artificial intelligence problems. The variety of neural network types and their application to drug discovery requires expert knowledge to choose the most appropriate approach. In this review, the authors discuss traditional and newly emerging neural network approaches to drug discovery. Their focus is on backpropagation neural networks and their variants, self-organizing maps and associated methods, and a relatively new technique, deep learning. The most important technical issues are discussed including overfitting and its prevention through regularization, ensemble and multitask modeling, model interpretation, and estimation of applicability domain. Different aspects of using neural networks in drug discovery are considered: building structure-activity models with respect to various targets; predicting drug selectivity, toxicity profiles, ADMET and physicochemical properties; characteristics of drug-delivery systems and virtual screening. Neural networks continue to grow in importance for drug discovery. Recent developments in deep learning suggests further improvements may be gained in the analysis of large chemical data sets. It's anticipated that neural networks will be more widely used in drug discovery in the future, and applied in non-traditional areas such as drug delivery systems, biologically compatible materials, and regenerative medicine.

The optimal power puzzle: scrutiny of the monotone likelihood ratio assumption in multiple testing.

PubMed

Cao, Hongyuan; Sun, Wenguang; Kosorok, Michael R

2013-01-01

In single hypothesis testing, power is a non-decreasing function of type I error rate; hence it is desirable to test at the nominal level exactly to achieve optimal power. The puzzle lies in the fact that for multiple testing, under the false discovery rate paradigm, such a monotonic relationship may not hold. In particular, exact false discovery rate control may lead to a less powerful testing procedure if a test statistic fails to fulfil the monotone likelihood ratio condition. In this article, we identify different scenarios wherein the condition fails and give caveats for conducting multiple testing in practical settings.

Advances in genome-wide RNAi cellular screens: a case study using the Drosophila JAK/STAT pathway

PubMed Central

2012-01-01

Background Genome-scale RNA-interference (RNAi) screens are becoming ever more common gene discovery tools. However, whilst every screen identifies interacting genes, less attention has been given to how factors such as library design and post-screening bioinformatics may be effecting the data generated. Results Here we present a new genome-wide RNAi screen of the Drosophila JAK/STAT signalling pathway undertaken in the Sheffield RNAi Screening Facility (SRSF). This screen was carried out using a second-generation, computationally optimised dsRNA library and analysed using current methods and bioinformatic tools. To examine advances in RNAi screening technology, we compare this screen to a biologically very similar screen undertaken in 2005 with a first-generation library. Both screens used the same cell line, reporters and experimental design, with the SRSF screen identifying 42 putative regulators of JAK/STAT signalling, 22 of which verified in a secondary screen and 16 verified with an independent probe design. Following reanalysis of the original screen data, comparisons of the two gene lists allows us to make estimates of false discovery rates in the SRSF data and to conduct an assessment of off-target effects (OTEs) associated with both libraries. We discuss the differences and similarities between the resulting data sets and examine the relative improvements in gene discovery protocols. Conclusions Our work represents one of the first direct comparisons between first- and second-generation libraries and shows that modern library designs together with methodological advances have had a significant influence on genome-scale RNAi screens. PMID:23006893

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

OCEAN: Optimized Cross rEActivity estimatioN.

PubMed

Czodrowski, Paul; Bolick, Wolf-Guido

2016-10-24

The prediction of molecular targets is highly beneficial during the drug discovery process, be it for off-target elucidation or deconvolution of phenotypic screens. Here, we present OCEAN, a target prediction tool exclusively utilizing publically available ChEMBL data. OCEAN uses a heuristics approach based on a validation set containing almost 1000 drug ← → target relationships. New ChEMBL data (ChEMBL20 as well as ChEMBL21) released after the validation was used for a prospective OCEAN performance check. The success rates of OCEAN to predict correctly the targets within the TOP10 ranks are 77% for recently marketed drugs and 62% for all new ChEMBL20 compounds and 51% for all new ChEMBL21 compounds. OCEAN is also capable of identifying polypharmacological compounds; the success rate for molecules simultaneously hitting at least two targets is 64% to be correctly predicted within the TOP10 ranks. The source code of OCEAN can be found at http://www.github.com/rdkit/OCEAN.

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

NASA Astrophysics Data System (ADS)

McLaughlin, Russell L.; Schijven, Dick; van Rheenen, Wouter; van Eijk, Kristel R.; O'Brien, Margaret; Kahn, René S.; Ophoff, Roel A.; Goris, An; Bradley, Daniel G.; Al-Chalabi, Ammar; van den Berg, Leonard H.; Luykx, Jurjen J.; Hardiman, Orla; Veldink, Jan H.; Shatunov, Aleksey; Dekker, Annelot M.; Diekstra, Frank P.; Pulit, Sara L.; van der Spek, Rick A. A.; van Doormaal, Perry T. C.; Sproviero, William; Jones, Ashley R.; Nicholson, Garth A.; Rowe, Dominic B.; Pamphlett, Roger; Kiernan, Matthew C.; Bauer, Denis; Kahlke, Tim; Williams, Kelly; Eftimov, Filip; Fogh, Isabella; Ticozzi, Nicola; Lin, Kuang; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S.; Rojas-García, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E.; Shaw, Pamela J.; Hardy, John; Orrell, Richard W.; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Petri, Susanne; Abdulla, Susanna; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; van Deerlin, Vivianna M.; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Basak, Nazli; Meitinger, Thomas; Lichtner, Peter; Blagojevic-Radivojkov, Milena; Andres, Christian R.; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A. M.; Saker-Delye, Safa; Dürr, Alexandra; Wood, Nicholas; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Nöuthen, Markus M.; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean-François; Uitterlinden, Andre G.; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; van der Kooi, Anneke J.; de Visser, Marianne; Weber, Markus; Shaw, Christopher E.; Smith, Bradley N.; Pansarasa, Orietta; Cereda, Cristina; Del Bo, Roberto; Comi, Giacomo P.; D'Alfonso, Sandra; Bertolin, Cinzia; Sorarù, Gianni; Mazzini, Letizia; Pensato, Viviana; Gellera, Cinzia; Tiloca, Cinzia; Ratti, Antonia; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Arcuti, Simon; Capozzo, Rosa; Zecca, Chiara; Lunetta, Christian; Penco, Silvana; Riva, Nilo; Padovani, Alessandro; Filosto, Massimiliano; Blair, Ian; Leigh, P. Nigel; Casale, Federico; Chio, Adriano; Beghi, Ettore; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Powell, John; Ludolph, Albert C.; Weishaupt, Jochen H.; Robberecht, Wim; van Damme, Philip; Brown, Robert H.; Glass, Jonathan; Landers, John E.; Andersen, Peter M.; Corcia, Philippe; Vourc'h, Patrick; Silani, Vincenzo; van Es, Michael A.; Pasterkamp, R. Jeroen; Lewis, Cathryn M.; Breen, Gerome; Ripke, Stephan; Neale, Benjamin M.; Corvin, Aiden; Walters, James T. R.; Farh, Kai-How; Holmans, Peter A.; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberley D.; Chan, Raymond C. K.; Chan, Ronald Y. L.; Chen, Eric Y. H.; Cheng, Wei; Cheung, Eric F. C.; Chong, Siow Ann; Cloninger, C. Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; Del Favero, Jurgen; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Friedman, Joseph I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Giegling, Ina; Giusti-Rodríguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Golimbet, Vera; Gopal, Srihari; Gratten, Jacob; de Haan, Lieuwe; Hammer, Christian; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V.; Hougaard, David M.; Ikeda, Masashi; Joa, Inge; Julià, Antonio; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Kähler, Anna K.; Laurent, Claudine; Lee, Jimmy; Lee, S. Hong; Legge, Sophie E.; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Loughland, Carmel M.; Lubinski, Jan; Lönnqvist, Jouko; Macek, Milan; Magnusson, Patrik K. E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; McIntosh, Andrew M.; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Mors, Ole; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Müller-Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; O'Neill, F. Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Pejovic-Milovancevic, Milica; Perkins, Diana O.; Pietiläinen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Schubert, Christian R.; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Sigurdsson, Engilbert; Silagadze, Teimuraz; Silverman, Jeremy M.; Sim, Kang; Slominsky, Petr; Smoller, Jordan W.; So, Hon-Cheong; Spencer, Chris C. A.; Stahl, Eli A.; Stefansson, Hreinn; Steinberg, Stacy; Stogmann, Elisabeth; Straub, Richard E.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Söderman, Erik; Thirumalai, Srinivas; Toncheva, Draga; Tosato, Sarah; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H. M.; Wormley, Brandon K.; Xi, Hualin Simon; Zai, Clement C.; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R.; Stefansson, Kari; Visscher, Peter M.; Adolfsson, Rolf; Andreassen, Ole A.; Blackwood, Douglas H. R.; Bramon, Elvira; Buxbaum, Joseph D.; Børglum, Anders D.; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tõnu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jönsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F.; Li, Qingqin S.; Liu, Jianjun; Malhotra, Anil K.; McCarroll, Steven A.; McQuillin, Andrew; Moran, Jennifer L.; Mortensen, Preben B.; Mowry, Bryan J.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos N.; Petryshen, Tracey L.; Posthuma, Danielle; Riley, Brien P.; Rujescu, Dan; Sham, Pak C.; Sklar, Pamela; St Clair, David; Weinberger, Daniel R.; Wendland, Jens R.; Werge, Thomas; Daly, Mark J.; Sullivan, Patrick F.; O'Donovan, Michael C.

2017-03-01

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6 P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia.

PubMed

McLaughlin, Russell L; Schijven, Dick; van Rheenen, Wouter; van Eijk, Kristel R; O'Brien, Margaret; Kahn, René S; Ophoff, Roel A; Goris, An; Bradley, Daniel G; Al-Chalabi, Ammar; van den Berg, Leonard H; Luykx, Jurjen J; Hardiman, Orla; Veldink, Jan H

2017-03-21

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10 -4 ) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10 -7 ). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

Calibrated Multivariate Regression with Application to Neural Semantic Basis Discovery.

PubMed

Liu, Han; Wang, Lie; Zhao, Tuo

2015-08-01

We propose a calibrated multivariate regression method named CMR for fitting high dimensional multivariate regression models. Compared with existing methods, CMR calibrates regularization for each regression task with respect to its noise level so that it simultaneously attains improved finite-sample performance and tuning insensitiveness. Theoretically, we provide sufficient conditions under which CMR achieves the optimal rate of convergence in parameter estimation. Computationally, we propose an efficient smoothed proximal gradient algorithm with a worst-case numerical rate of convergence O (1/ ϵ ), where ϵ is a pre-specified accuracy of the objective function value. We conduct thorough numerical simulations to illustrate that CMR consistently outperforms other high dimensional multivariate regression methods. We also apply CMR to solve a brain activity prediction problem and find that it is as competitive as a handcrafted model created by human experts. The R package camel implementing the proposed method is available on the Comprehensive R Archive Network http://cran.r-project.org/web/packages/camel/.

The Sima de los Huesos hominids date to beyond U/Th equilibrium (>350 kyr) and perhaps to 400-500 kyr: New radiometric dates

USGS Publications Warehouse

Bischoff, J.L.; Shamp, D.D.; Aramburu, Arantza; Arsuaga, J.L.; Carbonell, E.; Bermudez de Castro, Jose Maria

2003-01-01

The Sima de los Huesos site of the Atapuerca complex near Burgos, Spain contains the skeletal remains of at least 28 individuals in a mud breccia underlying an accumulation of the Middle Pleistocene cave bear (U. deningeri). Earlier dating estimates of 200 to 320 kyr were based on U-series and ESR methods applied to bones, made inaccurate by unquantifiable uranium cycling. We report here on a new discovery within the Sima de los Huesos of human bones stratigraphically underlying an in situ speleothem. U-series analyses of the speleothem shows the lower part to be at isotopic U/Th equilibrium, translating to a firm lower limit of 350 kyr for the SH hominids. Finite dates on the upper part suggest a speleothem growth rate of c. 1 cm/32 kyr. This rate, along with paleontological constraints, place the likely age of the hominids in the interval of 400 to 600 kyr. ?? 2002 Elsevier Science Ltd. All rights reserved.

Mixture models for detecting differentially expressed genes in microarrays.

PubMed

Jones, Liat Ben-Tovim; Bean, Richard; McLachlan, Geoffrey J; Zhu, Justin Xi

2006-10-01

An important and common problem in microarray experiments is the detection of genes that are differentially expressed in a given number of classes. As this problem concerns the selection of significant genes from a large pool of candidate genes, it needs to be carried out within the framework of multiple hypothesis testing. In this paper, we focus on the use of mixture models to handle the multiplicity issue. With this approach, a measure of the local FDR (false discovery rate) is provided for each gene. An attractive feature of the mixture model approach is that it provides a framework for the estimation of the prior probability that a gene is not differentially expressed, and this probability can subsequently be used in forming a decision rule. The rule can also be formed to take the false negative rate into account. We apply this approach to a well-known publicly available data set on breast cancer, and discuss our findings with reference to other approaches.

Estimating decay rate of X^{{± }}(5568)→ B_sπ ^{{± }} while assuming them to be molecular states

NASA Astrophysics Data System (ADS)

Ke, Hong-Wei; Li, Xue-Qian

2018-05-01

Discovery of X(5568) brings up a tremendous interest because it is very special, i.e. made of four different flavors. The D0 collaboration claimed that they observed this resonance through portal X(5568)→ B_sπ , but unfortunately, later the LHCb, CMS, CDF and ATLAS collaborations' reports indicate that no such state was found. Almost on the Eve of 2017, the D0 collaboration reconfirmed existence of X(5568) via the semileptonic decay of B_s. To further reveal the discrepancy, supposing X(5568) as a molecular state, we calculate the decay rate of X(5568)→ B_sπ ^+ in an extended light front model. Numerically, the theoretically predicted decay width of Γ (X(5568)→ B_sπ ^+) is 20.28 MeV which is consistent with the result of the D0 collaboration (Γ =18.6^{+7.9}_{-6.1}({it{stat}})^{+3.5}_{-3.8}({it{syst}}) MeV). Since the resonance is narrow, signals might be drowned in a messy background. In analog, two open-charm molecular states DK and BD named as X_a and X_b, could be in the same situation. The rates of X_a→ D_sπ ^0 and X_b→ B_cπ ^0 are estimated as about 30 and 20 MeV respectively. We suggest the experimental collaborations round the world to search for these two modes and accurate measurements may provide us with valuable information.

COLDz: KARL G. JANSKY VERY LARGE ARRAY DISCOVERY OF A GAS-RICH GALAXY IN COSMOS

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

Lentati, L.; Wagg, J.; Carilli, C. L.

2015-02-10

The broad spectral bandwidth at millimeter and centimeter wavelengths provided by the recent upgrades to the Karl G. Jansky Very Large Array (VLA) has made it possible to conduct unbiased searches for molecular CO line emission at redshifts, z > 1.31. We present the discovery of a gas-rich, star-forming galaxy at z = 2.48 through the detection of CO J = 1-0 line emission in the COLDz survey and through a sensitive, Ka-band (31-39 GHz) VLA survey of a 6.5 arcmin{sup 2} region of the COSMOS field. We argue that the broad line (FWHM ∼ 570 ± 80 km s{supmore » –1}) is most likely to be CO J = 1-0 at z = 2.48, as the integrated emission is spatially coincident with an infrared-detected galaxy with a photometric redshift estimate of z {sub phot} = 3.2 ± 0.4. The CO J = 1-0 line luminosity is L{sub CO}{sup ′}=(2.2±0.3)×10{sup 10} K km s{sup –1} pc{sup 2}, suggesting a cold molecular gas mass of M {sub gas} ∼ (2-8) × 10{sup 10} M {sub ☉} depending on the assumed value of the molecular gas mass to CO luminosity ratio α{sub CO}. The estimated infrared luminosity from the (rest-frame) far-infrared spectral energy distribution (SED) is L {sub IR} = 2.5 × 10{sup 12} L {sub ☉} and the star formation rate is ∼250 M {sub ☉} yr{sup –1}, with the SED shape indicating substantial dust obscuration of the stellar light. The infrared to CO line luminosity ratio is ∼114 ± 19 L {sub ☉}/(K km s{sup –1} pc{sup 2}), similar to galaxies with similar SFRs selected at UV/optical to radio wavelengths. This discovery confirms the potential for molecular emission line surveys as a route to study populations of gas-rich galaxies in the future.« less

A Scientometric Prediction of the Discovery of the First Potentially Habitable Planet with a Mass Similar to Earth

PubMed Central

Arbesman, Samuel; Laughlin, Gregory

2010-01-01

Background The search for a habitable extrasolar planet has long interested scientists, but only recently have the tools become available to search for such planets. In the past decades, the number of known extrasolar planets has ballooned into the hundreds, and with it, the expectation that the discovery of the first Earth-like extrasolar planet is not far off. Methodology/Principal Findings Here, we develop a novel metric of habitability for discovered planets and use this to arrive at a prediction for when the first habitable planet will be discovered. Using a bootstrap analysis of currently discovered exoplanets, we predict the discovery of the first Earth-like planet to be announced in the first half of 2011, with the likeliest date being early May 2011. Conclusions/Significance Our predictions, using only the properties of previously discovered exoplanets, accord well with external estimates for the discovery of the first potentially habitable extrasolar planet and highlight the the usefulness of predictive scientometric techniques to understand the pace of scientific discovery in many fields. PMID:20957226

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

A Tutorial on Multiple Testing: False Discovery Control

NASA Astrophysics Data System (ADS)

Chatelain, F.

2016-09-01

This paper presents an overview of criteria and methods in multiple testing, with an emphasis on the false discovery rate control. The popular Benjamini and Hochberg procedure is described. The rationale for this approach is explained through a simple Bayesian interpretation. Some state-of-the-art variations and extensions are also presented.

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

The promise of discovering population-specific disease-associated genes in South Asia.

PubMed

Nakatsuka, Nathan; Moorjani, Priya; Rai, Niraj; Sarkar, Biswanath; Tandon, Arti; Patterson, Nick; Bhavani, Gandham SriLakshmi; Girisha, Katta Mohan; Mustak, Mohammed S; Srinivasan, Sudha; Kaushik, Amit; Vahab, Saadi Abdul; Jagadeesh, Sujatha M; Satyamoorthy, Kapaettu; Singh, Lalji; Reich, David; Thangaraj, Kumarasamy

2017-09-01

The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identified 81 unique groups, 14 of which had estimated census sizes of more than 1 million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identified multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an underappreciated opportunity for decreasing disease burden among South Asians through discovery of and testing for recessive disease-associated genes.

Maximum number of habitable planets at the time of Earth's origin: new hints for panspermia?

PubMed

von Bloh, Werner; Franck, Siegfried; Bounama, Christine; Schellnhuber, Hans-Joachim

2003-04-01

New discoveries have fuelled the ongoing discussion of panspermia, i.e. the transport of life from one planet to another within the solar system (interplanetary panspermia) or even between different planetary systems (interstellar panspermia). The main factor for the probability of interstellar panspermia is the average density of stellar systems containing habitable planets. The combination of recent results for the formation rate of Earth-like planets with our estimations of extrasolar habitable zones allows us to determine the number of habitable planets in the Milky Way over cosmological time scales. We find that there was a maximum number of habitable planets around the time of Earth's origin. If at all, interstellar panspermia was most probable at that time and may have kick-started life on our planet.

Systematic modelling and design evaluation of unperturbed tumour dynamics in xenografts.

PubMed

Parra Guillen, Zinnia P Patricia; Mangas Sanjuan, Victor; Garcia-Cremades, Maria; Troconiz, Inaki F; Mo, Gary; Pitou, Celine; Iversen, Philip W; Wallin, Johan E

2018-04-24

Xenograft mice are largely used to evaluate the efficacy of oncological drugs during preclinical phases of drug discovery and development. Mathematical models provide a useful tool to quantitatively characterise tumour growth dynamics and also optimise upcoming experiments. To the best of our knowledge, this is the first report where unperturbed growth of a large set of tumour cell lines (n=28) has been systematically analysed using the model proposed by Simeoni in the context of non-linear mixed effect (NLME). Exponential growth was identified as the governing mechanism in the majority of the cell lines, with constant rate values ranging from 0.0204 to 0.203 day -1 No common patterns could be observed across tumour types, highlighting the importance of combining information from different cell lines when evaluating drug activity. Overall, typical model parameters were precisely estimated using designs where tumour size measurements were taken every two days. Moreover, reducing the number of measurement to twice per week, or even once per week for cell lines with low growth rates, showed little impact on parameter precision. However, in order to accurately characterise parameter variability (i.e. relative standard errors below 50%), a sample size of at least 50 mice is needed. This work illustrates the feasibility to systematically apply NLME models to characterise tumour growth in drug discovery and development, and constitutes a valuable source of data to optimise experimental designs by providing an a priori sampling window and minimising the number of samples required. The American Society for Pharmacology and Experimental Therapeutics.

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.

DNA barcoding a nightmare taxon: assessing barcode index numbers and barcode gaps for sweat bees.

PubMed

Gibbs, Jason

2018-01-01

There is an ongoing campaign to DNA barcode the world's >20 000 bee species. Recent revisions of Lasioglossum (Dialictus) (Hymenoptera: Halictidae) for Canada and the eastern United States were completed using integrative taxonomy. DNA barcode data from 110 species of L. (Dialictus) are examined for their value in identification and discovering additional taxonomic diversity. Specimen identification success was estimated using the best close match method. Error rates were 20% relative to current taxonomic understanding. Barcode Index Numbers (BINs) assigned using Refined Single Linkage Analysis (RESL) and barcode gaps using the Automatic Barcode Gap Discovery (ABGD) method were also assessed. RESL was incongruent for 44.5% of species, although some cryptic diversity may exist. Forty-three of 110 species were part of merged BINs with multiple species. The barcode gap is non-existent for the data set as a whole and ABGD showed levels of discordance similar to the RESL. The viridatum species-group is particularly problematic, so that DNA barcodes alone would be misleading for species delimitation and specimen identification. Character-based methods using fixed nucleotide substitutions could improve specimen identification success in some cases. The use of DNA barcoding for species discovery for standard taxonomic practice in the absence of a well-defined barcode gap is discussed.

Accurate Evaluation Method of Molecular Binding Affinity from Fluctuation Frequency

NASA Astrophysics Data System (ADS)

Hoshino, Tyuji; Iwamoto, Koji; Ode, Hirotaka; Ohdomari, Iwao

2008-05-01

Exact estimation of the molecular binding affinity is significantly important for drug discovery. The energy calculation is a direct method to compute the strength of the interaction between two molecules. This energetic approach is, however, not accurate enough to evaluate a slight difference in binding affinity when distinguishing a prospective substance from dozens of candidates for medicine. Hence more accurate estimation of drug efficacy in a computer is currently demanded. Previously we proposed a concept of estimating molecular binding affinity, focusing on the fluctuation at an interface between two molecules. The aim of this paper is to demonstrate the compatibility between the proposed computational technique and experimental measurements, through several examples for computer simulations of an association of human immunodeficiency virus type-1 (HIV-1) protease and its inhibitor (an example for a drug-enzyme binding), a complexation of an antigen and its antibody (an example for a protein-protein binding), and a combination of estrogen receptor and its ligand chemicals (an example for a ligand-receptor binding). The proposed affinity estimation has proven to be a promising technique in the advanced stage of the discovery and the design of drugs.

A Projection and Density Estimation Method for Knowledge Discovery

PubMed Central

Stanski, Adam; Hellwich, Olaf

2012-01-01

A key ingredient to modern data analysis is probability density estimation. However, it is well known that the curse of dimensionality prevents a proper estimation of densities in high dimensions. The problem is typically circumvented by using a fixed set of assumptions about the data, e.g., by assuming partial independence of features, data on a manifold or a customized kernel. These fixed assumptions limit the applicability of a method. In this paper we propose a framework that uses a flexible set of assumptions instead. It allows to tailor a model to various problems by means of 1d-decompositions. The approach achieves a fast runtime and is not limited by the curse of dimensionality as all estimations are performed in 1d-space. The wide range of applications is demonstrated at two very different real world examples. The first is a data mining software that allows the fully automatic discovery of patterns. The software is publicly available for evaluation. As a second example an image segmentation method is realized. It achieves state of the art performance on a benchmark dataset although it uses only a fraction of the training data and very simple features. PMID:23049675

Better cancer biomarker discovery through better study design.

PubMed

Rundle, Andrew; Ahsan, Habibul; Vineis, Paolo

2012-12-01

High-throughput laboratory technologies coupled with sophisticated bioinformatics algorithms have tremendous potential for discovering novel biomarkers, or profiles of biomarkers, that could serve as predictors of disease risk, response to treatment or prognosis. We discuss methodological issues in wedding high-throughput approaches for biomarker discovery with the case-control study designs typically used in biomarker discovery studies, especially focusing on nested case-control designs. We review principles for nested case-control study design in relation to biomarker discovery studies and describe how the efficiency of biomarker discovery can be effected by study design choices. We develop a simulated prostate cancer cohort data set and a series of biomarker discovery case-control studies nested within the cohort to illustrate how study design choices can influence biomarker discovery process. Common elements of nested case-control design, incidence density sampling and matching of controls to cases are not typically factored correctly into biomarker discovery analyses, inducing bias in the discovery process. We illustrate how incidence density sampling and matching of controls to cases reduce the apparent specificity of truly valid biomarkers 'discovered' in a nested case-control study. We also propose and demonstrate a new case-control matching protocol, we call 'antimatching', that improves the efficiency of biomarker discovery studies. For a valid, but as yet undiscovered, biomarker(s) disjunctions between correctly designed epidemiologic studies and the practice of biomarker discovery reduce the likelihood that true biomarker(s) will be discovered and increases the false-positive discovery rate. © 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.

On the Relationship between Molecular Hit Rates in High-Throughput Screening and Molecular Descriptors.

PubMed

Hansson, Mari; Pemberton, John; Engkvist, Ola; Feierberg, Isabella; Brive, Lars; Jarvis, Philip; Zander-Balderud, Linda; Chen, Hongming

2014-06-01

High-throughput screening (HTS) is widely used in the pharmaceutical industry to identify novel chemical starting points for drug discovery projects. The current study focuses on the relationship between molecular hit rate in recent in-house HTS and four common molecular descriptors: lipophilicity (ClogP), size (heavy atom count, HEV), fraction of sp(3)-hybridized carbons (Fsp3), and fraction of molecular framework (f(MF)). The molecular hit rate is defined as the fraction of times the molecule has been assigned as active in the HTS campaigns where it has been screened. Beta-binomial statistical models were built to model the molecular hit rate as a function of these descriptors. The advantage of the beta-binomial statistical models is that the correlation between the descriptors is taken into account. Higher degree polynomial terms of the descriptors were also added into the beta-binomial statistic model to improve the model quality. The relative influence of different molecular descriptors on molecular hit rate has been estimated, taking into account that the descriptors are correlated to each other through applying beta-binomial statistical modeling. The results show that ClogP has the largest influence on the molecular hit rate, followed by Fsp3 and HEV. f(MF) has only a minor influence besides its correlation with the other molecular descriptors. © 2013 Society for Laboratory Automation and Screening.

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

Y-chromosome diversity in Catalan surname samples: insights into surname origin and frequency

PubMed Central

Solé-Morata, Neus; Bertranpetit, Jaume; Comas, David; Calafell, Francesc

2015-01-01

The biological behavior of the Y chromosome, which is paternally inherited, implies that males sharing the same surname may also share a similar Y chromosome. However, socio-cultural factors, such as polyphyletism, non-paternity, adoption, or matrilineal surname transmission, may prevent the joint transmission of the surname and the Y chromosome. By genotyping 17 Y-STRs and 68 SNPs in ~2500 male samples that each carried one of the 50 selected Catalan surnames, we could determine sets of descendants of a common ancestor, the population of origin of the common ancestor, and the date when such a common ancestor lived. Haplotype diversity was positively correlated with surname frequency, that is, rarer surnames showed the strongest signals of coancestry. Introgression rates of Y chromosomes into a surname by non-paternity, adoption, and transmission of the maternal surname were estimated at 1.5−2.6% per generation, with some local variation. Average ages for the founders of the surnames were estimated at ~500 years, suggesting a delay between the origin of surnames (twelfth and thirteenth centuries) and the systematization of their paternal transmission. We have found that, in general, a foreign etymology for a surname does not often result in a non-indigenous origin of surname founders; however, bearers of some surnames with an Arabic etymology show an excess of North African haplotypes. Finally, we estimate that surname prediction from a Y-chromosome haplotype, which may have interesting forensic applications, has a ~60% sensitivity but a 17% false discovery rate. PMID:25689924

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

Assessing differential expression in two-color microarrays: a resampling-based empirical Bayes approach.

PubMed

Li, Dongmei; Le Pape, Marc A; Parikh, Nisha I; Chen, Will X; Dye, Timothy D

2013-01-01

Microarrays are widely used for examining differential gene expression, identifying single nucleotide polymorphisms, and detecting methylation loci. Multiple testing methods in microarray data analysis aim at controlling both Type I and Type II error rates; however, real microarray data do not always fit their distribution assumptions. Smyth's ubiquitous parametric method, for example, inadequately accommodates violations of normality assumptions, resulting in inflated Type I error rates. The Significance Analysis of Microarrays, another widely used microarray data analysis method, is based on a permutation test and is robust to non-normally distributed data; however, the Significance Analysis of Microarrays method fold change criteria are problematic, and can critically alter the conclusion of a study, as a result of compositional changes of the control data set in the analysis. We propose a novel approach, combining resampling with empirical Bayes methods: the Resampling-based empirical Bayes Methods. This approach not only reduces false discovery rates for non-normally distributed microarray data, but it is also impervious to fold change threshold since no control data set selection is needed. Through simulation studies, sensitivities, specificities, total rejections, and false discovery rates are compared across the Smyth's parametric method, the Significance Analysis of Microarrays, and the Resampling-based empirical Bayes Methods. Differences in false discovery rates controls between each approach are illustrated through a preterm delivery methylation study. The results show that the Resampling-based empirical Bayes Methods offer significantly higher specificity and lower false discovery rates compared to Smyth's parametric method when data are not normally distributed. The Resampling-based empirical Bayes Methods also offers higher statistical power than the Significance Analysis of Microarrays method when the proportion of significantly differentially expressed genes is large for both normally and non-normally distributed data. Finally, the Resampling-based empirical Bayes Methods are generalizable to next generation sequencing RNA-seq data analysis.

Testing a single regression coefficient in high dimensional linear models

PubMed Central

Zhong, Ping-Shou; Li, Runze; Wang, Hansheng; Tsai, Chih-Ling

2017-01-01

In linear regression models with high dimensional data, the classical z-test (or t-test) for testing the significance of each single regression coefficient is no longer applicable. This is mainly because the number of covariates exceeds the sample size. In this paper, we propose a simple and novel alternative by introducing the Correlated Predictors Screening (CPS) method to control for predictors that are highly correlated with the target covariate. Accordingly, the classical ordinary least squares approach can be employed to estimate the regression coefficient associated with the target covariate. In addition, we demonstrate that the resulting estimator is consistent and asymptotically normal even if the random errors are heteroscedastic. This enables us to apply the z-test to assess the significance of each covariate. Based on the p-value obtained from testing the significance of each covariate, we further conduct multiple hypothesis testing by controlling the false discovery rate at the nominal level. Then, we show that the multiple hypothesis testing achieves consistent model selection. Simulation studies and empirical examples are presented to illustrate the finite sample performance and the usefulness of the proposed method, respectively. PMID:28663668

Testing a single regression coefficient in high dimensional linear models.

PubMed

Lan, Wei; Zhong, Ping-Shou; Li, Runze; Wang, Hansheng; Tsai, Chih-Ling

2016-11-01

In linear regression models with high dimensional data, the classical z -test (or t -test) for testing the significance of each single regression coefficient is no longer applicable. This is mainly because the number of covariates exceeds the sample size. In this paper, we propose a simple and novel alternative by introducing the Correlated Predictors Screening (CPS) method to control for predictors that are highly correlated with the target covariate. Accordingly, the classical ordinary least squares approach can be employed to estimate the regression coefficient associated with the target covariate. In addition, we demonstrate that the resulting estimator is consistent and asymptotically normal even if the random errors are heteroscedastic. This enables us to apply the z -test to assess the significance of each covariate. Based on the p -value obtained from testing the significance of each covariate, we further conduct multiple hypothesis testing by controlling the false discovery rate at the nominal level. Then, we show that the multiple hypothesis testing achieves consistent model selection. Simulation studies and empirical examples are presented to illustrate the finite sample performance and the usefulness of the proposed method, respectively.

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

UCAC3 PROPER MOTION SURVEY. I. DISCOVERY OF NEW PROPER MOTION STARS IN UCAC3 WITH 0.''40 yr{sup -1} > {mu} {>=} 0.''18 yr{sup -1} BETWEEN DECLINATIONS -90{sup 0} AND -47{sup 0}

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

Finch, Charlie T.; Zacharias, Norbert; Henry, Todd J., E-mail: finch@usno.navy.mi

2010-09-15

This paper presents 442 new proper motion stellar systems in the southern sky between declinations -90{sup 0} and -47{sup 0} with 0.''40 yr{sup -1} > {mu} {>=} 0.''18 yr{sup -1}. These systems constitute a 25.3% increase in new systems for the same region of the sky covered by previous SuperCOSMOS RECONS (SCR) searches that used Schmidt plates as the primary source of discovery. Among the new systems are 25 multiples, plus an additional 7 new common proper motion (CPM) companions to previously known primaries. All stars have been discovered using the third U.S. Naval Observatory (USNO) CCD Astrograph Catalog (UCAC3).more » A comparison of the UCAC3 proper motions to those from the Hipparcos, Tycho-2, Southern Proper Motion (SPM4), and SuperCOSMOS efforts is presented and shows that UCAC3 provides similar values and precision to the first three surveys. The comparison between UCAC3 and SuperCOSMOS indicates that proper motions in R.A. are systematically shifted in the SuperCOSMOS data but are consistent in decl. data, while overall showing a significantly higher scatter. Distance estimates are derived for stars having SuperCOSMOS Sky Survey B{sub J} , R{sub 59F}, and I{sub IVN} plate magnitudes and Two-Micron All Sky Survey infrared photometry. We find 15 systems estimated to be within 25 pc, including UPM 1710-5300 our closest new discovery estimated at 13.5 pc. Such new discoveries suggest that more nearby stars are yet to be found in these slower proper motion regimes, indicating that more work is needed to develop a complete map of the solar neighborhood.« less

Tick-Borne Pathogen – Reversed and Conventional Discovery of Disease

PubMed Central

Tijsse-Klasen, Ellen; Koopmans, Marion P. G.; Sprong, Hein

2014-01-01

Molecular methods have increased the number of known microorganisms associated with ticks significantly. Some of these newly identified microorganisms are readily linked to human disease while others are yet unknown to cause human disease. The face of tick-borne disease discovery has changed with more diseases now being discovered in a “reversed way,” detecting disease cases only years after the tick-borne microorganism was first discovered. Compared to the conventional discovery of infectious diseases, reverse order discovery presents researchers with new challenges. Estimating public health risks of such agents is especially challenging, as case definitions and diagnostic procedures may initially be missing. We discuss the advantages and shortcomings of molecular methods, serology, and epidemiological studies that might be used to study some fundamental questions regarding newly identified tick-borne diseases. With increased tick-exposure and improved detection methods, more tick-borne microorganisms will be added to the list of pathogens causing disease in humans in the future. PMID:25072045

Object-graphs for context-aware visual category discovery.

PubMed

Lee, Yong Jae; Grauman, Kristen

2012-02-01

How can knowing about some categories help us to discover new ones in unlabeled images? Unsupervised visual category discovery is useful to mine for recurring objects without human supervision, but existing methods assume no prior information and thus tend to perform poorly for cluttered scenes with multiple objects. We propose to leverage knowledge about previously learned categories to enable more accurate discovery, and address challenges in estimating their familiarity in unsegmented, unlabeled images. We introduce two variants of a novel object-graph descriptor to encode the 2D and 3D spatial layout of object-level co-occurrence patterns relative to an unfamiliar region and show that by using them to model the interaction between an image’s known and unknown objects, we can better detect new visual categories. Rather than mine for all categories from scratch, our method identifies new objects while drawing on useful cues from familiar ones. We evaluate our approach on several benchmark data sets and demonstrate clear improvements in discovery over conventional purely appearance-based baselines.

Cosmic Discovery

NASA Astrophysics Data System (ADS)

Harwit, Martin

1984-04-01

In the remarkable opening section of this book, a well-known Cornell astronomer gives precise thumbnail histories of the 43 basic cosmic discoveries - stars, planets, novae, pulsars, comets, gamma-ray bursts, and the like - that form the core of our knowledge of the universe. Many of them, he points out, were made accidentally and outside the mainstream of astronomical research and funding. This observation leads him to speculate on how many more major phenomena there might be and how they might be most effectively sought out in afield now dominated by large instruments and complex investigative modes and observational conditions. The book also examines discovery in terms of its political, financial, and sociological context - the role of new technologies and of industry and the military in revealing new knowledge; and methods of funding, of peer review, and of allotting time on our largest telescopes. It concludes with specific recommendations for organizing astronomy in ways that will best lead to the discovery of the many - at least sixty - phenomena that Harwit estimates are still waiting to be found.

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.

Novel opportunities for computational biology and sociology in drug discovery☆

PubMed Central

Yao, Lixia; Evans, James A.; Rzhetsky, Andrey

2013-01-01

Current drug discovery is impossible without sophisticated modeling and computation. In this review we outline previous advances in computational biology and, by tracing the steps involved in pharmaceutical development, explore a range of novel, high-value opportunities for computational innovation in modeling the biological process of disease and the social process of drug discovery. These opportunities include text mining for new drug leads, modeling molecular pathways and predicting the efficacy of drug cocktails, analyzing genetic overlap between diseases and predicting alternative drug use. Computation can also be used to model research teams and innovative regions and to estimate the value of academy–industry links for scientific and human benefit. Attention to these opportunities could promise punctuated advance and will complement the well-established computational work on which drug discovery currently relies. PMID:20349528

Searches for new Milky Way satellites from the first two years of data of the Subaru/Hyper Suprime-Cam survey: Discovery of Cetus III

NASA Astrophysics Data System (ADS)

Homma, Daisuke; Chiba, Masashi; Okamoto, Sakurako; Komiyama, Yutaka; Tanaka, Masayuki; Tanaka, Mikito; Ishigaki, Miho N.; Hayashi, Kohei; Arimoto, Nobuo; Garmilla, José A.; Lupton, Robert H.; Strauss, Michael A.; Miyazaki, Satoshi; Wang, Shiang-Yu; Murayama, Hitoshi

2018-01-01

We present the results from a search for new Milky Way (MW) satellites from the first two years of data from the Hyper Suprime-Cam (HSC) Subaru Strategic Program (SSP) ˜300 deg2 and report the discovery of a highly compelling ultra-faint dwarf galaxy candidate in Cetus. This is the second ultra-faint dwarf we have discovered after Virgo I reported in our previous paper. This satellite, Cetus III, has been identified as a statistically significant (10.7 σ) spatial overdensity of star-like objects, which are selected from a relevant isochrone filter designed for a metal-poor and old stellar population. This stellar system is located at a heliocentric distance of 251^{+24}_{-11}kpc with a most likely absolute magnitude of MV = -2.4 ± 0.6 mag estimated from a Monte Carlo analysis. Cetus III is extended with a half-light radius of r_h = 90^{+42}_{-17}pc, suggesting that this is a faint dwarf satellite in the MW located beyond the detection limit of the Sloan Digital Sky Survey. Further spectroscopic studies are needed to assess the nature of this stellar system. We also revisit and update the parameters for Virgo I, finding M_V = -0.33^{+0.75}_{-0.87}mag and r_h = 47^{+19}_{-13}pc. Using simulations of Λ-dominated cold dark matter models, we predict that we should find one or two new MW satellites from ˜300 deg2 HSC-SSP data, in rough agreement with the discovery rate so far. The further survey and completion of HSC-SSP over ˜1400 deg2 will provide robust insights into the missing satellites problem.

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.

Exploring the Role of Receptor Flexibility in Structure-Based Drug Discovery

PubMed Central

Feixas, Ferran; Lindert, Steffen; Sinko, William; McCammon, J. Andrew

2015-01-01

The proper understanding of biomolecular recognition mechanisms that take place in a drug target is of paramount importance to improve the efficiency of drug discovery and development. The intrinsic dynamic character of proteins has a strong influence on biomolecular recognition mechanisms and models such as conformational selection have been widely used to account for this dynamic association process. However, conformational changes occurring in the receptor prior and upon association with other molecules are diverse and not obvious to predict when only a few structures of the receptor are available. In view of the prominent role of protein flexibility in ligand binding and its implications for drug discovery, it is of great interest to identify receptor conformations that play a major role in biomolecular recognition before starting rational drug design efforts. In this review, we discuss a number of recent advances in computer-aided drug discovery techniques that have been proposed to incorporate receptor flexibility into structure-based drug design. The allowance for receptor flexibility provided by computational techniques such as molecular dynamics simulations or enhanced sampling techniques helps to improve the accuracy of methods used to estimate binding affinities and, thus, such methods can contribute to the discovery of novel drug leads. PMID:24332165

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.

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)

Pulsations, Shocks, and Mass Loss

NASA Technical Reports Server (NTRS)

Bally, John

1998-01-01

This grant provided long-term support for my investigation of the outflows powered by young stars. Several major research results emerged during the course of this research, including: (1) The discovery of giant Herbig-Haro outflows from young stars that can extend for many parsecs from their sources. The first parsec-scale outflow to be recognized led to the realization that Herbig-Haro outflows, even those produced by low mass young stellar objects, can extend orders of magnitude farther from their sources than previously thought. Our preconceptions were to a large extent driven by the narrow fields-of-view then provided by CCD detectors. With the recent advent of large format CCDs and CCD mosaics, we have come to realize that most outflows attain parsec-scale dimensions. Even at the distance of the Orion star forming clouds, such flows can subtend a degree on the sky. Our work has led to the recognition of over two dozen giant. (2) The discovery that outflows are highly clustered. Even regions of relatively isolated star formation such as those in Taurus frequently produce multiple outflows. (3) The discovery of a new family of externally irradiated jets. During the last year of support from this grant, we made the startling discovery that there is a class of jets from young stars that are illuminated by the ionizing radiation field of nearby massive stars. The first four examples were discovered in the vicinity of the a Orionis sub-group of the Orion OB Association which is believed to be at least 2 million years old. Since the jets are photo-ionized, their densities can be reliably estimated. Most HH jets are shock excited, and are therefore notoriously difficult to characterize since their visibility and observed properties depend on the complex and highly non-linear processes associated with shocks. Furthermore, many irradiated jets are one sided rather than bipolar. Thus, irradiated jets may for the first time be used to accurately diagnose jet densities and mass loss rates, and to probe the physics of jet collimation, and may indicate that the jet production phase of certain young stars may last more than a million years. These three discoveries provide us with fundamental new insights into the star formation process, into the physical conditions inside and near star forming clouds, and into new ways to probe the physics and chemistry of such clouds.

Discovery of a bright microlensing event with planetary features towards the Taurus region: a super-Earth planet

NASA Astrophysics Data System (ADS)

Nucita, A. A.; Licchelli, D.; De Paolis, F.; Ingrosso, G.; Strafella, F.; Katysheva, N.; Shugarov, S.

2018-05-01

The transient event labelled as TCP J05074264+2447555 recently discovered towards the Taurus region was quickly recognized to be an ongoing microlensing event on a source located at distance of only 700-800 pc from Earth. Here, we show that observations with high sampling rate close to the time of maximum magnification revealed features that imply the presence of a binary lens system with very low-mass ratio components. We present a complete description of the binary lens system, which host an Earth-like planet with most likely mass of 9.2 ± 6.6 M⊕. Furthermore, the source estimated location and detailed Monte Carlo simulations allowed us to classify the event as due to the closest lens system, being at a distance of ≃380 pc and mass ≃0.25 M⊙.

76 FR 77029 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-09

... statement made pursuant to section 19(a) or in the first report to shareholders following the discovery of... impression of fund gains. Based on a review of filings made with the Commission, the staff estimates that...

Estimating the domain of applicability for machine learning QSAR models: a study on aqueous solubility of drug discovery molecules.

PubMed

Schroeter, Timon Sebastian; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-12-01

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability (DOA) for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process (GP)), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.

Estimating the domain of applicability for machine learning QSAR models: a study on aqueous solubility of drug discovery molecules.

PubMed

Schroeter, Timon Sebastian; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-09-01

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability (DOA) for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process (GP)), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.

Compositional descriptor-based recommender system for the materials discovery

NASA Astrophysics Data System (ADS)

Seko, Atsuto; Hayashi, Hiroyuki; Tanaka, Isao

2018-06-01

Structures and properties of many inorganic compounds have been collected historically. However, it only covers a very small portion of possible inorganic crystals, which implies the presence of numerous currently unknown compounds. A powerful machine-learning strategy is mandatory to discover new inorganic compounds from all chemical combinations. Herein we propose a descriptor-based recommender-system approach to estimate the relevance of chemical compositions where crystals can be formed [i.e., chemically relevant compositions (CRCs)]. In addition to data-driven compositional similarity used in the literature, the use of compositional descriptors as a prior knowledge is helpful for the discovery of new compounds. We validate our recommender systems in two ways. First, one database is used to construct a model, while another is used for the validation. Second, we estimate the phase stability for compounds at expected CRCs using density functional theory calculations.

Estimating the domain of applicability for machine learning QSAR models: a study on aqueous solubility of drug discovery molecules

NASA Astrophysics Data System (ADS)

Schroeter, Timon Sebastian; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-12-01

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability (DOA) for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process (GP)), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.

Estimating the domain of applicability for machine learning QSAR models: a study on aqueous solubility of drug discovery molecules

NASA Astrophysics Data System (ADS)

Schroeter, Timon Sebastian; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-09-01

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability (DOA) for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process (GP)), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.

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

Jointly determining significance levels of primary and replication studies by controlling the false discovery rate in two-stage genome-wide association studies.

PubMed

Jiang, Wei; Yu, Weichuan

2017-01-01

In genome-wide association studies, we normally discover associations between genetic variants and diseases/traits in primary studies, and validate the findings in replication studies. We consider the associations identified in both primary and replication studies as true findings. An important question under this two-stage setting is how to determine significance levels in both studies. In traditional methods, significance levels of the primary and replication studies are determined separately. We argue that the separate determination strategy reduces the power in the overall two-stage study. Therefore, we propose a novel method to determine significance levels jointly. Our method is a reanalysis method that needs summary statistics from both studies. We find the most powerful significance levels when controlling the false discovery rate in the two-stage study. To enjoy the power improvement from the joint determination method, we need to select single nucleotide polymorphisms for replication at a less stringent significance level. This is a common practice in studies designed for discovery purpose. We suggest this practice is also suitable in studies with validation purpose in order to identify more true findings. Simulation experiments show that our method can provide more power than traditional methods and that the false discovery rate is well-controlled. Empirical experiments on datasets of five diseases/traits demonstrate that our method can help identify more associations. The R-package is available at: http://bioinformatics.ust.hk/RFdr.html .

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.

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.

Shrinkage estimation of effect sizes as an alternative to hypothesis testing followed by estimation in high-dimensional biology: applications to differential gene expression.

PubMed

Montazeri, Zahra; Yanofsky, Corey M; Bickel, David R

2010-01-01

Research on analyzing microarray data has focused on the problem of identifying differentially expressed genes to the neglect of the problem of how to integrate evidence that a gene is differentially expressed with information on the extent of its differential expression. Consequently, researchers currently prioritize genes for further study either on the basis of volcano plots or, more commonly, according to simple estimates of the fold change after filtering the genes with an arbitrary statistical significance threshold. While the subjective and informal nature of the former practice precludes quantification of its reliability, the latter practice is equivalent to using a hard-threshold estimator of the expression ratio that is not known to perform well in terms of mean-squared error, the sum of estimator variance and squared estimator bias. On the basis of two distinct simulation studies and data from different microarray studies, we systematically compared the performance of several estimators representing both current practice and shrinkage. We find that the threshold-based estimators usually perform worse than the maximum-likelihood estimator (MLE) and they often perform far worse as quantified by estimated mean-squared risk. By contrast, the shrinkage estimators tend to perform as well as or better than the MLE and never much worse than the MLE, as expected from what is known about shrinkage. However, a Bayesian measure of performance based on the prior information that few genes are differentially expressed indicates that hard-threshold estimators perform about as well as the local false discovery rate (FDR), the best of the shrinkage estimators studied. Based on the ability of the latter to leverage information across genes, we conclude that the use of the local-FDR estimator of the fold change instead of informal or threshold-based combinations of statistical tests and non-shrinkage estimators can be expected to substantially improve the reliability of gene prioritization at very little risk of doing so less reliably. Since the proposed replacement of post-selection estimates with shrunken estimates applies as well to other types of high-dimensional data, it could also improve the analysis of SNP data from genome-wide association studies.

Ionized and Neutral Outflows in the QUEST QSOs

NASA Astrophysics Data System (ADS)

Veilleux, Sylvain

2011-10-01

The role of galactic winds in gas-rich mergers is of crucial importance to understand galaxy and SMBH evolution. In recent months, our group has had three major scientific breakthroughs in this area: {1} The discovery with Herschel of massive molecular {OH-absorbing} outflows in several ULIRGs, including the nearest quasar, Mrk 231. {2} The independent discovery from mm-wave interferometric observations in the same object of a spatially resolved molecular {CO-emitting} wind with estimated mass outflow rate 3x larger than the star formation rate and spatially coincident with blueshifted neutral {Na ID-absorbing} gas in optical long-slit spectra. {3} The unambiguous determination from recent Gemini/IFU observations that the Na ID outflow in this object is wide-angle, thus driven by a QSO wind rather than a jet. This powerful outflow may be the long-sought "smoking gun" of quasar mechanical feedback purported to transform gas-rich mergers. However, our Herschel survey excludes all FIR-faint {UV-bright} "classic" QSOs by necessity. So here we propose a complementary FUV absorption-line survey of all FIR-bright -and- FIR-faint QSOs from the same parent sample. New {19 targets} and archival {11} spectra will be used to study, for the first time, the gaseous environments of QSOs as a function of host properties and age across the merger sequence ULIRG -> QSO. These data will allow us to distinguish between ionized & neutral quasar-driven outflows, starburst-driven winds, and tidal debris around the mergers. They will also be uniquely suited for a shallow but broad study of the warm & warm-hot intergalactic media, complementary to on-going surveys that are deeper but narrower.

Improving sensitivity in proteome studies by analysis of false discovery rates for multiple search engines

PubMed Central

Jones, Andrew R.; Siepen, Jennifer A.; Hubbard, Simon J.; Paton, Norman W.

2010-01-01

Tandem mass spectrometry, run in combination with liquid chromatography (LC-MS/MS), can generate large numbers of peptide and protein identifications, for which a variety of database search engines are available. Distinguishing correct identifications from false positives is far from trivial because all data sets are noisy, and tend to be too large for manual inspection, therefore probabilistic methods must be employed to balance the trade-off between sensitivity and specificity. Decoy databases are becoming widely used to place statistical confidence in results sets, allowing the false discovery rate (FDR) to be estimated. It has previously been demonstrated that different MS search engines produce different peptide identification sets, and as such, employing more than one search engine could result in an increased number of peptides being identified. However, such efforts are hindered by the lack of a single scoring framework employed by all search engines. We have developed a search engine independent scoring framework based on FDR which allows peptide identifications from different search engines to be combined, called the FDRScore. We observe that peptide identifications made by three search engines are infrequently false positives, and identifications made by only a single search engine, even with a strong score from the source search engine, are significantly more likely to be false positives. We have developed a second score based on the FDR within peptide identifications grouped according to the set of search engines that have made the identification, called the combined FDRScore. We demonstrate by searching large publicly available data sets that the combined FDRScore can differentiate between between correct and incorrect peptide identifications with high accuracy, allowing on average 35% more peptide identifications to be made at a fixed FDR than using a single search engine. PMID:19253293

ICan: An Optimized Ion-Current-Based Quantification Procedure with Enhanced Quantitative Accuracy and Sensitivity in Biomarker Discovery

PubMed Central

2015-01-01

The rapidly expanding availability of high-resolution mass spectrometry has substantially enhanced the ion-current-based relative quantification techniques. Despite the increasing interest in ion-current-based methods, quantitative sensitivity, accuracy, and false discovery rate remain the major concerns; consequently, comprehensive evaluation and development in these regards are urgently needed. Here we describe an integrated, new procedure for data normalization and protein ratio estimation, termed ICan, for improved ion-current-based analysis of data generated by high-resolution mass spectrometry (MS). ICan achieved significantly better accuracy and precision, and lower false-positive rate for discovering altered proteins, over current popular pipelines. A spiked-in experiment was used to evaluate the performance of ICan to detect small changes. In this study E. coli extracts were spiked with moderate-abundance proteins from human plasma (MAP, enriched by IgY14-SuperMix procedure) at two different levels to set a small change of 1.5-fold. Forty-five (92%, with an average ratio of 1.71 ± 0.13) of 49 identified MAP protein (i.e., the true positives) and none of the reference proteins (1.0-fold) were determined as significantly altered proteins, with cutoff thresholds of ≥1.3-fold change and p ≤ 0.05. This is the first study to evaluate and prove competitive performance of the ion-current-based approach for assigning significance to proteins with small changes. By comparison, other methods showed remarkably inferior performance. ICan can be broadly applicable to reliable and sensitive proteomic survey of multiple biological samples with the use of high-resolution MS. Moreover, many key features evaluated and optimized here such as normalization, protein ratio determination, and statistical analyses are also valuable for data analysis by isotope-labeling methods. PMID:25285707

Origin of Outer Solar System

NASA Technical Reports Server (NTRS)

Holman, Matthew J.; Boyce, J. (Technical Monitor)

2003-01-01

We feel that at the present moment the available theoretical models of the Kuiper belt are still in advance of the data, and thus our main task has been to conduct observational work guided by theoretical motivations. Our efforts over the past year can be divided into four categories: A) Wide-field Searches for Kuiper Belt Objects; B) Pencil-beam Searches for Kuiper Belt Objects; C) Wide-field Searches for Moons of the Outer Planets; D) Pencil-beam Searches for Faint Uranian and Neptunian Moons; E) Recovery Observations. As of April 2002, we have conducted several searches for Kuiper belt objects using large-format mosaic CCD camera on 4-meter class telescopes. In May 1999, we used the Kitt Peak 4-meter with the NOAO Mosaic camera we attempted a search for KBOs at a range of ecliptic latitudes. In addition to our wide-field searches, we have conducted three 'pencil-beam' searches in the past year. In a pencil-beam search we take repeated integrations of the same field throughout a night. After preprocessing the resulting images we shift and recombine them along a range of rates and directions consistent with the motion of KBOs. Stationary objects then smear out, while objects moving at near the shift rate appear as point sources. In addition to our searches for Kuiper belt objects, we are completing the inventory of the outer solar system by search for faint satellites of the outer planets. In August 2001 we conducted pencil beam searches for faint Uranian and Neptunian satellites at CFHT and CTIO. These searches resulted in the discover of two Neptunian and four Uranian satellite candidates. The discovery of Kuiper belt objects and outer planet satellites is of little use if the discoveries are not followed by systematic, repeated astrometric observations that permit reliable estimates of their orbits.

Development of a high-throughput brain slice method for studying drug distribution in the central nervous system.

PubMed

Fridén, Markus; Ducrozet, Frederic; Middleton, Brian; Antonsson, Madeleine; Bredberg, Ulf; Hammarlund-Udenaes, Margareta

2009-06-01

New, more efficient methods of estimating unbound drug concentrations in the central nervous system (CNS) combine the amount of drug in whole brain tissue samples measured by conventional methods with in vitro estimates of the unbound brain volume of distribution (V(u,brain)). Although the brain slice method is the most reliable in vitro method for measuring V(u,brain), it has not previously been adapted for the needs of drug discovery research. The aim of this study was to increase the throughput and optimize the experimental conditions of this method. Equilibrium of drug between the buffer and the brain slice within the 4 to 5 h of incubation is a fundamental requirement. However, it is difficult to meet this requirement for many of the extensively binding, lipophilic compounds in drug discovery programs. In this study, the dimensions of the incubation vessel and mode of stirring influenced the equilibration time, as did the amount of brain tissue per unit of buffer volume. The use of cassette experiments for investigating V(u,brain) in a linear drug concentration range increased the throughput of the method. The V(u,brain) for the model compounds ranged from 4 to 3000 ml . g brain(-1), and the sources of variability are discussed. The optimized setup of the brain slice method allows precise, robust estimation of V(u,brain) for drugs with diverse properties, including highly lipophilic compounds. This is a critical step forward for the implementation of relevant measurements of CNS exposure in the drug discovery setting.

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 a Satellite of the Large Trans-Neptunian Object (225088) 2007 OR{sub 10}

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

Kiss, Csaba; Marton, Gábor; Farkas-Takács, Anikó

2007 OR{sub 10} is currently the third largest known dwarf planet in the trans-Neptunian region, with an effective radiometric diameter of ∼1535 km. It has a slow rotation period of ∼45 hr that was suspected to be caused by tidal interactions with a satellite undetected at that time. Here, we report on the discovery of a likely moon of 2007 OR{sub 10}, identified on archival Hubble Space Telescope WFC3/UVIS system images. Although the satellite is detected at two epochs, this does not allow an unambiguous determination of the orbit and the orbital period. A feasible 1.5–5.8 · 10{sup 21} kgmore » estimate for the system mass leads to a likely 35–100 day orbital period. The moon is about 4.ͫ2 fainter than 2007 OR{sub 10} in HST images that corresponds to a diameter of 237 km assuming equal albedos with the primary. Due to the relatively small size of the moon, the previous size and albedo estimates for the primary remains unchanged. With this discovery all trans-Neptunian objects larger than 1000 km are now known to harbor satellites, an important constraint for moon formation theories in the young solar system.« less

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.

Quantifying Molecular Hydrogen Emissions and an Industrial Leakage Rate for the South Coast Air Basin of California

NASA Astrophysics Data System (ADS)

Irish, M. C.; Schroeder, J.; Beyersdorf, A. J.; Blake, D. R.

2015-12-01

The poorly understood atmospheric budget and distribution of molecular hydrogen (H2) have invited further research since the discovery that emissions from a hydrogen-based economy could have negative impacts on the global climate system and stratospheric ozone. The burgeoning fuel cell electric vehicle industry in the South Coast Air Basin of California (SoCAB) presents an opportunity to observe and constrain urban anthropogenic H2 emissions. This work presents the first H2 emissions estimate for the SoCAB and calculates an upper limit for the current rate of leakage from production and distribution infrastructure within the region. A top-down method utilized whole air samples collected during the Student Airborne Research Program (SARP) onboard the NASA DC-8 research aircraft from 23-25 June 2015 to estimate H2 emissions from combustion and non-combustion sources. H2:carbon monoxide (CO) and H2:carbon dioxide ratios from airborne observations were compared with experimentally established ratios from pure combustion source ratios and scaled with the well-constrained CO emissions inventory to yield H2 emissions of 24.9 ± 3.6 Gg a-1 (1σ) from combustion engines and 8.2 ± 4.7 Gg a-1 from non-combustion sources. Total daily production of H2 in the SoCAB was compared with the top-down results to estimate an upper limit leakage rate (5%) where all emissions not accounted for by incomplete combustion in engines were assumed to be emitted from H2 infrastructure. For bottom-up validation, the NOAA Hybrid Single Particle Lagrangian Integrated Trajectory dispersion model was run iteratively with all known stationary sources in attempt to constrain emissions. While this investigation determined that H2 emissions from non-combustion sources in the SoCAB are likely significant, more in-depth analysis is required to better predict the atmospheric implications of a hydrogen economy.

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.

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.

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

Building political and financial support for science and technology for agriculture.

PubMed

Beachy, Roger N

2014-04-05

The high rate of return on investments in research and development in agriculture, estimated at between 20- and 40-fold, provides a strong rationale for increasing financial support for such research. Furthermore, the urgency to provide sufficient nutrition for a growing population amid growing demands for an expanding bioeconomy, while facing population growth and changing global weather patterns heightens the urgency to expand research and development in this field. Unfortunately, support by governments for research has increased at a fraction of the rate of increases in support of research for health, energy, etc. Although there have been significant increases in investments by the private sector over the past two decades, much of the foundational research that supports private-sector activities is generated in the public sector. To achieve the greatest benefits of breakthroughs in research, it may be necessary to reconfigure research funding and technology transfer mechanisms in order to more rapidly apply discoveries to local needs as well as to global challenges. Some changes will likely require significant organizational, administrative and operational changes in education and research institutions.

Building political and financial support for science and technology for agriculture

PubMed Central

Beachy, Roger N.

2014-01-01

The high rate of return on investments in research and development in agriculture, estimated at between 20- and 40-fold, provides a strong rationale for increasing financial support for such research. Furthermore, the urgency to provide sufficient nutrition for a growing population amid growing demands for an expanding bioeconomy, while facing population growth and changing global weather patterns heightens the urgency to expand research and development in this field. Unfortunately, support by governments for research has increased at a fraction of the rate of increases in support of research for health, energy, etc. Although there have been significant increases in investments by the private sector over the past two decades, much of the foundational research that supports private-sector activities is generated in the public sector. To achieve the greatest benefits of breakthroughs in research, it may be necessary to reconfigure research funding and technology transfer mechanisms in order to more rapidly apply discoveries to local needs as well as to global challenges. Some changes will likely require significant organizational, administrative and operational changes in education and research institutions. PMID:24535386

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.

Detection of extended galactic sources with an underwater neutrino telescope

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

Leisos, A.; Tsirigotis, A. G.; Tzamarias, S. E.

2014-11-18

In this study we investigate the discovery capability of a Very Large Volume Neutrino Telescope to Galactic extended sources. We focus on the brightest HESS gamma rays sources which are considered also as very high energy neutrino emitters. We use the unbinned method taking into account both the spatial and the energy distribution of high energy neutrinos and we investigate parts of the Galactic plane where nearby potential neutrino emitters form neutrino source clusters. Neutrino source clusters as well as isolated neutrino sources are combined to estimate the observation period for 5 sigma discovery of neutrino signals from these objects.

The Solar Neighborhood. XXV. Discovery of New Proper Motion Stars with 0.40 sec/yr mu or = 0.18 sec/yr Between Declinations -47 deg and 00 deg

DTIC Science & Technology

2011-07-01

that the object was indeed a proper motion object. For real ob- jects, Two Micron All Sky Survey ( 2MASS ) positions, epochs, and JHKs photometry were...and vice versa, and to ensure the correct 2MASS data were collected. The blinking process led to the discovery of many common proper motion (CPM...Proper motion or position angle suspect. f No 2MASS data available, so no distance estimate. g Coordinates not J2000.0 due to lack of proper motion or

Weak affinity chromatography for evaluation of stereoisomers in early drug discovery.

PubMed

Duong-Thi, Minh-Dao; Bergström, Maria; Fex, Tomas; Svensson, Susanne; Ohlson, Sten; Isaksson, Roland

2013-07-01

In early drug discovery (e.g., in fragment screening), recognition of stereoisomeric structures is valuable and guides medicinal chemists to focus only on useful configurations. In this work, we concurrently screened mixtures of stereoisomers and estimated their affinities to a protein target (thrombin) using weak affinity chromatography-mass spectrometry (WAC-MS). Affinity determinations by WAC showed that minor changes in stereoisomeric configuration could have a major impact on affinity. The ability of WAC-MS to provide instant information about stereoselectivity and binding affinities directly from analyte mixtures is a great advantage in fragment library screening and drug lead development.

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.

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

A priori predictions of the rotational constants for HC13N, HC15N, C5O

NASA Technical Reports Server (NTRS)

DeFrees, D. J.; McLean, A. D.

1989-01-01

Ab initio molecular orbital theory is used to estimate the rotational constant for several carbon-chain molecules that are candidates for discovery in interstellar space. These estimated rotational constants can be used in laboratory or astronomical searches for the molecules. The rotational constant for HC13N is estimated to be 0.1073 +/- 0.0002 GHz and its dipole moment 5.4 D. The rotational constant for HC15N is estimated to be 0.0724 GHz, with a somewhat larger uncertainty. The rotational constant of C5O is estimated to be 1.360 +/- 2% GHz and its dipole moment 4.4. D.

Quantum key distribution in a multi-user network at gigahertz clock rates

NASA Astrophysics Data System (ADS)

Fernandez, Veronica; Gordon, Karen J.; Collins, Robert J.; Townsend, Paul D.; Cova, Sergio D.; Rech, Ivan; Buller, Gerald S.

2005-07-01

In recent years quantum information research has lead to the discovery of a number of remarkable new paradigms for information processing and communication. These developments include quantum cryptography schemes that offer unconditionally secure information transport guaranteed by quantum-mechanical laws. Such potentially disruptive security technologies could be of high strategic and economic value in the future. Two major issues confronting researchers in this field are the transmission range (typically <100km) and the key exchange rate, which can be as low as a few bits per second at long optical fiber distances. This paper describes further research of an approach to significantly enhance the key exchange rate in an optical fiber system at distances in the range of 1-20km. We will present results on a number of application scenarios, including point-to-point links and multi-user networks. Quantum key distribution systems have been developed, which use standard telecommunications optical fiber, and which are capable of operating at clock rates of up to 2GHz. They implement a polarization-encoded version of the B92 protocol and employ vertical-cavity surface-emitting lasers with emission wavelengths of 850 nm as weak coherent light sources, as well as silicon single-photon avalanche diodes as the single photon detectors. The point-to-point quantum key distribution system exhibited a quantum bit error rate of 1.4%, and an estimated net bit rate greater than 100,000 bits-1 for a 4.2 km transmission range.

Unexpectedly High Levels of Cryptic Diversity Uncovered by a Complete DNA Barcoding of Reptiles of the Socotra Archipelago.

PubMed

Vasconcelos, Raquel; Montero-Mendieta, Santiago; Simó-Riudalbas, Marc; Sindaco, Roberto; Santos, Xavier; Fasola, Mauro; Llorente, Gustavo; Razzetti, Edoardo; Carranza, Salvador

2016-01-01

Few DNA barcoding studies of squamate reptiles have been conducted. Due to the significance of the Socotra Archipelago (a UNESCO Natural World Heritage site and a biodiversity hotspot) and the conservation interest of its reptile fauna (94% endemics), we performed the most comprehensive DNA barcoding study on an island group to date to test its applicability to specimen identification and species discovery. Reptiles constitute Socotra's most important vertebrate fauna, yet their taxonomy remains under-studied. We successfully DNA-barcoded 380 individuals of all 31 presently recognized species. The specimen identification success rate is moderate to high, and almost all species presented local barcoding gaps. The unexpected high levels of intra-specific variability found within some species suggest cryptic diversity. Species richness may be under-estimated by 13.8-54.4%. This has implications in the species' ranges and conservation status that should be considered for conservation planning. Other phylogenetic studies using mitochondrial and nuclear markers are congruent with our results. We conclude that, despite its reduced length (663 base pairs), cytochrome c oxidase 1, COI, is very useful for specimen identification and for detecting intra-specific diversity, and has a good phylogenetic signal. We recommend DNA barcoding to be applied to other biodiversity hotspots for quickly and cost-efficiently flagging species discovery, preferentially incorporated into an integrative taxonomic framework.

Unexpectedly High Levels of Cryptic Diversity Uncovered by a Complete DNA Barcoding of Reptiles of the Socotra Archipelago

PubMed Central

Simó-Riudalbas, Marc; Sindaco, Roberto; Santos, Xavier; Fasola, Mauro; Llorente, Gustavo; Razzetti, Edoardo; Carranza, Salvador

2016-01-01

Few DNA barcoding studies of squamate reptiles have been conducted. Due to the significance of the Socotra Archipelago (a UNESCO Natural World Heritage site and a biodiversity hotspot) and the conservation interest of its reptile fauna (94% endemics), we performed the most comprehensive DNA barcoding study on an island group to date to test its applicability to specimen identification and species discovery. Reptiles constitute Socotra’s most important vertebrate fauna, yet their taxonomy remains under-studied. We successfully DNA-barcoded 380 individuals of all 31 presently recognized species. The specimen identification success rate is moderate to high, and almost all species presented local barcoding gaps. The unexpected high levels of intra-specific variability found within some species suggest cryptic diversity. Species richness may be under-estimated by 13.8–54.4%. This has implications in the species’ ranges and conservation status that should be considered for conservation planning. Other phylogenetic studies using mitochondrial and nuclear markers are congruent with our results. We conclude that, despite its reduced length (663 base pairs), cytochrome c oxidase 1, COI, is very useful for specimen identification and for detecting intra-specific diversity, and has a good phylogenetic signal. We recommend DNA barcoding to be applied to other biodiversity hotspots for quickly and cost-efficiently flagging species discovery, preferentially incorporated into an integrative taxonomic framework. PMID:26930572

Biomarker Discovery in Gulf War Veterans: Development of a War Illness Diagnostic Panel

DTIC Science & Technology

2014-10-17

estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the... data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this...that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it

Filtering Using Nonlinear Expectations

DTIC Science & Technology

2016-04-16

gives a solution to estimating a Markov chain observed in Gaussian noise when the variance of the noise is unkown. This paper is accepted for the IEEE...Optimization, an A* journal. A short third paper discusses how to estimate a change in the transition dynamics of a noisily observed Markov chain ...The change point time is hidden in a hidden Markov chain , so a second level of discovery is involved. This paper is accepted for Communications in

Controlling the Rate of GWAS False Discoveries

PubMed Central

Brzyski, Damian; Peterson, Christine B.; Sobczyk, Piotr; Candès, Emmanuel J.; Bogdan, Malgorzata; Sabatti, Chiara

2017-01-01

With the rise of both the number and the complexity of traits of interest, control of the false discovery rate (FDR) in genetic association studies has become an increasingly appealing and accepted target for multiple comparison adjustment. While a number of robust FDR-controlling strategies exist, the nature of this error rate is intimately tied to the precise way in which discoveries are counted, and the performance of FDR-controlling procedures is satisfactory only if there is a one-to-one correspondence between what scientists describe as unique discoveries and the number of rejected hypotheses. The presence of linkage disequilibrium between markers in genome-wide association studies (GWAS) often leads researchers to consider the signal associated to multiple neighboring SNPs as indicating the existence of a single genomic locus with possible influence on the phenotype. This a posteriori aggregation of rejected hypotheses results in inflation of the relevant FDR. We propose a novel approach to FDR control that is based on prescreening to identify the level of resolution of distinct hypotheses. We show how FDR-controlling strategies can be adapted to account for this initial selection both with theoretical results and simulations that mimic the dependence structure to be expected in GWAS. We demonstrate that our approach is versatile and useful when the data are analyzed using both tests based on single markers and multiple regression. We provide an R package that allows practitioners to apply our procedure on standard GWAS format data, and illustrate its performance on lipid traits in the North Finland Birth Cohort 66 cohort study. PMID:27784720

Controlling the Rate of GWAS False Discoveries.

PubMed

Brzyski, Damian; Peterson, Christine B; Sobczyk, Piotr; Candès, Emmanuel J; Bogdan, Malgorzata; Sabatti, Chiara

2017-01-01

With the rise of both the number and the complexity of traits of interest, control of the false discovery rate (FDR) in genetic association studies has become an increasingly appealing and accepted target for multiple comparison adjustment. While a number of robust FDR-controlling strategies exist, the nature of this error rate is intimately tied to the precise way in which discoveries are counted, and the performance of FDR-controlling procedures is satisfactory only if there is a one-to-one correspondence between what scientists describe as unique discoveries and the number of rejected hypotheses. The presence of linkage disequilibrium between markers in genome-wide association studies (GWAS) often leads researchers to consider the signal associated to multiple neighboring SNPs as indicating the existence of a single genomic locus with possible influence on the phenotype. This a posteriori aggregation of rejected hypotheses results in inflation of the relevant FDR. We propose a novel approach to FDR control that is based on prescreening to identify the level of resolution of distinct hypotheses. We show how FDR-controlling strategies can be adapted to account for this initial selection both with theoretical results and simulations that mimic the dependence structure to be expected in GWAS. We demonstrate that our approach is versatile and useful when the data are analyzed using both tests based on single markers and multiple regression. We provide an R package that allows practitioners to apply our procedure on standard GWAS format data, and illustrate its performance on lipid traits in the North Finland Birth Cohort 66 cohort study. Copyright © 2017 by the Genetics Society of America.

The drug discovery portal: a computational platform for identifying drug leads from academia.

PubMed

Clark, Rachel L; Johnston, Blair F; Mackay, Simon P; Breslin, Catherine J; Robertson, Murray N; Sutcliffe, Oliver B; Dufton, Mark J; Harvey, Alan L

2010-05-01

The Drug Discovery Portal (DDP) is a research initiative based at the University of Strathclyde in Glasgow, Scotland. It was initiated in 2007 by a group of researchers with expertise in virtual screening. Academic research groups in the university working in drug discovery programmes estimated there was a historical collection of physical compounds going back 50 years that had never been adequately catalogued. This invaluable resource has been harnessed to form the basis of the DDP library, and has attracted a high-percentage uptake from the Universities and Research Groups internationally. Its unique attributes include the diversity of the academic database, sourced from synthetic, medicinal and phytochemists working an academic laboratories and the ability to link biologists with appropriate chemical expertise through a target-matching virtual screening approach, and has resulted in seven emerging hit development programmes between international contributors.

Improving Upon String Methods for Transition State Discovery.

PubMed

Chaffey-Millar, Hugh; Nikodem, Astrid; Matveev, Alexei V; Krüger, Sven; Rösch, Notker

2012-02-14

Transition state discovery via application of string methods has been researched on two fronts. The first front involves development of a new string method, named the Searching String method, while the second one aims at estimating transition states from a discretized reaction path. The Searching String method has been benchmarked against a number of previously existing string methods and the Nudged Elastic Band method. The developed methods have led to a reduction in the number of gradient calls required to optimize a transition state, as compared to existing methods. The Searching String method reported here places new beads on a reaction pathway at the midpoint between existing beads, such that the resolution of the path discretization in the region containing the transition state grows exponentially with the number of beads. This approach leads to favorable convergence behavior and generates more accurate estimates of transition states from which convergence to the final transition states occurs more readily. Several techniques for generating improved estimates of transition states from a converged string or nudged elastic band have been developed and benchmarked on 13 chemical test cases. Optimization approaches for string methods, and pitfalls therein, are discussed.

76 FR 79122 - Magnuson-Stevens Act Provisions; Fisheries Off West Coast States; Pacific Coast Groundfish...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-21

... management measures for the remainder of the biennial period that would take into account new knowledge... precautionary, in response to the discovery of an error in the methods that were used to estimate landings of...

Bayesian estimation of differential transcript usage from RNA-seq data.

PubMed

Papastamoulis, Panagiotis; Rattray, Magnus

2017-11-27

Next generation sequencing allows the identification of genes consisting of differentially expressed transcripts, a term which usually refers to changes in the overall expression level. A specific type of differential expression is differential transcript usage (DTU) and targets changes in the relative within gene expression of a transcript. The contribution of this paper is to: (a) extend the use of cjBitSeq to the DTU context, a previously introduced Bayesian model which is originally designed for identifying changes in overall expression levels and (b) propose a Bayesian version of DRIMSeq, a frequentist model for inferring DTU. cjBitSeq is a read based model and performs fully Bayesian inference by MCMC sampling on the space of latent state of each transcript per gene. BayesDRIMSeq is a count based model and estimates the Bayes Factor of a DTU model against a null model using Laplace's approximation. The proposed models are benchmarked against the existing ones using a recent independent simulation study as well as a real RNA-seq dataset. Our results suggest that the Bayesian methods exhibit similar performance with DRIMSeq in terms of precision/recall but offer better calibration of False Discovery Rate.

Identifying and Assessing Interesting Subgroups in a Heterogeneous Population.

PubMed

Lee, Woojoo; Alexeyenko, Andrey; Pernemalm, Maria; Guegan, Justine; Dessen, Philippe; Lazar, Vladimir; Lehtiö, Janne; Pawitan, Yudi

2015-01-01

Biological heterogeneity is common in many diseases and it is often the reason for therapeutic failures. Thus, there is great interest in classifying a disease into subtypes that have clinical significance in terms of prognosis or therapy response. One of the most popular methods to uncover unrecognized subtypes is cluster analysis. However, classical clustering methods such as k-means clustering or hierarchical clustering are not guaranteed to produce clinically interesting subtypes. This could be because the main statistical variability--the basis of cluster generation--is dominated by genes not associated with the clinical phenotype of interest. Furthermore, a strong prognostic factor might be relevant for a certain subgroup but not for the whole population; thus an analysis of the whole sample may not reveal this prognostic factor. To address these problems we investigate methods to identify and assess clinically interesting subgroups in a heterogeneous population. The identification step uses a clustering algorithm and to assess significance we use a false discovery rate- (FDR-) based measure. Under the heterogeneity condition the standard FDR estimate is shown to overestimate the true FDR value, but this is remedied by an improved FDR estimation procedure. As illustrations, two real data examples from gene expression studies of lung cancer are provided.

Discovery of long-distance gamete dispersal in a lichen-forming ascomycete.

PubMed

Ronnås, Cecilia; Werth, Silke; Ovaskainen, Otso; Várkonyi, Gergely; Scheidegger, Christoph; Snäll, Tord

2017-10-01

Accurate estimates of gamete and offspring dispersal range are required for the understanding and prediction of spatial population dynamics and species persistence. Little is known about gamete dispersal in fungi, especially in lichen-forming ascomycetes. Here, we estimate the dispersal functions of clonal propagules, gametes and ascospores of the epiphytic lichen Lobaria pulmonaria. We use hierarchical Bayesian parentage analysis, which integrates genetic and ecological information from multiannual colonization and dispersal source data collected in a large, old-growth forest landscape. The effective dispersal range of gametes is several hundred metres to kilometres from potential paternal individuals. By contrast, clonal propagules disperse only tens of metres, and ascospores disperse over several thousand metres. Our study reveals the dispersal distances of individual reproductive units; clonal propagules, gametes and ascospores, which is of great importance for a thorough understanding of the spatial dynamics of ascomycetes. Sexual reproduction occurs between distant individuals. However, whereas gametes and ascospores disperse over long distances, the overall rate of colonization of trees is low. Hence, establishment is the limiting factor for the colonization of new host trees by the lichen in old-growth landscapes. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

A New Non-gaussian Turbulent Wind Field Generator to Estimate Design-Loads of Wind-Turbines

NASA Astrophysics Data System (ADS)

Schaffarczyk, A. P.; Gontier, H.; Kleinhans, D.; Friedrich, R.

Climate change and finite fossil fuel resources make it urgent to turn into electricity generation from mostly renewable energies. One major part will play wind-energy supplied by wind-turbines of rated power up to 10 MW. For their design and development wind field models have to be used. The standard models are based on the empirical spectra, for example by von Karman or Kaimal. From investigation of measured data it is clear that gusts are underrepresented in such models. Based on some fundamental discoveries of the nature of turbulence by Friedrich [1] derived from the Navier-Stokes equation directly, we used the concept of Continuous Time Random Walks to construct three dimensional wind fields obeying non-Gaussian statistics. These wind fields were used to estimate critical fatigue loads necessary within the certification process. Calculations are carried out with an implementation of a beam-model (FLEX5) for two types of state-of-the-art wind turbines The authors considered the edgewise and flapwise blade-root bending moments as well as tilt moment at tower top due to the standard wind field models and our new non-Gaussian wind field model. Clear differences in the loads were found.

Seismic evidence for convection-driven motion of the North American plate.

PubMed

Eaton, David W; Frederiksen, Andrew

2007-03-22

Since the discovery of plate tectonics, the relative importance of driving forces of plate motion has been debated. Resolution of this issue has been hindered by uncertainties in estimates of basal traction, which controls the coupling between lithospheric plates and underlying mantle convection. Hotspot tracks preserve records of past plate motion and provide markers with which the relative motion between a plate's surface and underlying mantle regions may be examined. Here we show that the 115-140-Myr surface expression of the Great Meteor hotspot track in eastern North America is misaligned with respect to its location at 200 km depth, as inferred from plate-reconstruction models and seismic tomographic studies. The misalignment increases with age and is consistent with westward displacement of the base of the plate relative to its surface, at an average rate of 3.8 +/- 1.8 mm yr(-1). Here age-constrained 'piercing points' have enabled direct estimation of relative motion between the surface and underside of a plate. The relative displacement of the base is approximately parallel to seismic fast axes and calculated mantle flow, suggesting that asthenospheric flow may be deforming the lithospheric keel and exerting a driving force on this part of the North American plate.

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.

Searching for Exoplanets using Artificial Intelligence

NASA Astrophysics Data System (ADS)

Pearson, Kyle Alexander; Palafox, Leon; Griffith, Caitlin Ann

2017-10-01

In the last decade, over a million stars were monitored to detect transiting planets. The large volume of data obtained from current and future missions (e.g. Kepler, K2, TESS and LSST) requires automated methods to detect the signature of a planet. Manual interpretation of potential exoplanet candidates is labor intensive and subject to human error, the results of which are difficult to quantify. Here we present a new method of detecting exoplanet candidates in large planetary search projects which, unlike current methods uses a neural network. Neural networks, also called ``deep learning'' or ``deep nets'', are a state of the art machine learning technique designed to give a computer perception into a specific problem by training it to recognize patterns. Unlike past transit detection algorithms, the deep net learns to characterize the data instead of relying on hand-coded metrics that humans perceive as the most representative. Exoplanet transits have different shapes, as a result of, e.g. the planet's and stellar atmosphere and transit geometry. Thus, a simple template does not suffice to capture the subtle details, especially if the signal is below the noise or strong systematics are present. Current false-positive rates from the Kepler data are estimated around 12.3% for Earth-like planets and there has been no study of the false negative rates. It is therefore important to ask how the properties of current algorithms exactly affect the results of the Kepler mission and, future missions such as TESS, which flies next year. These uncertainties affect the fundamental research derived from missions, such as the discovery of habitable planets, estimates of their occurrence rates and our understanding about the nature and evolution of planetary systems.

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

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.

Controlling the joint local false discovery rate is more powerful than meta-analysis methods in joint analysis of summary statistics from multiple genome-wide association studies.

PubMed

Jiang, Wei; Yu, Weichuan

2017-02-15

In genome-wide association studies (GWASs) of common diseases/traits, we often analyze multiple GWASs with the same phenotype together to discover associated genetic variants with higher power. Since it is difficult to access data with detailed individual measurements, summary-statistics-based meta-analysis methods have become popular to jointly analyze datasets from multiple GWASs. In this paper, we propose a novel summary-statistics-based joint analysis method based on controlling the joint local false discovery rate (Jlfdr). We prove that our method is the most powerful summary-statistics-based joint analysis method when controlling the false discovery rate at a certain level. In particular, the Jlfdr-based method achieves higher power than commonly used meta-analysis methods when analyzing heterogeneous datasets from multiple GWASs. Simulation experiments demonstrate the superior power of our method over meta-analysis methods. Also, our method discovers more associations than meta-analysis methods from empirical datasets of four phenotypes. The R-package is available at: http://bioinformatics.ust.hk/Jlfdr.html . eeyu@ust.hk. Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

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.

Biomass burning - Combustion emissions, satellite imagery, and biogenic emissions

NASA Technical Reports Server (NTRS)

Levine, Joel S.; Cofer, Wesley R., III; Winstead, Edward L.; Rhinehart, Robert P.; Cahoon, Donald R., Jr.; Sebacher, Daniel I.; Sebacher, Shirley; Stocks, Brian J.

1991-01-01

After detailing a technique for the estimation of the instantaneous emission of trace gases produced by biomass burning, using satellite imagery, attention is given to the recent discovery that burning results in significant enhancement of biogenic emissions of N2O, NO, and CH4. Biomass burning accordingly has an immediate and long-term impact on the production of atmospheric trace gases. It is presently demonstrated that satellite imagery of fires may be used to estimate combustion emissions, and could be used to estimate long-term postburn biogenic emission of trace gases to the atmosphere.

Distributed Noise Generation for Density Estimation Based Clustering without Trusted Third Party

NASA Astrophysics Data System (ADS)

Su, Chunhua; Bao, Feng; Zhou, Jianying; Takagi, Tsuyoshi; Sakurai, Kouichi

The rapid growth of the Internet provides people with tremendous opportunities for data collection, knowledge discovery and cooperative computation. However, it also brings the problem of sensitive information leakage. Both individuals and enterprises may suffer from the massive data collection and the information retrieval by distrusted parties. In this paper, we propose a privacy-preserving protocol for the distributed kernel density estimation-based clustering. Our scheme applies random data perturbation (RDP) technique and the verifiable secret sharing to solve the security problem of distributed kernel density estimation in [4] which assumed a mediate party to help in the computation.

Assessment of undiscovered oil and gas resources in the Cretaceous Nanushuk and Torok Formations, Alaska North Slope, and summary of resource potential of the National Petroleum Reserve in Alaska, 2017

USGS Publications Warehouse

Houseknecht, David W.; Lease, Richard O.; Schenk, Christopher J.; Mercier, Tracey J.; Rouse, William A.; Jarboe, Palma B.; Whidden, Katherine J.; Garrity, Christopher P.; Lewis, Kristen A.; Heller, Samuel; Craddock, William H.; Klett, Timothy R.; Le, Phuong A.; Smith, Rebecca; Tennyson, Marilyn E.; Gaswirth, Stephanie B.; Woodall, Cheryl A.; Brownfield, Michael E.; Leathers-Miller, Heidi M.; Finn, Thomas M.

2017-12-22

The U.S. Geological Survey estimated mean undiscovered, technically recoverable resources of 8.7 billion barrels of oil and 25 trillion cubic feet of natural gas (associated and nonassociated) in conventional accumulations in the Cretaceous Nanushuk and Torok Formations in the National Petroleum Reserve in Alaska, adjacent State and Native lands, and State waters. The estimated undiscovered oil resources in the Nanushuk and Torok Formations are significantly higher than previous estimates, owing primarily to recent, larger than anticipated oil discoveries.

A Network-Biology Informed Computational Drug Repositioning Strategy to Target Disease Risk Trajectories and Comorbidities of Peripheral Artery Disease.

PubMed

Shameer, Khader; Dow, Garrett; Glicksberg, Benjamin S; Johnson, Kipp W; Ze, Yi; Tomlinson, Max S; Readhead, Ben; Dudley, Joel T; Kullo, Iftikhar J

2018-01-01

Currently, drug discovery approaches focus on the design of therapies that alleviate an index symptom by reengineering the underlying biological mechanism in agonistic or antagonistic fashion. For example, medicines are routinely developed to target an essential gene that drives the disease mechanism. Therapeutic overloading where patients get multiple medications to reduce the primary and secondary side effect burden is standard practice. This single-symptom based approach may not be scalable, as we understand that diseases are more connected than random and molecular interactions drive disease comorbidities. In this work, we present a proof-of-concept drug discovery strategy by combining network biology, disease comorbidity estimates, and computational drug repositioning, by targeting the risk factors and comorbidities of peripheral artery disease, a vascular disease associated with high morbidity and mortality. Individualized risk estimation and recommending disease sequelae based therapies may help to lower the mortality and morbidity of peripheral artery disease.

Molecular Dynamics Simulations and Kinetic Measurements to Estimate and Predict Protein-Ligand Residence Times.

PubMed

Mollica, Luca; Theret, Isabelle; Antoine, Mathias; Perron-Sierra, Françoise; Charton, Yves; Fourquez, Jean-Marie; Wierzbicki, Michel; Boutin, Jean A; Ferry, Gilles; Decherchi, Sergio; Bottegoni, Giovanni; Ducrot, Pierre; Cavalli, Andrea

2016-08-11

Ligand-target residence time is emerging as a key drug discovery parameter because it can reliably predict drug efficacy in vivo. Experimental approaches to binding and unbinding kinetics are nowadays available, but we still lack reliable computational tools for predicting kinetics and residence time. Most attempts have been based on brute-force molecular dynamics (MD) simulations, which are CPU-demanding and not yet particularly accurate. We recently reported a new scaled-MD-based protocol, which showed potential for residence time prediction in drug discovery. Here, we further challenged our procedure's predictive ability by applying our methodology to a series of glucokinase activators that could be useful for treating type 2 diabetes mellitus. We combined scaled MD with experimental kinetics measurements and X-ray crystallography, promptly checking the protocol's reliability by directly comparing computational predictions and experimental measures. The good agreement highlights the potential of our scaled-MD-based approach as an innovative method for computationally estimating and predicting drug residence times.

A Network-Biology Informed Computational Drug Repositioning Strategy to Target Disease Risk Trajectories and Comorbidities of Peripheral Artery Disease

PubMed Central

Shameer, Khader; Dow, Garrett; Glicksberg, Benjamin S.; Johnson, Kipp W.; Ze, Yi; Tomlinson, Max S.; Readhead, Ben; Dudley, Joel T.; Kullo, Iftikhar J.

2018-01-01

Currently, drug discovery approaches focus on the design of therapies that alleviate an index symptom by reengineering the underlying biological mechanism in agonistic or antagonistic fashion. For example, medicines are routinely developed to target an essential gene that drives the disease mechanism. Therapeutic overloading where patients get multiple medications to reduce the primary and secondary side effect burden is standard practice. This single-symptom based approach may not be scalable, as we understand that diseases are more connected than random and molecular interactions drive disease comorbidities. In this work, we present a proof-of-concept drug discovery strategy by combining network biology, disease comorbidity estimates, and computational drug repositioning, by targeting the risk factors and comorbidities of peripheral artery disease, a vascular disease associated with high morbidity and mortality. Individualized risk estimation and recommending disease sequelae based therapies may help to lower the mortality and morbidity of peripheral artery disease. PMID:29888052

How Well Can We Detect Lineage-Specific Diversification-Rate Shifts? A Simulation Study of Sequential AIC Methods.

PubMed

May, Michael R; Moore, Brian R

2016-11-01

Evolutionary biologists have long been fascinated by the extreme differences in species numbers across branches of the Tree of Life. This has motivated the development of statistical methods for detecting shifts in the rate of lineage diversification across the branches of phylogenic trees. One of the most frequently used methods, MEDUSA, explores a set of diversification-rate models, where each model assigns branches of the phylogeny to a set of diversification-rate categories. Each model is first fit to the data, and the Akaike information criterion (AIC) is then used to identify the optimal diversification model. Surprisingly, the statistical behavior of this popular method is uncharacterized, which is a concern in light of: (1) the poor performance of the AIC as a means of choosing among models in other phylogenetic contexts; (2) the ad hoc algorithm used to visit diversification models, and; (3) errors that we reveal in the likelihood function used to fit diversification models to the phylogenetic data. Here, we perform an extensive simulation study demonstrating that MEDUSA (1) has a high false-discovery rate (on average, spurious diversification-rate shifts are identified [Formula: see text] of the time), and (2) provides biased estimates of diversification-rate parameters. Understanding the statistical behavior of MEDUSA is critical both to empirical researchers-in order to clarify whether these methods can make reliable inferences from empirical datasets-and to theoretical biologists-in order to clarify the specific problems that need to be solved in order to develop more reliable approaches for detecting shifts in the rate of lineage diversification. [Akaike information criterion; extinction; lineage-specific diversification rates; phylogenetic model selection; speciation.]. © The Author(s) 2016. Published by Oxford University Press, on behalf of the Society of Systematic Biologists.

How Well Can We Detect Lineage-Specific Diversification-Rate Shifts? A Simulation Study of Sequential AIC Methods

PubMed Central

May, Michael R.; Moore, Brian R.

2016-01-01

Evolutionary biologists have long been fascinated by the extreme differences in species numbers across branches of the Tree of Life. This has motivated the development of statistical methods for detecting shifts in the rate of lineage diversification across the branches of phylogenic trees. One of the most frequently used methods, MEDUSA, explores a set of diversification-rate models, where each model assigns branches of the phylogeny to a set of diversification-rate categories. Each model is first fit to the data, and the Akaike information criterion (AIC) is then used to identify the optimal diversification model. Surprisingly, the statistical behavior of this popular method is uncharacterized, which is a concern in light of: (1) the poor performance of the AIC as a means of choosing among models in other phylogenetic contexts; (2) the ad hoc algorithm used to visit diversification models, and; (3) errors that we reveal in the likelihood function used to fit diversification models to the phylogenetic data. Here, we perform an extensive simulation study demonstrating that MEDUSA (1) has a high false-discovery rate (on average, spurious diversification-rate shifts are identified ≈30% of the time), and (2) provides biased estimates of diversification-rate parameters. Understanding the statistical behavior of MEDUSA is critical both to empirical researchers—in order to clarify whether these methods can make reliable inferences from empirical datasets—and to theoretical biologists—in order to clarify the specific problems that need to be solved in order to develop more reliable approaches for detecting shifts in the rate of lineage diversification. [Akaike information criterion; extinction; lineage-specific diversification rates; phylogenetic model selection; speciation.] PMID:27037081

UCAC3 Proper Motion Survey. 2. Discovery of New Proper Motion Stars in UCAC3 with 0.40 yr-1 micro or = 0.18 yr-1 between Declinations -47 deg and 00 deg

DTIC Science & Technology

2012-02-01

Micron All Sky Survey ( 2MASS ) infrared photometry. We find five new red dwarf systems estimated to be within 25 pc. These discoveries support results...re-reduction of the pixel data (Zacharias 2010). In addition, data from the Two Micron All Sky Survey ( 2MASS ) were used in UCAC3 to probe for and...errors ranging from 50 to 200 mas when compared to 2MASS data. To identify previously known high proper motion (HPM) stars in the UCAC3, a source list was

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.

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.

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.

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.

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

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

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.

Regularized quantile regression for SNP marker estimation of pig growth curves.

PubMed

Barroso, L M A; Nascimento, M; Nascimento, A C C; Silva, F F; Serão, N V L; Cruz, C D; Resende, M D V; Silva, F L; Azevedo, C F; Lopes, P S; Guimarães, S E F

2017-01-01

Genomic growth curves are generally defined only in terms of population mean; an alternative approach that has not yet been exploited in genomic analyses of growth curves is the Quantile Regression (QR). This methodology allows for the estimation of marker effects at different levels of the variable of interest. We aimed to propose and evaluate a regularized quantile regression for SNP marker effect estimation of pig growth curves, as well as to identify the chromosome regions of the most relevant markers and to estimate the genetic individual weight trajectory over time (genomic growth curve) under different quantiles (levels). The regularized quantile regression (RQR) enabled the discovery, at different levels of interest (quantiles), of the most relevant markers allowing for the identification of QTL regions. We found the same relevant markers simultaneously affecting different growth curve parameters (mature weight and maturity rate): two (ALGA0096701 and ALGA0029483) for RQR(0.2), one (ALGA0096701) for RQR(0.5), and one (ALGA0003761) for RQR(0.8). Three average genomic growth curves were obtained and the behavior was explained by the curve in quantile 0.2, which differed from the others. RQR allowed for the construction of genomic growth curves, which is the key to identifying and selecting the most desirable animals for breeding purposes. Furthermore, the proposed model enabled us to find, at different levels of interest (quantiles), the most relevant markers for each trait (growth curve parameter estimates) and their respective chromosomal positions (identification of new QTL regions for growth curves in pigs). These markers can be exploited under the context of marker assisted selection while aiming to change the shape of pig growth curves.

Bias and variance reduction in estimating the proportion of true-null hypotheses

PubMed Central

Cheng, Yebin; Gao, Dexiang; Tong, Tiejun

2015-01-01

When testing a large number of hypotheses, estimating the proportion of true nulls, denoted by \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}$\\pi _0$\\end{document}, becomes increasingly important. This quantity has many applications in practice. For instance, a reliable estimate of \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}$\\pi _0$\\end{document} can eliminate the conservative bias of the Benjamini–Hochberg procedure on controlling the false discovery rate. It is known that most methods in the literature for estimating \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}$\\pi _0$\\end{document} are conservative. Recently, some attempts have been paid to reduce such estimation bias. Nevertheless, they are either over bias corrected or suffering from an unacceptably large estimation variance. In this paper, we propose a new method for estimating \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}$\\pi _0$\\end{document} that aims to reduce the bias and variance of the estimation simultaneously. To achieve this, we first utilize the probability density functions of false-null \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}$p$\\end{document}-values and then propose a novel algorithm to estimate the quantity of \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}$\\pi _0$\\end{document}. The statistical behavior of the proposed estimator is also investigated. Finally, we carry out extensive simulation studies and several real data analysis to evaluate the performance of the proposed estimator. Both simulated and real data demonstrate that the proposed method may improve the existing literature significantly. PMID:24963010

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.

Molecular property diagnostic suite (MPDS): Development of disease-specific open source web portals for drug discovery.

PubMed

Nagamani, S; Gaur, A S; Tanneeru, K; Muneeswaran, G; Madugula, S S; Consortium, Mpds; Druzhilovskiy, D; Poroikov, V V; Sastry, G N

2017-11-01

Molecular property diagnostic suite (MPDS) is a Galaxy-based open source drug discovery and development platform. MPDS web portals are designed for several diseases, such as tuberculosis, diabetes mellitus, and other metabolic disorders, specifically aimed to evaluate and estimate the drug-likeness of a given molecule. MPDS consists of three modules, namely data libraries, data processing, and data analysis tools which are configured and interconnected to assist drug discovery for specific diseases. The data library module encompasses vast information on chemical space, wherein the MPDS compound library comprises 110.31 million unique molecules generated from public domain databases. Every molecule is assigned with a unique ID and card, which provides complete information for the molecule. Some of the modules in the MPDS are specific to the diseases, while others are non-specific. Importantly, a suitably altered protocol can be effectively generated for another disease-specific MPDS web portal by modifying some of the modules. Thus, the MPDS suite of web portals shows great promise to emerge as disease-specific portals of great value, integrating chemoinformatics, bioinformatics, molecular modelling, and structure- and analogue-based drug discovery approaches.

Target validation: linking target and chemical properties to desired product profile.

PubMed

Wyatt, Paul G; Gilbert, Ian H; Read, Kevin D; Fairlamb, Alan H

2011-01-01

The discovery of drugs is a lengthy, high-risk and expensive business taking at least 12 years and is estimated to cost upwards of US$800 million for each drug to be successfully approved for clinical use. Much of this cost is driven by the late phase clinical trials and therefore the ability to terminate early those projects destined to fail is paramount to prevent unwanted costs and wasted effort. Although neglected diseases drug discovery is driven more by unmet medical need rather than financial considerations, the need to minimise wasted money and resources is even more vital in this under-funded area. To ensure any drug discovery project is addressing the requirements of the patients and health care providers and delivering a benefit over existing therapies, the ideal attributes of a novel drug needs to be pre-defined by a set of criteria called a target product profile. Using a target product profile the drug discovery process, clinical study design, and compound characteristics can be defined all the way back through to the suitability or druggability of the intended biochemical target. Assessment and prioritisation of the most promising targets for entry into screening programmes is crucial for maximising chances of success.

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

An Empirical Limit on the Kilonova Rate from the DLT40 One Day Cadence Supernova Survey

NASA Astrophysics Data System (ADS)

Yang, Sheng; Valenti, Stefano; Cappellaro, Enrico; Sand, David J.; Tartaglia, Leonardo; Corsi, Alessandra; Reichart, Daniel E.; Haislip, Joshua; Kouprianov, Vladimir

2017-12-01

Binary neutron star mergers are important in understanding stellar evolution, the chemical enrichment of the universe via the r-process, the physics of short gamma-ray bursts, gravitational waves, and pulsars. The rates at which these coalescences happen is uncertain, but it can be constrained in different ways. One of those is to search for the optical transients produced at the moment of the merging, called a kilonova, in ongoing supernova (SN) searches. However, until now, only theoretical models for a kilonova light curve were available to estimate their rates. The recent kilonova discovery of AT 2017gfo/DLT17ck gives us the opportunity to constrain the rate of kilonovae using the light curve of a real event. We constrain the rate of binary neutron star mergers using the DLT40 Supernova search and the native AT 2017gfo/DLT17ck light curve obtained with the same telescope and software system. Excluding AT 2017gfo/DLT17ck due to visibility issues, which was only discovered thanks to the aLIGO/aVirgo trigger, no other similar transients were detected during the 13 months of daily cadence observations of ∼2200 nearby (<40 Mpc) galaxies. We find that the rate of BNS mergers is lower than 0.47–0.55 kilonovae per 100 years per 1010 {L}{Bȯ } (depending on the adopted extinction distribution). In volume, this translates to < 0.99× {10}-4{}-0.15+0.19, {{Mpc}}-3 {{yr}}-1 (SNe Ia–like extinction distribution), consistent with previous BNS coalescence rates. Based on our rate limit, and the sensitivity of aLIGO/aVirgo during O2, it is very unlikely that kilonova events are lurking in old pointed galaxy SN search data sets.

How many species of cichlid fishes are there in African lakes?

PubMed

Turner, G F; Seehausen, O; Knight, M E; Allender, C J; Robinson, R L

2001-03-01

The endemic cichlid fishes of Lakes Malawi, Tanganyika and Victoria are textbook examples of explosive speciation and adaptive radiation, and their study promises to yield important insights into these processes. Accurate estimates of species richness of lineages in these lakes, and elsewhere, will be a necessary prerequisite for a thorough comparative analysis of the intrinsic and extrinsic factors influencing rates of diversification. This review presents recent findings on the discoveries of new species and species flocks and critically appraises the relevant evidence on species richness from recent studies of polymorphism and assortative mating, generally using behavioural and molecular methods. Within the haplochromines, the most species-rich lineage, there are few reported cases of postzygotic isolation, and these are generally among allopatric taxa that are likely to have diverged a relatively long time in the past. However, many taxa, including many which occur sympatrically and do not interbreed in nature, produce viable, fertile hybrids. Prezygotic barriers are more important, and persist in laboratory conditions in which environmental factors have been controlled, indicating the primary importance of direct mate preferences. Studies to date indicate that estimates of alpha (within-site) diversity appear to be robust. Although within-species colour polymorphisms are common, these have been taken into account in previous estimates of species richness. However, overall estimates of species richness in Lakes Malawi and Victoria are heavily dependent on the assignation of species status to allopatric populations differing in male colour. Appropriate methods for testing the specific status of allopatric cichlid taxa are reviewed and preliminary results presented.

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.

The Mouse House: A brief history of the ORNL mouse-genetics program, 1947–2009

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

Russell, Liane B.

The large mouse genetics program at the Oak Ridge National Lab is often re-membered chiefly for the germ-cell mutation-rate data it generated and their uses in estimating the risk of heritable radiation damage. In fact, it soon became a multi-faceted research effort that, over a period of almost 60 years, generated a wealth of information in the areas of mammalian mutagenesis, basic genetics (later enriched by molecular techniques), cytogenetics, reproductive biology, biochemistry of germ cells, and teratology. Research in the area of germ-cell mutagenesis explored the important physical and biological factors that affect the frequency and nature of induced mutationsmore » and made several unexpected discoveries, such as the major importance of the perigametic interval (the zygote stage) for the origin of spontaneous mutations and for the sensitivity to induced genetic change. Of practical value was the discovery that ethylnitrosourea was a supermutagen for point mutations, making high-efficiency mutagenesis in the mouse feasible worldwide. Teratogenesis findings resulted in recommendations still generally accepted in radiological practice. Studies supporting the mutagenesis research added whole bodies of information about mammalian germ-cell development and about molecular targets in germ cells. The early decision to not merely count but propagate genetic variants of all sorts made possible further discoveries, such as the Y-Chromosome s importance in mammalian sex determination and the identification of rare X-autosome translocations, which, in turn, led to the formulation of the single-active-X hypothesis and provided tools for studies of functional mosaicism for autosomal genes, male sterility, and chromosome-pairing mechanism. Extensive genetic and then molecular analyses of large numbers of induced specific-locus mutants resulted in fine-structure physical and correlated functional mapping of significant portions of the mouse genome and constituted a valuable source of mouse models for human genetic disorders.« less

The Mouse House: a brief history of the ORNL mouse-genetics program, 1947-2009.

PubMed

Russell, Liane B

2013-01-01

The large mouse genetics program at the Oak Ridge National Laboratory (ORNL) is often remembered chiefly for the germ-cell mutation-rate data it generated and their uses in estimating the risk of heritable radiation damage. In fact, it soon became a multi-faceted research effort that, over a period of almost 60 years, generated a wealth of information in the areas of mammalian mutagenesis, basic genetics (later enriched by molecular techniques), cytogenetics, reproductive biology, biochemistry of germ cells, and teratology. Research in the area of germ-cell mutagenesis explored the important physical and biological factors that affect the frequency and nature of induced mutations and made several unexpected discoveries, such as the major importance of the perigametic interval (the zygote stage) for the origin of spontaneous mutations and for the sensitivity to induced genetic change. Of practical value was the discovery that ethylnitrosourea was a supermutagen for point mutations, making high-efficiency mutagenesis in the mouse feasible worldwide. Teratogenesis findings resulted in recommendations still generally accepted in radiological practice. Studies supporting the mutagenesis research added whole bodies of information about mammalian germ-cell development and about molecular targets in germ cells. The early decision to not merely count but propagate genetic variants of all sorts made possible further discoveries, such as the Y-chromosome's importance in mammalian sex determination and the identification of rare X-autosome translocations, which, in turn, led to the formulation of the single-active-X hypothesis and provided tools for studies of functional mosaicism for autosomal genes, male sterility, and chromosome-pairing mechanism. Extensive genetic and then molecular analyses of large numbers of induced specific-locus mutants resulted in fine-structure physical and correlated functional mapping of significant portions of the mouse genome and constituted a valuable source of mouse models for human genetic disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

Multiplicity Control in Structural Equation Modeling

ERIC Educational Resources Information Center

Cribbie, Robert A.

2007-01-01

Researchers conducting structural equation modeling analyses rarely, if ever, control for the inflated probability of Type I errors when evaluating the statistical significance of multiple parameters in a model. In this study, the Type I error control, power and true model rates of famsilywise and false discovery rate controlling procedures were…

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...

ksc-88pc-1176

NASA Image and Video Library

1988-09-29

NASA employees, their family and friends gather on the NASA causeway over the Banana River, south of Kennedy Space Center, the morning of the launch of STS-26 and the Space Shuttle Discovery. An estimated 1 million people were expected to view the 11:37 a.m. launch from various locations in Central Florida

OGLE16aaa - a signature of a hungry supermassive black hole

NASA Astrophysics Data System (ADS)

Wyrzykowski, Łukasz; Zieliński, M.; Kostrzewa-Rutkowska, Z.; Hamanowicz, A.; Jonker, P. G.; Arcavi, I.; Guillochon, J.; Brown, P. J.; Kozłowski, S.; Udalski, A.; Szymański, M. K.; Soszyński, I.; Poleski, R.; Pietrukowicz, P.; Skowron, J.; Mróz, P.; Ulaczyk, K.; Pawlak, M.; Rybicki, K. A.; Greiner, J.; Krühler, T.; Bolmer, J.; Smartt, S. J.; Maguire, K.; Smith, K.

2017-02-01

We present the discovery and first three months of follow-up observations of a currently on-going unusual transient detected by the Optical Gravitational Lensing Experiment (OGLE-IV) survey, located in the centre of a galaxy at redshift z = 0.1655. The long rise to absolute magnitude of -20.5 mag, slow decline, very broad He and H spectral features make OGLE16aaa similar to other optical/UV tidal disruption events (TDEs). Weak narrow emission lines in the spectrum and archival photometric observations suggest the host galaxy is a weak-line active galactic nucleus, which has been accreting at higher rate in the past. OGLE16aaa, along with SDSS J0748, seems to form a sub-class of TDEs by weakly or recently active supermassive black holes (SMBHs). This class might bridge the TDEs by quiescent SMBHs and flares observed as `changing-look quasars', if we interpret the latter as TDEs. If this picture is true, the previously applied requirement for identifying a flare as a TDE that it had to come from an inactive nucleus, could be leading to observational bias in TDE selection, thus affecting TDE-rate estimations.

The Fast and Non-capillary Fluid Filling Mechanism in the Hummingbird's Tongue

NASA Astrophysics Data System (ADS)

Rico-Guevara, Alejandro; Fan, Tai-Hsi; Rubega, Margaret

2014-03-01

Hummingbirds gather nectar by inserting their beaks inside flowers and cycling their tongues at a frequency of up to 20 Hz. It is unclear how they achieve efficiency at this high licking rate. Ever since proposed in 1833, it has been believed that hummingbird tongues are a pair of tiny straws filled with nectar by capillary rise. Our discoveries are very different from this general consensus. The tongue does not draw up floral nectar via capillary action under experimental conditions that resemble natural ones. Theoretical models based on capillary rise were mistaken and unsuitable for estimating the fluid intake rate and to support foraging theories. We filmed (up to 1265 frames/s) the fluid uptake in 20 species of hummingbirds that belong to 7 out of the 9 main hummingbird clades. We found that the fluid filling within the portions of the tongue that remain outside the nectar is about five times faster than capillary filling. We present strong evidence to rule out the capillarity model. We introduce a new fluid-structure interaction and hydrodynamic model and compare the results with field experimental data to explain how hummingbirds actually extract fluid from flowers at the lick level.

Photodegradation of methylmercury in lakes

NASA Astrophysics Data System (ADS)

Seller, P.; Kelly, C. A.; Rudd, J. W. M.; Machutchon, A. R.

1996-04-01

METHYLMERCURY can accumulate in fish to concentrations that threaten human health1. Fish methylmercury concentrations are high in many reservoirs2 and acidic lakes3, and also in many remote lakes4,5-a fact that may be related to increased atmospheric deposition of anthropogenically mobilized mercury during the past few decades6. Although sources of methylmercury to lakes and reservoirs are known7, in-lake destruction has not been demonstrated to occur at the low concentrations found in most water bodies. Here we report in situ incubations of lake water that show that methylmercury is decomposed by photo- degradation in surface waters. This process is abiotic and the rate is first-order with respect to methylmercury concentration and the intensity of solar radiation. In our study lake, the calculated annual rates of methylmercury photodegradation are almost double the estimated external inputs of methylmercury from rain, snow, streamflow and land runoff, implying the existence of a large source of methylmercury from bottom sediments. Photodegradation could also be an important process in the mercury cycle of other aquatic systems. This discovery fundamentally changes our understanding of aquatic mercury cycling, and challenges the long-accepted view that microbial demethylation dominates methylmercury degradation in natural fresh waters.

Difference between two species of emu hides a test for lepton flavour violation

NASA Astrophysics Data System (ADS)

Lester, Christopher G.; Brunt, Benjamin H.

2017-03-01

We argue that an LHC measurement of some simple quantities related to the ratio of rates of e + μ - to e - μ + events is surprisingly sensitive to as-yet unexcluded R-parity violating supersymmetric models with non-zero λ 231 ' couplings. The search relies upon the approximate lepton universality in the Standard Model, the sign of the charge of the proton, and a collection of favourable detector biases. The proposed search is unusual because: it does not require any of the displaced vertices, hadronic neutralino decay products, or squark/gluino production relied upon by existing LHC RPV searches; it could work in cases in which the only light sparticles were smuons and neutralinos; and it could make a discovery (though not necessarily with optimal significance) without requiring the computation of a leading-order Monte Carlo estimate of any background rate. The LHC has shown no strong hints of post-Higgs physics and so precision Standard Model measurements are becoming ever more important. We argue that in this environment growing profits are to be made from searches that place detector biases and symmetries of the Standard Model at their core — searches based around `controls' rather than around signals.

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

Detecting dark-matter waves with a network of precision-measurement tools

NASA Astrophysics Data System (ADS)

Derevianko, Andrei

2018-04-01

Virialized ultralight fields (VULFs) are viable cold dark-matter candidates and include scalar and pseudoscalar bosonic fields, such as axions and dilatons. Direct searches for VULFs rely on low-energy precision-measurement tools. While previous proposals have focused on detecting coherent oscillations of the VULF signals at the VULF Compton frequencies for individual devices, here I consider a network of such devices. Virialized ultralight fields are essentially dark-matter waves and as such they carry both temporal and spatial phase information. Thereby, the discovery reach can be improved by using networks of precision-measurement tools. To formalize this idea, I derive a spatiotemporal two-point correlation function for the ultralight dark-matter fields in the framework of the standard halo model. Due to VULFs being Gaussian random fields, the derived two-point correlation function fully determines N -point correlation functions. For a network of ND devices within the coherence length of the field, the sensitivity compared to a single device can be improved by a factor of √{ND}. Further, I derive a VULF dark-matter signal profile for an individual device. The resulting line shape is strongly asymmetric due to the parabolic dispersion relation for massive nonrelativistic bosons. I discuss the aliasing effect that extends the discovery reach to VULF frequencies higher than the experimental sampling rate. I present sensitivity estimates and develop a stochastic field signal-to-noise ratio statistic. Finally, I consider an application of the formalism developed to atomic clocks and their networks.

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.

Cancer biomarker discovery is improved by accounting for variability in general levels of drug sensitivity in pre-clinical models.

PubMed

Geeleher, Paul; Cox, Nancy J; Huang, R Stephanie

2016-09-21

We show that variability in general levels of drug sensitivity in pre-clinical cancer models confounds biomarker discovery. However, using a very large panel of cell lines, each treated with many drugs, we could estimate a general level of sensitivity to all drugs in each cell line. By conditioning on this variable, biomarkers were identified that were more likely to be effective in clinical trials than those identified using a conventional uncorrected approach. We find that differences in general levels of drug sensitivity are driven by biologically relevant processes. We developed a gene expression based method that can be used to correct for this confounder in future studies.

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.

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

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

Growth in conventional fields in high-cost areas: a case study

USGS Publications Warehouse

Attanasi, E.D.

2000-01-01

Exploration managers commonly base future drilling decisions on past experience in an area. To do this well, they should consider both discovered and undiscovered resources to characterize total future potential. Discovery-size estimates should be adjusted to account for future field growth; otherwise, the relative efficiency of recent exploration will be undervalued. This study models and projects field growth for pre-1997 discoveries in the U.S. Federal Gulf of Mexico (GOM) Outer Continental Shelf (OCS). Projected additions to reserves for these fields from field growth through 2020 are 5.2 billion bbl of oil and 46 Tcfg. Projections include growth associated with sizable new oil discoveries in deepwater areas and initial reserve additions from new subsalt plays discovered through 1996. This article focuses on the U.S. GOM because it has produced longer than other worldwide offshore areas. Its field-growth profile may be prototypical of other offshore provinces such as the North Sea, Scotian Shelf and deepwater Angola, as well as high-cost onshore areas.

A brief history of Alzheimer's disease gene discovery.

PubMed

Tanzi, Rudolph E

2013-01-01

The rich and colorful history of gene discovery in Alzheimer's disease (AD) over the past three decades is as complex and heterogeneous as the disease, itself. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations inAPP, PSEN1, and PSEN2 are fully penetrant for early-onset (<60 years) familial AD, which represents <5% of AD. On the other hand, common gene polymorphisms, such as the 4 and 2 variants of the APOE gene, influence susceptibility for common (>95%) late-onset AD. These four genes account for 30-50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of additional highly confirmed AD candidate genes. Here, I review the past, present, and future of attempts to elucidate the complex and heterogeneous genetic underpinnings of AD along with some of the unique events that made these discoveries possible.

Computer-Aided Drug Discovery Approaches against the Tropical Infectious Diseases Malaria, Tuberculosis, Trypanosomiasis, and Leishmaniasis.

PubMed

Njogu, Peter M; Guantai, Eric M; Pavadai, Elumalai; Chibale, Kelly

2016-01-08

Despite the tremendous improvement in overall global health heralded by the adoption of the Millennium Declaration in the year 2000, tropical infections remain a major health problem in the developing world. Recent estimates indicate that the major tropical infectious diseases, namely, malaria, tuberculosis, trypanosomiasis, and leishmaniasis, account for more than 2.2 million deaths and a loss of approximately 85 million disability-adjusted life years annually. The crucial role of chemotherapy in curtailing the deleterious health and economic impacts of these infections has invigorated the search for new drugs against tropical infectious diseases. The research efforts have involved increased application of computational technologies in mainstream drug discovery programs at the hit identification, hit-to-lead, and lead optimization stages. This review highlights various computer-aided drug discovery approaches that have been utilized in efforts to identify novel antimalarial, antitubercular, antitrypanosomal, and antileishmanial agents. The focus is largely on developments over the past 5 years (2010-2014).

New approaches to structure-based discovery of dengue protease inhibitors.

PubMed

Tomlinson, S M; Malmstrom, R D; Watowich, S J

2009-06-01

Dengue virus (DENV), a member of the family Flaviviridae, presents a tremendous threat to global health since an estimated 2.5 billion people worldwide are at risk for epidemic transmission. DENV infections are primarily restricted to sub-tropical and tropical regions; however, there is concern that the virus will spread into new regions including the United States. There are no approved antiviral drugs or vaccines to combat dengue infection, although DENV vaccines have entered Phase 3 clinical trials. Drug discovery and development efforts against DENV and other viral pathogens must overcome specificity, efficacy, safety, and resistance challenges before the shortage of licensed drugs to treat viral infections can be relieved. Current drug discovery methods are largely inefficient and thus relatively ineffective at tackling the growing threat to public health presented by emerging and remerging viral pathogens. This review discusses current and newly implemented structure-based computational efforts to discover antivirals that target the DENV NS3 protease, although it is clear that these computational tools can be applied to most disease targets.

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.

Terrestrial cosmogenic 3He: where are we 30 years after its discovery?

NASA Astrophysics Data System (ADS)

Blard, Pierre-Henri; Pik, Raphaël; Farley, Kenneth A.; Lavé, Jérôme; Marrocchi, Yves

2016-04-01

It is now 30 years since cosmogenic 3He has been detected for the first time in a terrestrial sample (Kurz, 1986). 3He is now a widely used geochemical tool in many fields of Earth sciences: volcanology, tectonics, paleoclimatology. 3He has the advantage to have a high "production rate" to "detection limit" ratio, allowing surfaces as young as hundred of years to be dated. Although its nuclear stability implies several limitations, it moreover represents a useful alternative to 10Be in mafic environments. This contribution is a review of the progresses that have been accomplished since this discovery, and discuss strategies to improve both the accuracy and the precision of this geochronometer. 1) Measurement of cosmogenic 3He Correction of magmatic 3He. To estimate the non-cosmogenic magmatic 3He, Kurz (1986) invented a two steps method involving crushing of phenocrysts (to analyze the isotopic ratio of the magmatic component), followed by a subsequent melting of the sample, to extract the remaining components, including the cosmogenic 3He: 3Hec = 3Hemelt -4Hemelt x (3He/4He)magmatic (1) Several studies suggested that the preliminary crushing may induce a loss of cosmogenic 3He (Hilton et al., 1993; Yokochi et al., 2005; Blard et al., 2006), implying an underestimate of the cosmogenic 3He measurement. However, subsequent work did not replicate these observations (Blard et al., 2008; Goerhing et al., 2010), suggesting an influence of the used apparatus. An isochron method (by directly melting several phenocrysts aliquots) is an alternative to avoid the preliminary crushing step (Blard and Pik, 2008). Atmospheric contamination. Protin et al. (in press) provides robust evidences for a large and irreversible contamination of atmospheric helium on silicate surfaces. This unexpected behavior may reconcile the contrasted observations about the amplitude of crushing loss. This undesirable atmospheric contamination is negligible if grain fractions smaller than 150 mm are removed before melting. Correction of radiogenic 4He and nucleogenic 3He. Equation 1 is valid only if the 4He extracted by melting is entirely magmatic. To account for a possible radiogenic 4He component, it is crucial to properly estimate the radiogenic 4He production rate, by measuring the U, Th and Sm concentrations of both phenocryst and host, and the phenocryst size. Estimating the nucleogenic 3He also requires measuring Li in the phenocryst. Accuracy of analytical systems. A recent inter-laboratory comparison involving 6 different groups indicated systematic offsets between labs (up to 7%) (Blard et al., 2015). Efforts must be pursued to remove these inaccuracies. 2) Production rates Absolute calibration. There are 25 3He calibration sites among the world, from -47° S to 64° N in latitude, and from 35 to 3800 m in elevation. After scaling these production rates to sea level high latitude, this dataset reveals a significant statistical dispersion (ca. 13%). Efforts should be focused on regions that are free of data and others, such as the Eastern Atlantic that yields values systematically off. 3He/10Be cross calibrations. Some studies (Gayer et al., 2004 ; Amidon et al., 2009) identified an altitude dependence of the 3He/10Be production ratio in the Himalayas, while other data from the Andes and Africa did not (Blard et al., 2013b ; Schimmelpfennig et al., 2011). There is thus a crucial need for new data at high and low elevation, with and without snow, to precisely quantify the cosmogenic thermal neutron production. Artificial target experiments may also be useful.

Prediction and discovery of new geothermal resources in the Great Basin: Multiple evidence of a large undiscovered resource base

USGS Publications Warehouse

Coolbaugh, M.F.; Raines, G.L.; Zehner, R.E.; Shevenell, L.; Williams, C.F.

2006-01-01

Geothermal potential maps by themselves cannot directly be used to estimate undiscovered resources. To address the undiscovered resource base in the Great Basin, a new and relatively quantitative methodology is presented. The methodology involves three steps, the first being the construction of a data-driven probabilistic model of the location of known geothermal systems using weights of evidence. The second step is the construction of a degree-of-exploration model. This degree-of-exploration model uses expert judgment in a fuzzy logic context to estimate how well each spot in the state has been explored, using as constraints digital maps of the depth to the water table, presence of the carbonate aquifer, and the location, depth, and type of drill-holes. Finally, the exploration model and the data-driven occurrence model are combined together quantitatively using area-weighted modifications to the weights-of-evidence equations. Using this methodology in the state of Nevada, the number of undiscovered geothermal systems with reservoir temperatures ???100??C is estimated at 157, which is 3.2 times greater than the 69 known systems. Currently, nine of the 69 known systems are producing electricity. If it is conservatively assumed that an additional nine for a total of 18 of the known systems will eventually produce electricity, then the model predicts 59 known and undiscovered geothermal systems are capable of producing electricity under current economic conditions in the state, a figure that is more than six times higher than the current number. Many additional geothermal systems could potentially become economic under improved economic conditions or with improved methods of reservoir stimulation (Enhanced Geothermal Systems).This large predicted geothermal resource base appears corroborated by recent grass-roots geothermal discoveries in the state of Nevada. At least two and possibly three newly recognized geothermal systems with estimated reservoir temperatures ???150??C have been identified on the Pyramid Lake Paiute Reservation in west-central Nevada. Evidence of three blind geothermal systems has recently been uncovered near the borate-bearing playas at Rhodes, Teels, and Columbus Marshes in southwestern Nevada. Recent gold exploration drilling has resulted in at least four new geothermal discoveries, including the McGinness Hills geothermal system with an estimated reservoir temperature of roughly 200??C. All of this evidence suggests that the potential for expansion of geothermal power production in Nevada is significant.

The Solar Neighborhood. XXVII. Discovery of New Proper Motion Stars with μ >= 0farcs18 yr-1 in the Southern Sky with 16.5 < R 59F <= 18.0

NASA Astrophysics Data System (ADS)

Boyd, Mark R.; Henry, Todd J.; Jao, Wei-Chun; Subasavage, John P.; Hambly, Nigel C.

2011-09-01

Here we present 1584 new southern proper motion systems with μ >= 0farcs18 yr-1 and 16.5 > R 59F >= 18.0. This search complements the six previous SuperCOSMOS-RECONS (SCR) proper motion searches of the southern sky for stars within the same proper motion range, but with R 59F <= 16.5. As in previous papers, we present distance estimates for these systems and find that three systems are estimated to be within 25 pc, including one, SCR 1546-5534, possibly within the RECONS 10 pc horizon at 6.7 pc, making it the second nearest discovery of the searches. We find 97 white dwarf candidates with distance estimates between 10 and 120 pc, as well as 557 cool subdwarf candidates. The subdwarfs found in this paper make up nearly half of the subdwarf systems reported from our SCR searches and are significantly redder than those discovered thus far. The SCR searches have now found 155 red dwarfs estimated to be within 25 pc, including 10 within 10 pc. In addition, 143 white dwarf candidates and 1155 cool subdwarf candidates have been discovered. The 1584 systems reported here augment the sample of 4724 systems previously discovered in our SCR searches and imply that additional systems fainter than R 59F = 18.0 are yet to be discovered.

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.

Inferring Planet Occurrence Rates With a Q1-Q16 Kepler Planet Candidate Catalog Produced by a Machine Learning Classifier

NASA Astrophysics Data System (ADS)

Catanzarite, Joseph; Jenkins, Jon Michael; Burke, Christopher J.; McCauliff, Sean D.; Kepler Science Operations Center

2015-01-01

NASA's Kepler Space Telescope monitored the photometric variations of over 170,000 stars within a ~100 square degree field in the constellation Cygnus, at half-hour cadence, over its four year prime mission. The Kepler SOC (Science Operations Center) pipeline calibrates the pixels of the target apertures for each star, corrects light curves for systematic error, and detects TCEs (threshold-crossing events) that may be due to transiting planets. Finally the pipeline estimates planet parameters for all TCEs and computes quantitative diagnostics that are used by the TCERT (Threshold Crossing Event Review Team) to produce a catalog containing KOIs (Kepler Objects of Interest). KOIs are TCEs that are determined to be either likely transiting planets or astrophysical false positives such as background eclipsing binary stars. Using examples from the Q1-Q16 TCERT KOI catalog as a training set, we created a machine-learning classifier that dispositions the TCEs into categories of PC (planet candidate), AFP (astrophysical false positive) and NTP (non-transiting phenomenon). The classifier uniformly and consistently applies heuristics developed by TCERT as well as other diagnostics to the Q1-Q16 TCEs to produce a more robust and reliable catalog of planet candidates than is possible with only human classification. In this work, we estimate planet occurrence rates, based on the machine-learning-produced catalog of Kepler planet candidates. Kepler was selected as the 10th mission of the Discovery Program. Funding for this mission is provided by NASA, Science Mission Directorate.

Q-nexus: a comprehensive and efficient analysis pipeline designed for ChIP-nexus.

PubMed

Hansen, Peter; Hecht, Jochen; Ibn-Salem, Jonas; Menkuec, Benjamin S; Roskosch, Sebastian; Truss, Matthias; Robinson, Peter N

2016-11-04

ChIP-nexus, an extension of the ChIP-exo protocol, can be used to map the borders of protein-bound DNA sequences at nucleotide resolution, requires less input DNA and enables selective PCR duplicate removal using random barcodes. However, the use of random barcodes requires additional preprocessing of the mapping data, which complicates the computational analysis. To date, only a very limited number of software packages are available for the analysis of ChIP-exo data, which have not yet been systematically tested and compared on ChIP-nexus data. Here, we present a comprehensive software package for ChIP-nexus data that exploits the random barcodes for selective removal of PCR duplicates and for quality control. Furthermore, we developed bespoke methods to estimate the width of the protected region resulting from protein-DNA binding and to infer binding positions from ChIP-nexus data. Finally, we applied our peak calling method as well as the two other methods MACE and MACS2 to the available ChIP-nexus data. The Q-nexus software is efficient and easy to use. Novel statistics about duplication rates in consideration of random barcodes are calculated. Our method for the estimation of the width of the protected region yields unbiased signatures that are highly reproducible for biological replicates and at the same time very specific for the respective factors analyzed. As judged by the irreproducible discovery rate (IDR), our peak calling algorithm shows a substantially better reproducibility. An implementation of Q-nexus is available at http://charite.github.io/Q/ .

Circulation, retention, and mixing of waters within the Weddell-Scotia Confluence, Southern Ocean: The role of stratified Taylor columns

NASA Astrophysics Data System (ADS)

Meredith, Michael P.; Meijers, Andrew S.; Naveira Garabato, Alberto C.; Brown, Peter J.; Venables, Hugh J.; Abrahamsen, E. Povl; Jullion, Loïc.; Messias, Marie-José

2015-01-01

The waters of the Weddell-Scotia Confluence (WSC) lie above the rugged topography of the South Scotia Ridge in the Southern Ocean. Meridional exchanges across the WSC transfer water and tracers between the Antarctic Circumpolar Current (ACC) to the north and the subpolar Weddell Gyre to the south. Here, we examine the role of topographic interactions in mediating these exchanges, and in modifying the waters transferred. A case study is presented using data from a free-drifting, intermediate-depth float, which circulated anticyclonically over Discovery Bank on the South Scotia Ridge for close to 4 years. Dimensional analysis indicates that the local conditions are conducive to the formation of Taylor columns. Contemporaneous ship-derived transient tracer data enable estimation of the rate of isopycnal mixing associated with this column, with values of O(1000 m2/s) obtained. Although necessarily coarse, this is of the same order as the rate of isopycnal mixing induced by transient mesoscale eddies within the ACC. A picture emerges of the Taylor column acting as a slow, steady blender, retaining the waters in the vicinity of the WSC for lengthy periods during which they can be subject to significant modification. A full regional float data set, bathymetric data, and a Southern Ocean state estimate are used to identify other potential sites for Taylor column formation. We find that they are likely to be sufficiently widespread to exert a significant influence on water mass modification and meridional fluxes across the southern edge of the ACC in this sector of the Southern Ocean.

POWER-ENHANCED MULTIPLE DECISION FUNCTIONS CONTROLLING FAMILY-WISE ERROR AND FALSE DISCOVERY RATES.

PubMed

Peña, Edsel A; Habiger, Joshua D; Wu, Wensong

2011-02-01

Improved procedures, in terms of smaller missed discovery rates (MDR), for performing multiple hypotheses testing with weak and strong control of the family-wise error rate (FWER) or the false discovery rate (FDR) are developed and studied. The improvement over existing procedures such as the Šidák procedure for FWER control and the Benjamini-Hochberg (BH) procedure for FDR control is achieved by exploiting possible differences in the powers of the individual tests. Results signal the need to take into account the powers of the individual tests and to have multiple hypotheses decision functions which are not limited to simply using the individual p -values, as is the case, for example, with the Šidák, Bonferroni, or BH procedures. They also enhance understanding of the role of the powers of individual tests, or more precisely the receiver operating characteristic (ROC) functions of decision processes, in the search for better multiple hypotheses testing procedures. A decision-theoretic framework is utilized, and through auxiliary randomizers the procedures could be used with discrete or mixed-type data or with rank-based nonparametric tests. This is in contrast to existing p -value based procedures whose theoretical validity is contingent on each of these p -value statistics being stochastically equal to or greater than a standard uniform variable under the null hypothesis. Proposed procedures are relevant in the analysis of high-dimensional "large M , small n " data sets arising in the natural, physical, medical, economic and social sciences, whose generation and creation is accelerated by advances in high-throughput technology, notably, but not limited to, microarray technology.

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.

The variability of the rainfall rate as a function of area

NASA Astrophysics Data System (ADS)

Jameson, A. R.; Larsen, M. L.

2016-01-01

Distributions of drop sizes can be expressed as DSD = Nt × PSD, where Nt is the total number of drops in a sample and PSD is the frequency distribution of drop diameters (D). Their discovery permitted remote sensing techniques for rainfall estimation using radars and satellites measuring over large domains of several kilometers. Because these techniques depend heavily on higher moments of the PSD, there has been a bias toward attributing the variability of the intrinsic rainfall rates R over areas (σR) to the variability of the PSDs. While this variability does increase up to a point with increasing domain dimension L, the variability of the rainfall rate R also depends upon the variability in the total number of drops Nt. We show that while the importance of PSDs looms large for small domains used in past studies, it is the variability of Nt that dominates the variability of R as L increases to 1 km and beyond. The PSDs contribute to the variability of R through the relative dispersion of χ = D3Vt, where Vt is the terminal fall speed of drops of diameter D. However, the variability of χ is inherently limited because drop sizes and fall speeds are physically limited. In contrast, it is shown that the variance of Nt continuously increases as the domain expands for physical reasons explained below. Over domains larger than around 1 km, it is shown that Nt dominates the variance of the rainfall rate with increasing L regardless of the PSD.

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.

Directed Shotgun Proteomics Guided by Saturated RNA-seq Identifies a Complete Expressed Prokaryotic Proteome

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

Omasits, U.; Quebatte, Maxime; Stekhoven, Daniel J.

2013-11-01

Prokaryotes, due to their moderate complexity, are particularly amenable to the comprehensive identification of the protein repertoire expressed under different conditions. We applied a generic strategy to identify a complete expressed prokaryotic proteome, which is based on the analysis of RNA and proteins extracted from matched samples. Saturated transcriptome profiling by RNA-seq provided an endpoint estimate of the protein-coding genes expressed under two conditions which mimic the interaction of Bartonella henselae with its mammalian host. Directed shotgun proteomics experiments were carried out on four subcellular fractions. By specifically targeting proteins which are short, basic, low abundant, and membrane localized, wemore » could eliminate their initial underrepresentation compared to the estimated endpoint. A total of 1250 proteins were identified with an estimated false discovery rate below 1%. This represents 85% of all distinct annotated proteins and ~90% of the expressed protein-coding genes. Genes that were detected at the transcript but not protein level, were found to be highly enriched in several genomic islands. Furthermore, genes that lacked an ortholog and a functional annotation were not detected at the protein level; these may represent examples of overprediction in genome annotations. A dramatic membrane proteome reorganization was observed, including differential regulation of autotransporters, adhesins, and hemin binding proteins. Particularly noteworthy was the complete membrane proteome coverage, which included expression of all members of the VirB/D4 type IV secretion system, a key virulence factor.« less

Directed shotgun proteomics guided by saturated RNA-seq identifies a complete expressed prokaryotic proteome

PubMed Central

Omasits, Ulrich; Quebatte, Maxime; Stekhoven, Daniel J.; Fortes, Claudia; Roschitzki, Bernd; Robinson, Mark D.; Dehio, Christoph; Ahrens, Christian H.

2013-01-01

Prokaryotes, due to their moderate complexity, are particularly amenable to the comprehensive identification of the protein repertoire expressed under different conditions. We applied a generic strategy to identify a complete expressed prokaryotic proteome, which is based on the analysis of RNA and proteins extracted from matched samples. Saturated transcriptome profiling by RNA-seq provided an endpoint estimate of the protein-coding genes expressed under two conditions which mimic the interaction of Bartonella henselae with its mammalian host. Directed shotgun proteomics experiments were carried out on four subcellular fractions. By specifically targeting proteins which are short, basic, low abundant, and membrane localized, we could eliminate their initial underrepresentation compared to the estimated endpoint. A total of 1250 proteins were identified with an estimated false discovery rate below 1%. This represents 85% of all distinct annotated proteins and ∼90% of the expressed protein-coding genes. Genes that were detected at the transcript but not protein level, were found to be highly enriched in several genomic islands. Furthermore, genes that lacked an ortholog and a functional annotation were not detected at the protein level; these may represent examples of overprediction in genome annotations. A dramatic membrane proteome reorganization was observed, including differential regulation of autotransporters, adhesins, and hemin binding proteins. Particularly noteworthy was the complete membrane proteome coverage, which included expression of all members of the VirB/D4 type IV secretion system, a key virulence factor. PMID:23878158

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

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.

Estimating the diversity of dinosaurs

NASA Astrophysics Data System (ADS)

Wang, Steve C.; Dodson, Peter

2006-09-01

Despite current interest in estimating the diversity of fossil and extant groups, little effort has been devoted to estimating the diversity of dinosaurs. Here we estimate the diversity of nonavian dinosaurs at ≈1,850 genera, including those that remain to be discovered. With 527 genera currently described, at least 71% of dinosaur genera thus remain unknown. Although known diversity declined in the last stage of the Cretaceous, estimated diversity was steady, suggesting that dinosaurs as a whole were not in decline in the 10 million years before their ultimate extinction. We also show that known diversity is biased by the availability of fossiliferous rock outcrop. Finally, by using a logistic model, we predict that 75% of discoverable genera will be known within 60-100 years and 90% within 100-140 years. Because of nonrandom factors affecting the process of fossil discovery (which preclude the possibility of computing realistic confidence bounds), our estimate of diversity is likely to be a lower bound.

Genome-wide gene–environment interaction analysis for asbestos exposure in lung cancer susceptibility

PubMed Central

Wei, Qingyi Wei

2012-01-01

Asbestos exposure is a known risk factor for lung cancer. Although recent genome-wide association studies (GWASs) have identified some novel loci for lung cancer risk, few addressed genome-wide gene–environment interactions. To determine gene–asbestos interactions in lung cancer risk, we conducted genome-wide gene–environment interaction analyses at levels of single nucleotide polymorphisms (SNPs), genes and pathways, using our published Texas lung cancer GWAS dataset. This dataset included 317 498 SNPs from 1154 lung cancer cases and 1137 cancer-free controls. The initial SNP-level P-values for interactions between genetic variants and self-reported asbestos exposure were estimated by unconditional logistic regression models with adjustment for age, sex, smoking status and pack-years. The P-value for the most significant SNP rs13383928 was 2.17×10–6, which did not reach the genome-wide statistical significance. Using a versatile gene-based test approach, we found that the top significant gene was C7orf54, located on 7q32.1 (P = 8.90×10–5). Interestingly, most of the other significant genes were located on 11q13. When we used an improved gene-set-enrichment analysis approach, we found that the Fas signaling pathway and the antigen processing and presentation pathway were most significant (nominal P < 0.001; false discovery rate < 0.05) among 250 pathways containing 17 572 genes. We believe that our analysis is a pilot study that first describes the gene–asbestos interaction in lung cancer risk at levels of SNPs, genes and pathways. Our findings suggest that immune function regulation-related pathways may be mechanistically involved in asbestos-associated lung cancer risk. Abbreviations:CIconfidence intervalEenvironmentFDRfalse discovery rateGgeneGSEAgene-set-enrichment analysisGWASgenome-wide association studiesi-GSEAimproved gene-set-enrichment analysis approachORodds ratioSNPsingle nucleotide polymorphism PMID:22637743

Program Annual Technology Report: Physics of the Cosmos Program Office

NASA Technical Reports Server (NTRS)

Pham, Bruce Thai; Cardiff, Ann H.

2017-01-01

From ancient times, humans have looked up at the night sky and wondered: Are we alone? How did the universe come to be? How does the universe work? PCOS focuses on that last question. Scientists investigating this broad theme use the universe as their laboratory, investigating its fundamental laws and properties. They test Einstein’s General Theory of Relativity to see if our current understanding of space-time is borne out by observations. They examine the behavior of the most extreme environments – supermassive black holes, active galactic nuclei, and others – and the farthest reaches of the universe, to expand our understanding. With instruments sensitive across the spectrum, from radio, through infrared (IR), visible light, ultraviolet (UV), to X rays and gamma rays, as well as gravitational waves (GWs), they peer across billions of light-years, observing echoes of events that occurred instants after the Big Bang. Last year, the LISA Pathfinder (LPF) mission exceeded expectations in proving the maturity of technologies needed for the Laser Interferometer Space Antenna (LISA) mission, and the Laser Interferometer Gravitational-Wave Observatory (LIGO) recorded the first direct measurements of long-theorized GWs. Another surprising recent discovery is that the universe is expanding at an ever-accelerating rate, the first hint of so-called “dark energy,” estimated to account for 75% of mass-energy in the universe. Dark matter, so called because we can only observe its effects on regular matter, is thought to account for another20%, leaving only 5% for regular matter and energy. Scientists now also search for special polarization in the cosmic microwave background to support the notion that in the split-second after the Big Bang, the universe inflated faster than the speed of light! The most exciting aspect of this grand enterprise today is the extraordinary rate at which we can harness technologies to enable these key discoveries.

ksc-88pc-1193

NASA Image and Video Library

1988-09-29

KENNEDY SPACE CENTER, FLA. -- NASA employees, their families and friends gather on the NASA Causeway over the Banana River, south of Kennedy Space Center, the morning of the launch of STS-26 and the Space Shuttle Discovery. An estimated 1 million people were expected to view the 11:37 a.m. launch from various locations in Central Florida

DETECTION OF AN ULTRA-BRIGHT SUBMILLIMETER GALAXY BEHIND THE SMALL MAGELLANIC CLOUD

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

Takekoshi, Tatsuya; Minamidani, Tetsuhiro; Sorai, Kazuo

2013-09-10

We report the discovery of a new ultra-bright submillimeter galaxy (SMG) behind the Small Magellanic Cloud (SMC). This SMG is detected as a 43.3 {+-} 8.4 mJy point source (MM J01071-7302, hereafter MMJ0107) in the 1.1 mm continuum survey of the SMC by AzTEC on the ASTE telescope. MMJ0107 is also detected in the radio (843 MHz), Herschel/SPIRE, Spitzer MIPS 24 {mu}m, all IRAC bands, Wide-field Infrared Survey Explorer, and near-infrared (J, H, K{sub S} ). We find an optical (U, B, V) source, which might be the lensing object, at a distance of 1.''4 from near-infrared and IRAC sources.more » Photometric redshift estimates for the SMG using representative spectral energy distribution templates show the redshifts of 1.4-3.9. We estimate total far-infrared luminosity of (0.3-2.2) Multiplication-Sign 10{sup 14} {mu}{sup -1} L{sub Sun} and a star formation rate of 5600-39, 000 {mu}{sup -1} M{sub Sun} yr{sup -1}, where {mu} is the gravitational magnification factor. This apparent extreme star formation activity is likely explained by a highly magnified gravitational lens system.« less

An ultraluminous quasar with a twelve-billion-solar-mass black hole at redshift 6.30.

PubMed

Wu, Xue-Bing; Wang, Feige; Fan, Xiaohui; Yi, Weimin; Zuo, Wenwen; Bian, Fuyan; Jiang, Linhua; McGreer, Ian D; Wang, Ran; Yang, Jinyi; Yang, Qian; Thompson, David; Beletsky, Yuri

2015-02-26

So far, roughly 40 quasars with redshifts greater than z = 6 have been discovered. Each quasar contains a black hole with a mass of about one billion solar masses (10(9) M Sun symbol). The existence of such black holes when the Universe was less than one billion years old presents substantial challenges to theories of the formation and growth of black holes and the coevolution of black holes and galaxies. Here we report the discovery of an ultraluminous quasar, SDSS J010013.02+280225.8, at redshift z = 6.30. It has an optical and near-infrared luminosity a few times greater than those of previously known z > 6 quasars. On the basis of the deep absorption trough on the blue side of the Lyman-α emission line in the spectrum, we estimate the proper size of the ionized proximity zone associated with the quasar to be about 26 million light years, larger than found with other z > 6.1 quasars with lower luminosities. We estimate (on the basis of a near-infrared spectrum) that the black hole has a mass of ∼1.2 × 10(10) M Sun symbol, which is consistent with the 1.3 × 10(10) M Sun symbol derived by assuming an Eddington-limited accretion rate.

Identifying and Assessing Interesting Subgroups in a Heterogeneous Population

PubMed Central

Lee, Woojoo; Alexeyenko, Andrey; Pernemalm, Maria; Guegan, Justine; Dessen, Philippe; Lazar, Vladimir; Lehtiö, Janne; Pawitan, Yudi

2015-01-01

Biological heterogeneity is common in many diseases and it is often the reason for therapeutic failures. Thus, there is great interest in classifying a disease into subtypes that have clinical significance in terms of prognosis or therapy response. One of the most popular methods to uncover unrecognized subtypes is cluster analysis. However, classical clustering methods such as k-means clustering or hierarchical clustering are not guaranteed to produce clinically interesting subtypes. This could be because the main statistical variability—the basis of cluster generation—is dominated by genes not associated with the clinical phenotype of interest. Furthermore, a strong prognostic factor might be relevant for a certain subgroup but not for the whole population; thus an analysis of the whole sample may not reveal this prognostic factor. To address these problems we investigate methods to identify and assess clinically interesting subgroups in a heterogeneous population. The identification step uses a clustering algorithm and to assess significance we use a false discovery rate- (FDR-) based measure. Under the heterogeneity condition the standard FDR estimate is shown to overestimate the true FDR value, but this is remedied by an improved FDR estimation procedure. As illustrations, two real data examples from gene expression studies of lung cancer are provided. PMID:26339613

Post processing of protein-compound docking for fragment-based drug discovery (FBDD): in-silico structure-based drug screening and ligand-binding pose prediction.

PubMed

Fukunishi, Yoshifumi

2010-01-01

For fragment-based drug development, both hit (active) compound prediction and docking-pose (protein-ligand complex structure) prediction of the hit compound are important, since chemical modification (fragment linking, fragment evolution) subsequent to the hit discovery must be performed based on the protein-ligand complex structure. However, the naïve protein-compound docking calculation shows poor accuracy in terms of docking-pose prediction. Thus, post-processing of the protein-compound docking is necessary. Recently, several methods for the post-processing of protein-compound docking have been proposed. In FBDD, the compounds are smaller than those for conventional drug screening. This makes it difficult to perform the protein-compound docking calculation. A method to avoid this problem has been reported. Protein-ligand binding free energy estimation is useful to reduce the procedures involved in the chemical modification of the hit fragment. Several prediction methods have been proposed for high-accuracy estimation of protein-ligand binding free energy. This paper summarizes the various computational methods proposed for docking-pose prediction and their usefulness in FBDD.

Data sources and compilation: Chapter 27 in Petroleum systems and geologic assessment of oil and gas in the San Joaquin Basin Province, California

USGS Publications Warehouse

Klett, T.R.; Schmoker, James W.

2007-01-01

Geologic, production, and exploration/discovery-history data are used by the U.S. Geological Survey to aid in the assessment of petroleum resources. These data, as well as the broad knowledge and experience of the assessing geologists, are synthesized to provide, for each assessment unit, geologic and exploration models upon which estimates are made of the number and sizes of undiscovered accumulations for conventional assessment units or number and total recoverable volumes of untested cells for continuous assessment units (input data for resource calculations). Quantified geologic information and trends in production and exploration/discovery-history data with respect to time and exploration effort provide guides for the estimating parameters of variables recorded on the input-data forms (input data) used to calculate petroleum resources. An Assessment Review Team reviews proposed geologic and exploration models and input data for each assessment unit in formal assessment meetings. The Assessment Review Team maintains the accuracy and consistency of the assessment procedure during the formal assessment meetings.

Discovery of a Brown Dwarf Companion to Gliese 570ABC: A 2MASS T Dwarf Significantly Cooler than Gliese 229B.

PubMed

Burgasser; Kirkpatrick; Cutri; McCallon; Kopan; Gizis; Liebert; Reid; Brown; Monet; Dahn; Beichman; Skrutskie

2000-03-01

We report the discovery of a widely separated (258&farcs;3+/-0&farcs;4) T dwarf companion to the Gl 570ABC system. This new component, Gl 570D, was initially identified from the Two Micron All-Sky Survey. Its near-infrared spectrum shows the 1.6 and 2.2 µm CH4 absorption bands characteristic of T dwarfs, while its common proper motion with the Gl 570ABC system confirms companionship. Gl 570D (MJ=16.47+/-0.07) is nearly a full magnitude dimmer than the only other known T dwarf companion, Gl 229B, and estimates of L=&parl0;2.8+/-0.3&parr0;x10-6 L middle dot in circle and Teff=750+/-50 K make it significantly cooler and less luminous than any other known brown dwarf companion. Using evolutionary models by Burrows et al. and an adopted age of 2-10 Gyr, we derive a mass estimate of 50+/-20 MJup for this object.

Discovery of a z = 0.65 post-starburst BAL quasar in the DES supernova fields

DOE PAGES

Mudd, Dale; Martini, Paul; Tie, Suk Sien; ...

2017-03-23

In this paper, we present the discovery of a z = 0.65 low-ionization broad absorption line (LoBAL) quasar in a post-starburst galaxy in data from the Dark Energy Survey (DES) and spectroscopy from the Australian Dark Energy Survey (OzDES). LoBAL quasars are a minority of all BALs, and rarer still is that this object also exhibits broad Fe ii (an FeLoBAL) and Balmer absorption. This is the first BAL quasar that has signatures of recently truncated star formation, which we estimate ended about 40 Myr ago. The characteristic signatures of an FeLoBAL require high column densities, which could be explainedmore » by the emergence of a young quasar from an early, dust-enshrouded phase, or by clouds compressed by a blast wave. Finally, the age of the starburst component is comparable to estimates of the lifetime of quasars, so if we assume the quasar activity is related to the truncation of the star formation, this object is better explained by the blast wave scenario.« less

Discovery of a z = 0.65 post-starburst BAL quasar in the DES supernova fields

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

Mudd, Dale; Martini, Paul; Tie, Suk Sien

We present the discovery of a z=0.65 low-ionization broad absorption line (LoBAL) quasar in a post-starburst galaxy in data from the Dark Energy Survey (DES) and spectroscopy from the Australian Dark Energy Survey (OzDES). LoBAL quasars are a minority of all BALs, and rarer still is that this object also exhibits broad FeII (an FeLoBAL) and Balmer absorption. This is the first BAL quasar that has signatures of recently truncated star formation, which we estimate ended about 40 Myr ago. The characteristic signatures of an FeLoBAL require high column densities, which could be explained by the emergence of a youngmore » quasar from an early, dust-enshrouded phase, or by clouds compressed by a blast wave. The age of the starburst component is comparable to estimates of the lifetime of quasars, so if we assume the quasar activity is related to the truncation of the star formation, this object is better explained by the blast wave scenario.« less

Discovery of a z = 0.65 post-starburst BAL quasar in the DES supernova fields

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

Mudd, Dale; Martini, Paul; Tie, Suk Sien

In this paper, we present the discovery of a z = 0.65 low-ionization broad absorption line (LoBAL) quasar in a post-starburst galaxy in data from the Dark Energy Survey (DES) and spectroscopy from the Australian Dark Energy Survey (OzDES). LoBAL quasars are a minority of all BALs, and rarer still is that this object also exhibits broad Fe ii (an FeLoBAL) and Balmer absorption. This is the first BAL quasar that has signatures of recently truncated star formation, which we estimate ended about 40 Myr ago. The characteristic signatures of an FeLoBAL require high column densities, which could be explainedmore » by the emergence of a young quasar from an early, dust-enshrouded phase, or by clouds compressed by a blast wave. Finally, the age of the starburst component is comparable to estimates of the lifetime of quasars, so if we assume the quasar activity is related to the truncation of the star formation, this object is better explained by the blast wave scenario.« less

Sizing up the population of gamma-ray binaries

NASA Astrophysics Data System (ADS)

Dubus, Guillaume; Guillard, Nicolas; Petrucci, Pierre-Olivier; Martin, Pierrick

2017-12-01

Context. Gamma-ray binaries are thought to be composed of a young pulsar in orbit around a massive O or Be star with their gamma-ray emission powered by pulsar spin-down. The number of such systems in our Galaxy is not known. Aims: We aim to estimate the total number of gamma-ray binaries in our Galaxy and to evaluate the prospects for new detections in the GeV and TeV energy range, taking into account that their gamma-ray emission is modulated on the orbital period. Methods: We modelled the population of gamma-ray binaries and evaluated the fraction of detected systems in surveys with the Fermi-LAT (GeV), H.E.S.S., HAWC and CTA (TeV) using observation-based and synthetic template light curves. Results: The detected fraction depends more on the orbit-average flux than on the light-curve shape. Our best estimate for the number of gamma-ray binaries is 101-52+89 systems. A handful of discoveries are expected by pursuing the Fermi-LAT survey. Discoveries in TeV surveys are less likely. However, this depends on the relative amounts of power emitted in GeV and TeV domains. There could be as many as ≈ 200 HESS J0632+057-like systems with a high ratio of TeV to GeV emission compared to other gamma-ray binaries. Statistics allow for as many as three discoveries in five years of HAWC observations and five discoveries in the first two years of the CTA Galactic Plane survey. Conclusions: We favour continued Fermi-LAT observations over ground-based TeV surveys to find new gamma-ray binaries. Gamma-ray observations are most sensitive to short orbital period systems with a high spin-down pulsar power. Radio pulsar surveys (SKA) are likely to be more efficient in detecting long orbital period systems, providing a complementary probe into the gamma-ray binary population.

Systematical Optimization of Reverse-phase Chromatography for Shotgun Proteomics

PubMed Central

Xu, Ping; Duong, Duc M.; Peng, Junmin

2009-01-01

Summary We report the optimization of a common LC/MS/MS platform to maximize the number of proteins identified from a complex biological sample. The platform uses digested yeast lysate on a 75 μm internal diameter × 12 cm reverse-phase column that is combined with an LTQ-Orbitrap mass spectrometer. We first generated a yeast peptide mix that was quantified by multiple methods including the strategy of stable isotope labeling with amino acids in cell culture (SILAC). The peptide mix was analyzed on a highly reproducible, automated nanoLC/MS/MS system with systematic adjustment of loading amount, flow rate, elution gradient range and length. Interestingly, the column was found to be almost saturated by loading ~1 μg of the sample. Whereas the optimal flow rate (~0.2 μl/min) and elution buffer range (13–32% of acetonitrile) appeared to be independent of the loading amount, the best gradient length varied according to the amount of samples: 160 min for 1 μg of the peptide mix, but 40 min for 10 ng of the same sample. The effect of these parameters on elution peptide peak width is evaluated. After full optimization, 1,012 proteins (clustered in 806 groups) with an estimated protein false discovery rate of ~3% were identified in 1 μg of yeast lysate in a single 160-min LC/MS/MS run. PMID:19566079

On a Formal Tool for Reasoning About Flight Software Cost Analysis

NASA Technical Reports Server (NTRS)

Spagnuolo, John N., Jr.; Stukes, Sherry A.

2013-01-01

A report focuses on the development of flight software (FSW) cost estimates for 16 Discovery-class missions at JPL. The techniques and procedures developed enabled streamlining of the FSW analysis process, and provided instantaneous confirmation that the data and processes used for these estimates were consistent across all missions. The research provides direction as to how to build a prototype rule-based system for FSW cost estimation that would provide (1) FSW cost estimates, (2) explanation of how the estimates were arrived at, (3) mapping of costs, (4) mathematical trend charts with explanations of why the trends are what they are, (5) tables with ancillary FSW data of interest to analysts, (6) a facility for expert modification/enhancement of the rules, and (7) a basis for conceptually convenient expansion into more complex, useful, and general rule-based systems.

Estimating diversification rates for higher taxa: BAMM can give problematic estimates of rates and rate shifts.

PubMed

Meyer, Andreas L S; Wiens, John J

2018-01-01

Estimates of diversification rates are invaluable for many macroevolutionary studies. Recently, an approach called BAMM (Bayesian Analysis of Macro-evolutionary Mixtures) has become widely used for estimating diversification rates and rate shifts. At the same time, several articles have concluded that estimates of net diversification rates from the method-of-moments (MS) estimators are inaccurate. Yet, no studies have compared the ability of these two methods to accurately estimate clade diversification rates. Here, we use simulations to compare their performance. We found that BAMM yielded relatively weak relationships between true and estimated diversification rates. This occurred because BAMM underestimated the number of rates shifts across each tree, and assigned high rates to small clades with low rates. Errors in both speciation and extinction rates contributed to these errors, showing that using BAMM to estimate only speciation rates is also problematic. In contrast, the MS estimators (particularly using stem group ages), yielded stronger relationships between true and estimated diversification rates, by roughly twofold. Furthermore, the MS approach remained relatively accurate when diversification rates were heterogeneous within clades, despite the widespread assumption that it requires constant rates within clades. Overall, we caution that BAMM may be problematic for estimating diversification rates and rate shifts. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

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

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.

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.

Sex-Specific Associations between Particulate Matter Exposure and Gene Expression in Independent Discovery and Validation Cohorts of Middle-Aged Men and Women.

PubMed

Vrijens, Karen; Winckelmans, Ellen; Tsamou, Maria; Baeyens, Willy; De Boever, Patrick; Jennen, Danyel; de Kok, Theo M; Den Hond, Elly; Lefebvre, Wouter; Plusquin, Michelle; Reynders, Hans; Schoeters, Greet; Van Larebeke, Nicolas; Vanpoucke, Charlotte; Kleinjans, Jos; Nawrot, Tim S

2017-04-01

Particulate matter (PM) exposure leads to premature death, mainly due to respiratory and cardiovascular diseases. Identification of transcriptomic biomarkers of air pollution exposure and effect in a healthy adult population. Microarray analyses were performed in 98 healthy volunteers (48 men, 50 women). The expression of eight sex-specific candidate biomarker genes (significantly associated with PM 10 in the discovery cohort and with a reported link to air pollution-related disease) was measured with qPCR in an independent validation cohort (75 men, 94 women). Pathway analysis was performed using Gene Set Enrichment Analysis. Average daily PM 2.5 and PM 10 exposures over 2-years were estimated for each participant's residential address using spatiotemporal interpolation in combination with a dispersion model. Average long-term PM 10 was 25.9 (± 5.4) and 23.7 (± 2.3) μg/m 3 in the discovery and validation cohorts, respectively. In discovery analysis, associations between PM 10 and the expression of individual genes differed by sex. In the validation cohort, long-term PM 10 was associated with the expression of DNAJB5 and EAPP in men and ARHGAP4 ( p = 0.053) in women. AKAP6 and LIMK1 were significantly associated with PM 10 in women, although associations differed in direction between the discovery and validation cohorts. Expression of the eight candidate genes in the discovery cohort differentiated between validation cohort participants with high versus low PM 10 exposure (area under the receiver operating curve = 0.92; 95% CI: 0.85, 1.00; p = 0.0002 in men, 0.86; 95% CI: 0.76, 0.96; p = 0.004 in women). Expression of the sex-specific candidate genes identified in the discovery population predicted PM 10 exposure in an independent cohort of adults from the same area. Confirmation in other populations may further support this as a new approach for exposure assessment, and may contribute to the discovery of molecular mechanisms for PM-induced health effects.

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.

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.

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.

Toward global mapping of river discharge using satellite images and at-many-stations hydraulic geometry

PubMed Central

Gleason, Colin J.; Smith, Laurence C.

2014-01-01

Rivers provide critical water supply for many human societies and ecosystems, yet global knowledge of their flow rates is poor. We show that useful estimates of absolute river discharge (in cubic meters per second) may be derived solely from satellite images, with no ground-based or a priori information whatsoever. The approach works owing to discovery of a characteristic scaling law uniquely fundamental to natural rivers, here termed a river’s at-many-stations hydraulic geometry. A first demonstration using Landsat Thematic Mapper images over three rivers in the United States, Canada, and China yields absolute discharges agreeing to within 20–30% of traditional in situ gauging station measurements and good tracking of flow changes over time. Within such accuracies, the door appears open for quantifying river resources globally with repeat imaging, both retroactively and henceforth into the future, with strong implications for water resource management, food security, ecosystem studies, flood forecasting, and geopolitics. PMID:24639551

RUBIC identifies driver genes by detecting recurrent DNA copy number breaks

PubMed Central

van Dyk, Ewald; Hoogstraat, Marlous; ten Hoeve, Jelle; Reinders, Marcel J. T.; Wessels, Lodewyk F. A.

2016-01-01

The frequent recurrence of copy number aberrations across tumour samples is a reliable hallmark of certain cancer driver genes. However, state-of-the-art algorithms for detecting recurrent aberrations fail to detect several known drivers. In this study, we propose RUBIC, an approach that detects recurrent copy number breaks, rather than recurrently amplified or deleted regions. This change of perspective allows for a simplified approach as recursive peak splitting procedures and repeated re-estimation of the background model are avoided. Furthermore, we control the false discovery rate on the level of called regions, rather than at the probe level, as in competing algorithms. We benchmark RUBIC against GISTIC2 (a state-of-the-art approach) and RAIG (a recently proposed approach) on simulated copy number data and on three SNP6 and NGS copy number data sets from TCGA. We show that RUBIC calls more focal recurrent regions and identifies a much larger fraction of known cancer genes. PMID:27396759

GRIDSS: sensitive and specific genomic rearrangement detection using positional de Bruijn graph assembly

PubMed Central

Do, Hongdo; Molania, Ramyar

2017-01-01

The identification of genomic rearrangements with high sensitivity and specificity using massively parallel sequencing remains a major challenge, particularly in precision medicine and cancer research. Here, we describe a new method for detecting rearrangements, GRIDSS (Genome Rearrangement IDentification Software Suite). GRIDSS is a multithreaded structural variant (SV) caller that performs efficient genome-wide break-end assembly prior to variant calling using a novel positional de Bruijn graph-based assembler. By combining assembly, split read, and read pair evidence using a probabilistic scoring, GRIDSS achieves high sensitivity and specificity on simulated, cell line, and patient tumor data, recently winning SV subchallenge #5 of the ICGC-TCGA DREAM8.5 Somatic Mutation Calling Challenge. On human cell line data, GRIDSS halves the false discovery rate compared to other recent methods while matching or exceeding their sensitivity. GRIDSS identifies nontemplate sequence insertions, microhomologies, and large imperfect homologies, estimates a quality score for each breakpoint, stratifies calls into high or low confidence, and supports multisample analysis. PMID:29097403

De Novo Coding Variants Are Strongly Associated with Tourette Disorder

PubMed Central

Willsey, A. Jeremy; Fernandez, Thomas V.; Yu, Dongmei; King, Robert A.; Dietrich, Andrea; Xing, Jinchuan; Sanders, Stephan J.; Mandell, Jeffrey D.; Huang, Alden Y.; Richer, Petra; Smith, Louw; Dong, Shan; Samocha, Kaitlin E.; Neale, Benjamin M.; Coppola, Giovanni; Mathews, Carol A.; Tischfield, Jay A.; Scharf, Jeremiah M.; State, Matthew W.; Heiman, Gary A.

2017-01-01

SUMMARY Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. PMID:28472652

PepArML: A Meta-Search Peptide Identification Platform

PubMed Central

Edwards, Nathan J.

2014-01-01

The PepArML meta-search peptide identification platform provides a unified search interface to seven search engines; a robust cluster, grid, and cloud computing scheduler for large-scale searches; and an unsupervised, model-free, machine-learning-based result combiner, which selects the best peptide identification for each spectrum, estimates false-discovery rates, and outputs pepXML format identifications. The meta-search platform supports Mascot; Tandem with native, k-score, and s-score scoring; OMSSA; MyriMatch; and InsPecT with MS-GF spectral probability scores — reformatting spectral data and constructing search configurations for each search engine on the fly. The combiner selects the best peptide identification for each spectrum based on search engine results and features that model enzymatic digestion, retention time, precursor isotope clusters, mass accuracy, and proteotypic peptide properties, requiring no prior knowledge of feature utility or weighting. The PepArML meta-search peptide identification platform often identifies 2–3 times more spectra than individual search engines at 10% FDR. PMID:25663956

Toward global mapping of river discharge using satellite images and at-many-stations hydraulic geometry.

PubMed

Gleason, Colin J; Smith, Laurence C

2014-04-01

Rivers provide critical water supply for many human societies and ecosystems, yet global knowledge of their flow rates is poor. We show that useful estimates of absolute river discharge (in cubic meters per second) may be derived solely from satellite images, with no ground-based or a priori information whatsoever. The approach works owing to discovery of a characteristic scaling law uniquely fundamental to natural rivers, here termed a river's at-many-stations hydraulic geometry. A first demonstration using Landsat Thematic Mapper images over three rivers in the United States, Canada, and China yields absolute discharges agreeing to within 20-30% of traditional in situ gauging station measurements and good tracking of flow changes over time. Within such accuracies, the door appears open for quantifying river resources globally with repeat imaging, both retroactively and henceforth into the future, with strong implications for water resource management, food security, ecosystem studies, flood forecasting, and geopolitics.

Journey to a metal world: Concept for a Discovery mission to Psyche

NASA Astrophysics Data System (ADS)

Wenkert, D.; Elkins-Tanton, L. T.; Asphaug, E. I.; Bairstow, S.; Bell, J. F.; Bercovici, D. A.; Bills, B. G.; Binzel, R. P.; Bottke, W. F.; Jun, I.; Landau, D.; Marchi, S.; Oh, D.; Weiss, B. P.; Zuber, M. T.

2013-12-01

Psyche is one of the most singular asteroids in the main belt. It is thought to be the core of a Vesta-sized planetesimal, exposed through collisions. Based on spectra, radar surface properties, and bulk density estimates, it appears to be a world not of ice or silicate rock, but of iron. By understanding its nature, we can glean insights into the differentiation of planetesimals, the growth of planets, the composition and structure of a planetary core, and the geology of a metallic body. For all of these reasons, and its relative accessibility to low cost rendezvous and orbit, Psyche is a superb target for a Discovery-class mission that would measure its geology and geomorphology, shape, composition, magnetic field, and mass distribution.

Optimized Next-Generation Sequencing Genotype-Haplotype Calling for Genome Variability Analysis

PubMed Central

Navarro, Javier; Nevado, Bruno; Hernández, Porfidio; Vera, Gonzalo; Ramos-Onsins, Sebastián E

2017-01-01

The accurate estimation of nucleotide variability using next-generation sequencing data is challenged by the high number of sequencing errors produced by new sequencing technologies, especially for nonmodel species, where reference sequences may not be available and the read depth may be low due to limited budgets. The most popular single-nucleotide polymorphism (SNP) callers are designed to obtain a high SNP recovery and low false discovery rate but are not designed to account appropriately the frequency of the variants. Instead, algorithms designed to account for the frequency of SNPs give precise results for estimating the levels and the patterns of variability. These algorithms are focused on the unbiased estimation of the variability and not on the high recovery of SNPs. Here, we implemented a fast and optimized parallel algorithm that includes the method developed by Roesti et al and Lynch, which estimates the genotype of each individual at each site, considering the possibility to call both bases from the genotype, a single one or none. This algorithm does not consider the reference and therefore is independent of biases related to the reference nucleotide specified. The pipeline starts from a BAM file converted to pileup or mpileup format and the software outputs a FASTA file. The new program not only reduces the running times but also, given the improved use of resources, it allows its usage with smaller computers and large parallel computers, expanding its benefits to a wider range of researchers. The output file can be analyzed using software for population genetics analysis, such as the R library PopGenome, the software VariScan, and the program mstatspop for analysis considering positions with missing data. PMID:28894353

Genomic patterns of introgression in rainbow and westslope cutthroat trout illuminated by overlapping paired-end RAD sequencing

USGS Publications Warehouse

Hohenlohe, Paul A.; Day, Mitch D.; Amish, Stephen J.; Miller, Michael R.; Kamps-Hughes, Nick; Boyer, Matthew C.; Muhlfeld, Clint C.; Allendorf, Fred W.; Johnson, Eric A.; Luikart, Gordon

2013-01-01

Rapid and inexpensive methods for genomewide single nucleotide polymorphism (SNP) discovery and genotyping are urgently needed for population management and conservation. In hybridized populations, genomic techniques that can identify and genotype thousands of species-diagnostic markers would allow precise estimates of population- and individual-level admixture as well as identification of 'super invasive' alleles, which show elevated rates of introgression above the genomewide background (likely due to natural selection). Techniques like restriction-site-associated DNA (RAD) sequencing can discover and genotype large numbers of SNPs, but they have been limited by the length of continuous sequence data they produce with Illumina short-read sequencing. We present a novel approach, overlapping paired-end RAD sequencing, to generate RAD contigs of >300–400 bp. These contigs provide sufficient flanking sequence for design of high-throughput SNP genotyping arrays and strict filtering to identify duplicate paralogous loci. We applied this approach in five populations of native westslope cutthroat trout that previously showed varying (low) levels of admixture from introduced rainbow trout (RBT). We produced 77 141 RAD contigs and used these data to filter and genotype 3180 previously identified species-diagnostic SNP loci. Our population-level and individual-level estimates of admixture were generally consistent with previous microsatellite-based estimates from the same individuals. However, we observed slightly lower admixture estimates from genomewide markers, which might result from natural selection against certain genome regions, different genomic locations for microsatellites vs. RAD-derived SNPs and/or sampling error from the small number of microsatellite loci (n = 7). We also identified candidate adaptive super invasive alleles from RBT that had excessively high admixture proportions in hybridized cutthroat trout populations.

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).

Testing jumps via false discovery rate control.

PubMed

Yen, Yu-Min

2013-01-01

Many recently developed nonparametric jump tests can be viewed as multiple hypothesis testing problems. For such multiple hypothesis tests, it is well known that controlling type I error often makes a large proportion of erroneous rejections, and such situation becomes even worse when the jump occurrence is a rare event. To obtain more reliable results, we aim to control the false discovery rate (FDR), an efficient compound error measure for erroneous rejections in multiple testing problems. We perform the test via the Barndorff-Nielsen and Shephard (BNS) test statistic, and control the FDR with the Benjamini and Hochberg (BH) procedure. We provide asymptotic results for the FDR control. From simulations, we examine relevant theoretical results and demonstrate the advantages of controlling the FDR. The hybrid approach is then applied to empirical analysis on two benchmark stock indices with high frequency data.

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

THE FIRST HUNDRED BROWN DWARFS DISCOVERED BY THE WIDE-FIELD INFRARED SURVEY EXPLORER (WISE)

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

Davy Kirkpatrick, J.; Gelino, Christopher R.; Griffith, Roger L.

2011-12-01

We present ground-based spectroscopic verification of 6 Y dwarfs (see also Cushing et al.), 89 T dwarfs, 8 L dwarfs, and 1 M dwarf identified by the Wide-field Infrared Survey Explorer (WISE). Eighty of these are cold brown dwarfs with spectral types {>=}T6, six of which have been announced earlier by Mainzer et al. and Burgasser et al. We present color-color and color-type diagrams showing the locus of M, L, T, and Y dwarfs in WISE color space. Near-infrared and, in a few cases, optical spectra are presented for these discoveries. Near-infrared classifications as late as early Y are presentedmore » and objects with peculiar spectra are discussed. Using these new discoveries, we are also able to extend the optical T dwarf classification scheme from T8 to T9. After deriving an absolute WISE 4.6 {mu}m (W2) magnitude versus spectral type relation, we estimate spectrophotometric distances to our discoveries. We also use available astrometric measurements to provide preliminary trigonometric parallaxes to four of our discoveries, which have types of L9 pec (red), T8, T9, and Y0; all of these lie within 10 pc of the Sun. The Y0 dwarf, WISE 1541-2250, is the closest at 2.8{sup +1.3}{sub -0.6} pc; if this 2.8 pc value persists after continued monitoring, WISE 1541-2250 will become the seventh closest stellar system to the Sun. Another 10 objects, with types between T6 and >Y0, have spectrophotometric distance estimates also placing them within 10 pc. The closest of these, the T6 dwarf WISE 1506+7027, is believed to fall at a distance of {approx}4.9 pc. WISE multi-epoch positions supplemented with positional info primarily from the Spitzer/Infrared Array Camera allow us to calculate proper motions and tangential velocities for roughly one-half of the new discoveries. This work represents the first step by WISE to complete a full-sky, volume-limited census of late-T and Y dwarfs. Using early results from this census, we present preliminary, lower limits to the space density of these objects and discuss constraints on both the functional form of the mass function and the low-mass limit of star formation.« less

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.

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

HIV in Young Adults: An Exploration of Knowledge and Risk

ERIC Educational Resources Information Center

Sabato, Todd

2015-01-01

Over three decades since its discovery, HIV/AIDS remains a critical public health challenge. An estimated 1.41 million AIDS cases, and approximately 659,000 AIDS-related deaths, were reported to the Centers for Disease Control and Prevention (CDC) through 2013 (Stine, 2013). While 53% of documented AIDS cases in the United States have occurred…

Report of Surface Collection and Testing at 18 Sites Near Abiquiu Reservoir, Northern New Mexico

DTIC Science & Technology

1989-10-01

Arroyo del Cobre , and near the headwaters of the Rio Puerco (Whatley and Rancier 1986:5-11). The nearest outcrop is estimated as 6 km distant from LA...1978b Archaeological Studies in the Abiquiu Reservoir District. Discovery 2:41-69. 1978c The Mechanical and Chemical Effects of Inundation at

Advanced Natural Language Processing and Temporal Mining for Clinical Discovery

ERIC Educational Resources Information Center

Mehrabi, Saeed

2016-01-01

There has been vast and growing amount of healthcare data especially with the rapid adoption of electronic health records (EHRs) as a result of the HITECH act of 2009. It is estimated that around 80% of the clinical information resides in the unstructured narrative of an EHR. Recently, natural language processing (NLP) techniques have offered…

19 CFR 148.19 - False or fraudulent statement.

Code of Federal Regulations, 2011 CFR

2011-04-01

... officer is or may be induced to pass an article free of duty or at less than the proper amount of duty, or...(c) shall be demanded from the passenger. The amount demanded in lieu of seizure shall be determined..., the estimated duties shall be demanded of the passenger as soon as possible after the discovery of the...

19 CFR 148.19 - False or fraudulent statement.

Code of Federal Regulations, 2010 CFR

2010-04-01

... officer is or may be induced to pass an article free of duty or at less than the proper amount of duty, or...(c) shall be demanded from the passenger. The amount demanded in lieu of seizure shall be determined..., the estimated duties shall be demanded of the passenger as soon as possible after the discovery of the...

Two decades of hydrocarbon exploration activity in Indonesia

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

Suardy, A.; Taruno, J.; Simbolon, P.H.

1986-07-01

During the past two decades, hydrocarbon exploration activity within Indonesia has been based on the Indonesian Energy Policy, aims of which include intensifying and expanding hydrocarbon exploration programs. Expansion into the offshore regions of the nation has resulted in the discovery of petroliferous basins. The first offshore oil production came on stream in 1971. Since then, significant achievements have been made in developing these resources. Intensified onshore exploration has resulted in additional oil fields being discovered in these more mature areas. Among the significant gas fields discovered during the past 20 years, Arun and Badak both supply major LNG projects.more » Oil fields have been found in the onshore areas of Sumatra, Kalimantan, Java, and Irian Jaya, and in the offshore areas around West Java, Madura, Natuna, and East Kalimantan. The exploration drilling success during this time has been approximately 32%. In addition, the ratio of oil field development to these discoveries is about 54%. For technical and economic reasons, not all discoveries can be developed into oil fields. Recently, Pertamina's Research and Development Division organized the study of data contributed by Pertamina exploration, foreign contractors, and science institutes. This study reveals that 60 basins are spread throughout the onshore and offshore areas of the nation. Using PAUS (plan and analysis of uncertainty situation), a Monte Carolo simulation program, the hydrocarbon potential of each basin has been estimated. These estimates will be continually revised as more data are made available to the study, as the geology of Indonesia is better understood in terms of plate tectonic theory, and as computing techniques improve.« less

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

Methods of Data Collection, Sample Processing, and Data Analysis for Edge-of-Field, Streamgaging, Subsurface-Tile, and Meteorological Stations at Discovery Farms and Pioneer Farm in Wisconsin, 2001-7

USGS Publications Warehouse

Stuntebeck, Todd D.; Komiskey, Matthew J.; Owens, David W.; Hall, David W.

2008-01-01

The University of Wisconsin (UW)-Madison Discovery Farms (Discovery Farms) and UW-Platteville Pioneer Farm (Pioneer Farm) programs were created in 2000 to help Wisconsin farmers meet environmental and economic challenges. As a partner with each program, and in cooperation with the Wisconsin Department of Natural Resources and the Sand County Foundation, the U.S. Geological Survey (USGS) Wisconsin Water Science Center (WWSC) installed, maintained, and operated equipment to collect water-quantity and water-quality data from 25 edge-offield, 6 streamgaging, and 5 subsurface-tile stations at 7 Discovery Farms and Pioneer Farm. The farms are located in the southern half of Wisconsin and represent a variety of landscape settings and crop- and animal-production enterprises common to Wisconsin agriculture. Meteorological stations were established at most farms to measure precipitation, wind speed and direction, air and soil temperature (in profile), relative humidity, solar radiation, and soil moisture (in profile). Data collection began in September 2001 and is continuing through the present (2008). This report describes methods used by USGS WWSC personnel to collect, process, and analyze water-quantity, water-quality, and meteorological data for edge-of-field, streamgaging, subsurface-tile, and meteorological stations at Discovery Farms and Pioneer Farm from September 2001 through October 2007. Information presented includes equipment used; event-monitoring and samplecollection procedures; station maintenance; sample handling and processing procedures; water-quantity, waterquality, and precipitation data analyses; and procedures for determining estimated constituent concentrations for unsampled runoff events.

A network-based multi-target computational estimation scheme for anticoagulant activities of compounds.

PubMed

Li, Qian; Li, Xudong; Li, Canghai; Chen, Lirong; Song, Jun; Tang, Yalin; Xu, Xiaojie

2011-03-22

Traditional virtual screening method pays more attention on predicted binding affinity between drug molecule and target related to a certain disease instead of phenotypic data of drug molecule against disease system, as is often less effective on discovery of the drug which is used to treat many types of complex diseases. Virtual screening against a complex disease by general network estimation has become feasible with the development of network biology and system biology. More effective methods of computational estimation for the whole efficacy of a compound in a complex disease system are needed, given the distinct weightiness of the different target in a biological process and the standpoint that partial inhibition of several targets can be more efficient than the complete inhibition of a single target. We developed a novel approach by integrating the affinity predictions from multi-target docking studies with biological network efficiency analysis to estimate the anticoagulant activities of compounds. From results of network efficiency calculation for human clotting cascade, factor Xa and thrombin were identified as the two most fragile enzymes, while the catalytic reaction mediated by complex IXa:VIIIa and the formation of the complex VIIIa:IXa were recognized as the two most fragile biological matter in the human clotting cascade system. Furthermore, the method which combined network efficiency with molecular docking scores was applied to estimate the anticoagulant activities of a serial of argatroban intermediates and eight natural products respectively. The better correlation (r = 0.671) between the experimental data and the decrease of the network deficiency suggests that the approach could be a promising computational systems biology tool to aid identification of anticoagulant activities of compounds in drug discovery. This article proposes a network-based multi-target computational estimation method for anticoagulant activities of compounds by combining network efficiency analysis with scoring function from molecular docking.

A Network-Based Multi-Target Computational Estimation Scheme for Anticoagulant Activities of Compounds

PubMed Central

Li, Canghai; Chen, Lirong; Song, Jun; Tang, Yalin; Xu, Xiaojie

2011-01-01

Background Traditional virtual screening method pays more attention on predicted binding affinity between drug molecule and target related to a certain disease instead of phenotypic data of drug molecule against disease system, as is often less effective on discovery of the drug which is used to treat many types of complex diseases. Virtual screening against a complex disease by general network estimation has become feasible with the development of network biology and system biology. More effective methods of computational estimation for the whole efficacy of a compound in a complex disease system are needed, given the distinct weightiness of the different target in a biological process and the standpoint that partial inhibition of several targets can be more efficient than the complete inhibition of a single target. Methodology We developed a novel approach by integrating the affinity predictions from multi-target docking studies with biological network efficiency analysis to estimate the anticoagulant activities of compounds. From results of network efficiency calculation for human clotting cascade, factor Xa and thrombin were identified as the two most fragile enzymes, while the catalytic reaction mediated by complex IXa:VIIIa and the formation of the complex VIIIa:IXa were recognized as the two most fragile biological matter in the human clotting cascade system. Furthermore, the method which combined network efficiency with molecular docking scores was applied to estimate the anticoagulant activities of a serial of argatroban intermediates and eight natural products respectively. The better correlation (r = 0.671) between the experimental data and the decrease of the network deficiency suggests that the approach could be a promising computational systems biology tool to aid identification of anticoagulant activities of compounds in drug discovery. Conclusions This article proposes a network-based multi-target computational estimation method for anticoagulant activities of compounds by combining network efficiency analysis with scoring function from molecular docking. PMID:21445339

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.

Regulation of gene expression in the mammalian eye and its relevance to eye disease.

PubMed

Scheetz, Todd E; Kim, Kwang-Youn A; Swiderski, Ruth E; Philp, Alisdair R; Braun, Terry A; Knudtson, Kevin L; Dorrance, Anne M; DiBona, Gerald F; Huang, Jian; Casavant, Thomas L; Sheffield, Val C; Stone, Edwin M

2006-09-26

We used expression quantitative trait locus mapping in the laboratory rat (Rattus norvegicus) to gain a broad perspective of gene regulation in the mammalian eye and to identify genetic variation relevant to human eye disease. Of >31,000 gene probes represented on an Affymetrix expression microarray, 18,976 exhibited sufficient signal for reliable analysis and at least 2-fold variation in expression among 120 F(2) rats generated from an SR/JrHsd x SHRSP intercross. Genome-wide linkage analysis with 399 genetic markers revealed significant linkage with at least one marker for 1,300 probes (alpha = 0.001; estimated empirical false discovery rate = 2%). Both contiguous and noncontiguous loci were found to be important in regulating mammalian eye gene expression. We investigated one locus of each type in greater detail and identified putative transcription-altering variations in both cases. We found an inserted cREL binding sequence in the 5' flanking sequence of the Abca4 gene associated with an increased expression level of that gene, and we found a mutation of the gene encoding thyroid hormone receptor beta2 associated with a decreased expression level of the gene encoding short-wavelength sensitive opsin (Opn1sw). In addition to these positional studies, we performed a pairwise analysis of gene expression to identify genes that are regulated in a coordinated manner and used this approach to validate two previously undescribed genes involved in the human disease Bardet-Biedl syndrome. These data and analytical approaches can be used to facilitate the discovery of additional genes and regulatory elements involved in human eye disease.

Incidence of solitary pulmonary nodules in Northeastern France: a population-based study in five regions.

PubMed

Marrer, Émilie; Jolly, Damien; Arveux, Patrick; Lejeune, Catherine; Woronoff-Lemsi, Marie-Christine; Jégu, Jérémie; Guillemin, Francis; Velten, Michel

2017-01-11

The discovery of a solitary pulmonary nodule (SPN) on a chest imaging exam is of major clinical concern. However, the incidence rates of SPNs in a general population have not been estimated. The objective of this study was to provide incidence estimates of SPNs in a general population in 5 northeastern regions of France. This population-based study was undertaken in 5 regions of northeastern France in May 2002-March 2003 and May 2004-June 2005. SPNs were identified by chest CT reports collected from all radiology centres in the study area by trained readers using a standardised procedure. All reports for patients at least 18 years old, without a previous history of cancer and showing an SPN between 1 and 3 cm, were included. A total of 11,705 and 20,075 chest CT reports were collected for the 2002-2003 and 2004-2005 periods, respectively. Among them, 154 and 297 reports showing a SPN were included, respectively for each period. The age-standardised incidence rate (IR) was 10.2 per 100,000 person-years (95% confidence interval 8.5-11.9) for 2002-2003 and 12.6 (11.0-14.2) for 2004-2005. From 2002 to 2005, the age-standardised IR evolved for men from 16.4 (13.2-19.6) to 17.7 (15.0-20.4) and for women from 4.9 (3.2-6.6) to 8.2 (6.4-10.0). In multivariate Poisson regression analysis, gender, age, region and period were significantly associated with incidence variation. This study provides reference incidence rates of SPN in France. Incidence was higher for men than women, increased with age for both gender and with time for women. Trends in smoking prevalence and improvement in radiological equipment may be related to incidence variations.

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.

Preventing preterm births: trends and potential reductions with current interventionsin 39 very high human development index countries

PubMed Central

Chang, Hannah H.; Larson, Jim; Blencowe, Hannah; Spong, Catherine Y.; Howson, Christopher P.; Cairns-Smith, Sarah; Lackritz, Eve M.; Lee, Shoo K.; Mason, Elizabeth; Serazin, Andrew C.; Walani, Salimah; Simpson, Joe Leigh; Lawn, Joy E.

2013-01-01

Summary Background Each year,1.1 million babies die from prematurity, andmany survivors are disabled. Worldwide, 15 million babies are preterm(<37 weeks’ gestation),withtwo decades of increasing ratesinalmost all countries with reliable data. Improved care of babies has reduced mortality in high-income countries, although effective interventions have yet to be scaled-up in most low-income countries. A 50% reduction goal for preterm-specific mortality by 2025 has been set in the “Born Too Soon” report. However, for preterm birth prevention,understanding of drivers and potential impact of preventive interventions is limited. We examine trends and estimate the potential reduction in preterm birthsforvery high human development index (VHHDI) countries if current evidence-based interventions were widely implemented. This analysis is to inform a “Born Too Soon” rate reduction target. Methods Countries were assessed for inclusion based on availability and quality ofpreterm prevalence data (2000-2010), and trend analyses with projections undertaken. We analysed drivers of rate increases in the USA, 1998-2004. For 39 VHHDI countrieswith >10,000 births, country-by-country analyses were performed based on target population, incremental coverage increase,and intervention efficacy. Cost savings were estimated based on reported costs for preterm care in the USAadjusted usingWorld Bank purchasing power parity. Findings From 2010, even if all VHHDI countries achieved annual preterm birth rate reductions of the best performers, (Sweden and Netherlands), 2000-2010 or 2005-2010(Lithuania, Estonia)), rates would experience a relative reduction of<5% by 2015 on average across the 39 countries.Our analysis of preterm birth rise 1998-2004 in USA suggests half the change is unexplained, but important drivers includeinductions/cesareandelivery and ART.For all 39 VHHDI countries, five interventionsmodeling at high coveragepredicted 5%preterm birth rate relative reduction from 9.59 to 9.07% of live births:smoking cessation (0.01 rate reduction), decreasing multiple embryo transfers during assisted reproductive technologies (0.06), cervical cerclage (0.15), progesterone supplementation (0.01), and reduction of non-medically indicated labour induction or caesarean delivery (0.29).These translate to 58,000 preterm births averted and total annual economic cost savings of ~US$ 3 billion. Interpretation Even with optimal coverage of current interventions, many being complex to implement, the estimated potential reduction in preterm birth is tiny. Hence we recommenda conservative target of 5% preterm birth rate relative reductionby 2015. Our findings highlight the urgent need for discovery research into underlying mechanisms of preterm birth, and developmentof innovative interventions. Furthermore, the highest preterm birth rates occur in low-income settings where the causes of prematurity may differand have simpler solutions, such as birth spacing and treatment of infections in pregnancy. Urgent focus on these settings also is critical to reduce preterm births worldwide. PMID:23158883

In Vivo Regulation of Human Skeletal Muscle Gene Expression by Thyroid Hormone

PubMed Central

Clément, Karine; Viguerie, Nathalie; Diehn, Maximilian; Alizadeh, Ash; Barbe, Pierre; Thalamas, Claire; Storey, John D.; Brown, Patrick O.; Barsh, Greg S.; Langin, Dominique

2002-01-01

Thyroid hormones are key regulators of metabolism that modulate transcription via nuclear receptors. Hyperthyroidism is associated with increased metabolic rate, protein breakdown, and weight loss. Although the molecular actions of thyroid hormones have been studied thoroughly, their pleiotropic effects are mediated by complex changes in expression of an unknown number of target genes. Here, we measured patterns of skeletal muscle gene expression in five healthy men treated for 14 days with 75 μg of triiodothyronine, using 24,000 cDNA element microarrays. To analyze the data, we used a new statistical method that identifies significant changes in expression and estimates the false discovery rate. The 381 up-regulated genes were involved in a wide range of cellular functions including transcriptional control, mRNA maturation, protein turnover, signal transduction, cellular trafficking, and energy metabolism. Only two genes were down-regulated. Most of the genes are novel targets of thyroid hormone. Cluster analysis of triiodothyronine-regulated gene expression among 19 different human tissues or cell lines revealed sets of coregulated genes that serve similar biologic functions. These results define molecular signatures that help to understand the physiology and pathophysiology of thyroid hormone action. [The list of transcripts corresponding to up-regulated and down-regulated genes is available as a web supplement at http://www.genome.org.] PMID:11827947

16 CFR 305.5 - Determinations of estimated annual energy consumption, estimated annual operating cost, and...

Code of Federal Regulations, 2010 CFR

2010-01-01

... consumption, estimated annual operating cost, and energy efficiency rating, and of water use rate. 305.5... energy efficiency rating, and of water use rate. (a) Procedures for determining the estimated annual energy consumption, the estimated annual operating costs, the energy efficiency ratings, and the efficacy...

Urotensin-II System in Genetic Control of Blood Pressure and Renal Function

PubMed Central

Debiec, Radoslaw; Christofidou, Paraskevi; Denniff, Matthew; Bloomer, Lisa D.; Bogdanski, Pawel; Wojnar, Lukasz; Musialik, Katarzyna; Charchar, Fadi J.; Thompson, John R.; Waterworth, Dawn; Song, Kijoung; Vollenweider, Peter; Waeber, Gerard; Zukowska-Szczechowska, Ewa; Samani, Nilesh J.; Lambert, David; Tomaszewski, Maciej

2013-01-01

Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates. PMID:24391740

Alprazolam as an in vivo probe for studying induction of CYP3A in cynomolgus monkeys.

PubMed

Ohtsuka, Tatsuyuki; Yoshikawa, Takahiro; Kozakai, Kazumasa; Tsuneto, Yumi; Uno, Yasuhiro; Utoh, Masahiro; Yamazaki, Hiroshi; Kume, Toshiyuki

2010-10-01

Induction of the cytochrome P450 (P450) enzyme is a major concern in the drug discovery processes. To predict the clinical significance of enzyme induction, it is helpful to investigate pharmacokinetic alterations of a coadministered drug in a suitable animal model. In this study, we focus on the induction of CYP3A, which is involved in the metabolism of approximately 50% of marketed drugs and is inducible in both the liver and intestine. As a marker substrate for CYP3A activity, alprazolam (APZ) was selected and characterized using recombinant CYP3A enzymes expressed in Escherichia coli. Both human CYP3A4 and its cynomolgus P450 ortholog predominantly catalyzed APZ 4-hydroxylation with sigmoidal kinetics. When administered intravenously and orally to cynomolgus monkeys, APZ had moderate clearance; its first-pass extraction ratio after oral dosing was estimated to be 0.09 in the liver and 0.45 in the intestine. Pretreatment with multiple doses of rifampicin (20 mg/kg p.o. for 5 days), a known CYP3A inducer, significantly decreased plasma concentrations of APZ after intravenous and oral administrations (0.5 mg/kg), and first-pass extraction ratios were increased to 0.39 in the liver and 0.63 in the intestine. The results were comparable to those obtained in clinical drug-drug interaction (DDI) reports related to CYP3A induction, although the rate of recovery of CYP3A activity seemed to be slower than rates estimated in clinical studies. In conclusion, pharmacokinetic studies using APZ as a probe in monkeys may provide useful information regarding the prediction of clinical DDIs due to CYP3A induction.

Population dynamics of zebra mussels Dreissena polymorpha (Pallas, 1771) during the initial invasion of the Upper Mississippi River, USA

USGS Publications Warehouse

Cope, W.G.; Bartsch, M.R.; Hightower, J.E.

2006-01-01

The aim of this study was to document and model the population dynamics of zebra mussels Dreissena polymorpha (Pallas, 1771) in Pool 8 of the Upper Mississippi River (UMR), USA, for five consecutive years (1992-1996) following their initial discovery in September 1991. Artificial substrates (concrete blocks, 0.49 m2 surface area) were deployed on or around the first of May at two sites within each of two habitat types (main channel border and contiguous backwater). Blocks were removed monthly (30 ?? 10 d) from the end of May to the end of October to obtain density and growth information. Some blocks deployed in May 1995 were retrieved in April 1996 to obtain information about overwinter growth and survival. The annual density of zebra mussels in Pool 8 of the UMR increased from 3.5/m2 in 1992 to 14,956/m 2 in 1996. The average May-October growth rate of newly recruited individuals, based on a von Bertalanffy growth model fitted to monthly shell-length composition data, was 0.11 mm/d. Model estimates of the average survival rate varied from 21 to 100% per month. Estimated recruitment varied substantially among months, with highest levels occurring in September-October of 1994 and 1996, and in July of 1995. Recruitment and density in both habitat types increased by two orders of magnitude in 1996. Follow-up studies will be necessary to assess the long-term stability of zebra mussel populations in the UMR; this study provides the critical baseline information needed for those future comparisons. ?? Published by Oxford University Press on behalf of The Malacological Society of London 2006.

Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome.

PubMed

Darrow, Sabrina M; Hirschtritt, Matthew E; Davis, Lea K; Illmann, Cornelia; Osiecki, Lisa; Grados, Marco; Sandor, Paul; Dion, Yves; King, Robert; Pauls, David; Budman, Cathy L; Cath, Danielle C; Greenberg, Erica; Lyon, Gholson J; Yu, Dongmei; McGrath, Lauren M; McMahon, William M; Lee, Paul C; Delucchi, Kevin L; Scharf, Jeremiah M; Mathews, Carol A

2017-04-01

Phenotypic heterogeneity in Tourette syndrome is partly due to complex genetic relationships among Tourette syndrome, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD). Identifying symptom-based endophenotypes across diagnoses may aid gene-finding efforts. Assessments for Tourette syndrome, OCD, and ADHD symptoms were conducted in a discovery sample of 3,494 individuals recruited for genetic studies. Symptom-level factor and latent class analyses were conducted in Tourette syndrome families and replicated in an independent sample of 882 individuals. Classes were characterized by comorbidity rates and proportion of parents included. Heritability and polygenic load associated with Tourette syndrome, OCD, and ADHD were estimated. The authors identified two cross-disorder symptom-based phenotypes across analyses: symmetry (symmetry, evening up, checking obsessions; ordering, arranging, counting, writing-rewriting compulsions, repetitive writing tics) and disinhibition (uttering syllables/words, echolalia/palilalia, coprolalia/copropraxia, and obsessive urges to offend/mutilate/be destructive). Heritability estimates for both endophenotypes were high and statistically significant (disinhibition factor=0.35, SE=0.03; symmetry factor=0.39, SE=0.03; symmetry class=0.38, SE=0.10). Mothers of Tourette syndrome probands had high rates of symmetry (49%) but not disinhibition (5%). Polygenic risk scores derived from a Tourette syndrome genome-wide association study (GWAS) were significantly associated with symmetry, while risk scores derived from an OCD GWAS were not. OCD polygenic risk scores were significantly associated with disinhibition, while Tourette syndrome and ADHD risk scores were not. The analyses identified two heritable endophenotypes related to Tourette syndrome that cross traditional diagnostic boundaries. The symmetry phenotype correlated with Tourette syndrome polygenic load and was present in otherwise Tourette-unaffected mothers, suggesting that this phenotype may reflect additional Tourette syndrome (rather than OCD) genetic liability that is not captured by traditional DSM-based diagnoses.

Suzaku Discovery of Ultra-fast Outflows in Radio-loud AGN

NASA Astrophysics Data System (ADS)

Sambruna, Rita M.; Tombesi, F.; Reeves, J.; Braito, V.; Gofford, J.; Cappi, M.

2010-03-01

We present the results of an analysis of the 3.5--10.5 keV spectra of five bright Broad-Line Radio Galaxies (BLRGs) using proprietary and archival Suzaku observations. In three sources -- 3C 111, 3C 120, and 3C 390.3 -- we find evidence, for the first time in a radio-loud AGN, for absorption features at observed energies 7 keV and 8--9 keV, with high significance according to both the F-test and extensive Monte Carlo simulations (99% or larger). In the remaining two BLRGs, 3C 382 and 3C 445, there is no evidence for such absorption features in the XIS spectra. If interpreted as due to Fe XXV and/or Fe XXVI K-shell resonance lines, the absorption features in 3C 111, 3C 120, and 3C 390.3 imply an origin from an ionized gas outflowing with velocities in the range v 0.04-0.15c, reminiscent of Ultra-Fast Outflows (UFOs) previously observed in radio-quiet Seyfert galaxies. A fit with specific photoionization models gives ionization parameters log ξ 4--5.6 erg s-1 cm and column densities of NH 1022-23 cm-2, similar to the values observed in Seyferts. Based on light travel time arguments, we estimate that the UFOs in the three BLRGs are located within 20--500 gravitational radii from the central black hole, and thus most likely are connected to disk winds/outflows. Our estimates show that the UFOs mass outflow rate is comparable to the accretion rate and their kinetic energy a significant fraction of the AGN bolometric luminosity, making these outflows significant for the global energetic of these systems, in particular for mechanisms of jet formation.

Comparison of methods used to estimate conventional undiscovered petroleum resources: World examples

USGS Publications Warehouse

Ahlbrandt, T.S.; Klett, T.R.

2005-01-01

Various methods for assessing undiscovered oil, natural gas, and natural gas liquid resources were compared in support of the USGS World Petroleum Assessment 2000. Discovery process, linear fractal, parabolic fractal, engineering estimates, PETRIMES, Delphi, and the USGS 2000 methods were compared. Three comparisons of these methods were made in: (1) the Neuquen Basin province, Argentina (different assessors, same input data); (2) provinces in North Africa, Oman, and Yemen (same assessors, different methods); and (3) the Arabian Peninsula, Arabian (Persian) Gulf, and North Sea (different assessors, different methods). A fourth comparison (same assessors, same assessment methods but different geologic models), between results from structural and stratigraphic assessment units in the North Sea used only the USGS 2000 method, and hence compared the type of assessment unit rather than the method. In comparing methods, differences arise from inherent differences in assumptions regarding: (1) the underlying distribution of the parent field population (all fields, discovered and undiscovered), (2) the population of fields being estimated; that is, the entire parent distribution or the undiscovered resource distribution, (3) inclusion or exclusion of large outlier fields; (4) inclusion or exclusion of field (reserve) growth, (5) deterministic or probabilistic models, (6) data requirements, and (7) scale and time frame of the assessment. Discovery process, Delphi subjective consensus, and the USGS 2000 method yield comparable results because similar procedures are employed. In mature areas such as the Neuquen Basin province in Argentina, the linear and parabolic fractal and engineering methods were conservative compared to the other five methods and relative to new reserve additions there since 1995. The PETRIMES method gave the most optimistic estimates in the Neuquen Basin. In less mature areas, the linear fractal method yielded larger estimates relative to other methods. A geologically based model, such as one using the total petroleum system approach, is preferred in that it combines the elements of petroleum source, reservoir, trap and seal with the tectono-stratigraphic history of basin evolution with petroleum resource potential. Care must be taken to demonstrate that homogeneous populations in terms of geology, geologic risk, exploration, and discovery processes are used in the assessment process. The USGS 2000 method (7th Approximation Model, EMC computational program) is robust; that is, it can be used in both mature and immature areas, and provides comparable results when using different geologic models (e.g. stratigraphic or structural) with differing amounts of subdivisions, assessment units, within the total petroleum system. ?? 2005 International Association for Mathematical Geology.

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

TYC 5780-308-1 Discovery of Stellar Duplicity During Asteroidal Occultation by (834) Burnhamia

NASA Astrophysics Data System (ADS)

Timerson, Brad; George, T.; Blank, Ted; Maley, Paul; Messner, Steve; Moore, John

2018-04-01

An occultation of TYC 5780-308-1 by the asteroid (834) Burnhamia on August 23, 2017 (UT) showed this star to be a double star. Both components of the double star were occulted as recorded by four observers. The separation of the two components is 0.0143 ± 0.0004 arcseconds at a position angle of 73.8 ± 2.7 degrees. The magnitude of the primary component is estimated to be 9.8 +/- 0.03 (Tycho2 VT). The magnitude of the secondary component is estimated to be 9.92 +/- 0.03 (Tycho2 VT).

Quick estimate of oil discovery from gas-condensate reservoirs

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

Sarem, A.M.

1966-10-24

A quick method of estimating the depletion performance of gas-condensate reservoirs is presented by graphical representations. The method is based on correlations reported in the literature and expresses recoverable liquid as function of gas reserves, producing gas-oil ratio, and initial and final reservoir pressures. The amount of recoverable liquid reserves (RLR) under depletion conditions, is estimated from an equation which is given. Where the liquid-reserves are in stock-tank barrels the gas reserves are in Mcf, with the arbitrary constant, N calculated from one graphical representation by dividing fractional oil recovery by the initial gas-oil ratio and multiplying 10U6D for convenience.more » An equation is given for estimating the coefficient C. These factors (N and C) can be determined from the graphical representations. An example calculation is included.« less

Porphyry copper assessment of British Columbia and Yukon Territory, Canada: Chapter C in Global mineral resource assessment

USGS Publications Warehouse

Mihalasky, Mark J.; Bookstrom, Arthur A.; Frost, Thomas P.; Ludington, Steve

2011-01-01

Western Canada has been thoroughly explored for porphyry copper deposits. The total estimated copper contained in known deposits is about 66.8 Mt (based on 2010 data), as compared to a 49 Mt mean of estimated copper in undiscovered deposits and a 34 Mt median of estimated copper in undiscovered deposits. The copper contained in known porphyry copper deposits represents about 58 percent of the total of known and undiscovered porphyry copper deposits (based on mean values). About 86 percent of the increase in estimated copper resources between 1993 and 2009 resulted from the discovery of extensions to known deposits. Nevertheless, exploration for undiscovered deposits continues, especially in and around significant prospects and in parts of permissive tracts that are mostly hidden beneath younger volcanic, sedimentary, or vegetated surficial cover.

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

Six months of multiwavelength follow-up of the tidal disruption candidate ASASSN-14li and implied TDE rates from ASAS-SN

DOE PAGES

Holoien, Thomas W. -S.; Kochanek, C. S.; Prieto, J. L.; ...

2015-11-25

In this paper, we present ground-based and Swift photometric and spectroscopic observations of the candidate tidal disruption event (TDE) ASASSN-14li, found at the centre of PGC 043234 (d ≃ 90 Mpc) by the All-Sky Automated Survey for SuperNovae (ASAS-SN). The source had a peak bolometric luminosity of L ≃ 10 44 erg s -1 and a total integrated energy of E ≃ 7 × 10 50 erg radiated over the ~6 months of observations presented. The UV/optical emission of the source is well fitted by a blackbody with roughly constant temperature of T ~ 35 000 K, while the luminositymore » declines by roughly a factor of 16 over this time. The optical/UV luminosity decline is broadly consistent with an exponential decline, L∝e -t/t0, with t 0 ≃ 60 d. ASASSN-14li also exhibits soft X-ray emission comparable in luminosity to the optical and UV emission but declining at a slower rate, and the X-ray emission now dominates. Spectra of the source show broad Balmer and helium lines in emission as well as strong blue continuum emission at all epochs. Finally, we use the discoveries of ASASSN-14li and ASASSN-14ae to estimate the TDE rate implied by ASAS-SN, finding an average rate of r ≃ 4.1 × 10 -5 yr -1 per galaxy with a 90 per cent confidence interval of (2.2–17.0) × 10 -5 yr -1 per galaxy. ASAS-SN found roughly 1 TDE for every 70 Type Ia supernovae in 2014, a rate that is much higher than that of other surveys.« less

Six months of multiwavelength follow-up of the tidal disruption candidate ASASSN-14li and implied TDE rates from ASAS-SN

NASA Astrophysics Data System (ADS)

Holoien, T. W.-S.; Kochanek, C. S.; Prieto, J. L.; Stanek, K. Z.; Dong, Subo; Shappee, B. J.; Grupe, D.; Brown, J. S.; Basu, U.; Beacom, J. F.; Bersier, D.; Brimacombe, J.; Danilet, A. B.; Falco, E.; Guo, Z.; Jose, J.; Herczeg, G. J.; Long, F.; Pojmanski, G.; Simonian, G. V.; Szczygieł, D. M.; Thompson, T. A.; Thorstensen, J. R.; Wagner, R. M.; Woźniak, P. R.

2016-01-01

We present ground-based and Swift photometric and spectroscopic observations of the candidate tidal disruption event (TDE) ASASSN-14li, found at the centre of PGC 043234 (d ≃ 90 Mpc) by the All-Sky Automated Survey for SuperNovae (ASAS-SN). The source had a peak bolometric luminosity of L ≃ 1044 erg s-1 and a total integrated energy of E ≃ 7 × 1050 erg radiated over the ˜6 months of observations presented. The UV/optical emission of the source is well fitted by a blackbody with roughly constant temperature of T ˜ 35 000 K, while the luminosity declines by roughly a factor of 16 over this time. The optical/UV luminosity decline is broadly consistent with an exponential decline, L∝ e^{-t/t_0}, with t0 ≃ 60 d. ASASSN-14li also exhibits soft X-ray emission comparable in luminosity to the optical and UV emission but declining at a slower rate, and the X-ray emission now dominates. Spectra of the source show broad Balmer and helium lines in emission as well as strong blue continuum emission at all epochs. We use the discoveries of ASASSN-14li and ASASSN-14ae to estimate the TDE rate implied by ASAS-SN, finding an average rate of r ≃ 4.1 × 10-5 yr-1 per galaxy with a 90 per cent confidence interval of (2.2-17.0) × 10-5 yr-1 per galaxy. ASAS-SN found roughly 1 TDE for every 70 Type Ia supernovae in 2014, a rate that is much higher than that of other surveys.

PockDrug: A Model for Predicting Pocket Druggability That Overcomes Pocket Estimation Uncertainties.

PubMed

Borrel, Alexandre; Regad, Leslie; Xhaard, Henri; Petitjean, Michel; Camproux, Anne-Claude

2015-04-27

Predicting protein druggability is a key interest in the target identification phase of drug discovery. Here, we assess the pocket estimation methods' influence on druggability predictions by comparing statistical models constructed from pockets estimated using different pocket estimation methods: a proximity of either 4 or 5.5 Å to a cocrystallized ligand or DoGSite and fpocket estimation methods. We developed PockDrug, a robust pocket druggability model that copes with uncertainties in pocket boundaries. It is based on a linear discriminant analysis from a pool of 52 descriptors combined with a selection of the most stable and efficient models using different pocket estimation methods. PockDrug retains the best combinations of three pocket properties which impact druggability: geometry, hydrophobicity, and aromaticity. It results in an average accuracy of 87.9% ± 4.7% using a test set and exhibits higher accuracy (∼5-10%) than previous studies that used an identical apo set. In conclusion, this study confirms the influence of pocket estimation on pocket druggability prediction and proposes PockDrug as a new model that overcomes pocket estimation variability.

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.

Behavior, sensitivity, and power of activation likelihood estimation characterized by massive empirical simulation.

PubMed

Eickhoff, Simon B; Nichols, Thomas E; Laird, Angela R; Hoffstaedter, Felix; Amunts, Katrin; Fox, Peter T; Bzdok, Danilo; Eickhoff, Claudia R

2016-08-15

Given the increasing number of neuroimaging publications, the automated knowledge extraction on brain-behavior associations by quantitative meta-analyses has become a highly important and rapidly growing field of research. Among several methods to perform coordinate-based neuroimaging meta-analyses, Activation Likelihood Estimation (ALE) has been widely adopted. In this paper, we addressed two pressing questions related to ALE meta-analysis: i) Which thresholding method is most appropriate to perform statistical inference? ii) Which sample size, i.e., number of experiments, is needed to perform robust meta-analyses? We provided quantitative answers to these questions by simulating more than 120,000 meta-analysis datasets using empirical parameters (i.e., number of subjects, number of reported foci, distribution of activation foci) derived from the BrainMap database. This allowed to characterize the behavior of ALE analyses, to derive first power estimates for neuroimaging meta-analyses, and to thus formulate recommendations for future ALE studies. We could show as a first consequence that cluster-level family-wise error (FWE) correction represents the most appropriate method for statistical inference, while voxel-level FWE correction is valid but more conservative. In contrast, uncorrected inference and false-discovery rate correction should be avoided. As a second consequence, researchers should aim to include at least 20 experiments into an ALE meta-analysis to achieve sufficient power for moderate effects. We would like to note, though, that these calculations and recommendations are specific to ALE and may not be extrapolated to other approaches for (neuroimaging) meta-analysis. Copyright © 2016 Elsevier Inc. All rights reserved.

Behavior, Sensitivity, and power of activation likelihood estimation characterized by massive empirical simulation

PubMed Central

Eickhoff, Simon B.; Nichols, Thomas E.; Laird, Angela R.; Hoffstaedter, Felix; Amunts, Katrin; Fox, Peter T.

2016-01-01

Given the increasing number of neuroimaging publications, the automated knowledge extraction on brain-behavior associations by quantitative meta-analyses has become a highly important and rapidly growing field of research. Among several methods to perform coordinate-based neuroimaging meta-analyses, Activation Likelihood Estimation (ALE) has been widely adopted. In this paper, we addressed two pressing questions related to ALE meta-analysis: i) Which thresholding method is most appropriate to perform statistical inference? ii) Which sample size, i.e., number of experiments, is needed to perform robust meta-analyses? We provided quantitative answers to these questions by simulating more than 120,000 meta-analysis datasets using empirical parameters (i.e., number of subjects, number of reported foci, distribution of activation foci) derived from the BrainMap database. This allowed to characterize the behavior of ALE analyses, to derive first power estimates for neuroimaging meta-analyses, and to thus formulate recommendations for future ALE studies. We could show as a first consequence that cluster-level family-wise error (FWE) correction represents the most appropriate method for statistical inference, while voxel-level FWE correction is valid but more conservative. In contrast, uncorrected inference and false-discovery rate correction should be avoided. As a second consequence, researchers should aim to include at least 20 experiments into an ALE meta-analysis to achieve sufficient power for moderate effects. We would like to note, though, that these calculations and recommendations are specific to ALE and may not be extrapolated to other approaches for (neuroimaging) meta-analysis. PMID:27179606

Discovery of a radio nebula around PSR J0855-4644

NASA Astrophysics Data System (ADS)

Maitra, C.; Roy, S.; Acero, F.; Gupta, Y.

2018-06-01

We report the discovery of a diffuse radio emission around PSR J0855-4644 using an upgraded GMRT (uGMRT) observation at 1.35 GHz. The radio emission is spatially coincident with the diffuse X-ray pulsar wind nebula (PWN) seen with XMM-Newton but is much larger in extent compared to the compact axisymmetric PWN seen with Chandra. The morphology of the emission, with a bright partial ring-like structure and two faint tail-like features strongly resembles a bow shock nebula, and indicates a velocity of 100 km s-1 through the ambient medium. We conclude that the emission is most likely to be associated with the radio PWN of PSR J0855-4644. From the integrated flux density, we estimate the energetics of the PWN.

Scout: orbit analysis and hazard assessment for NEOCP objects

NASA Astrophysics Data System (ADS)

Farnocchia, Davide; Chesley, Steven R.; Chamberlin, Alan B.

2016-10-01

It typically takes a few days for a newly discovered asteroid to be officially recognized as a real object. During this time, the tentative discovery is published on the Minor Planet Center's Near-Earth Object Confirmation Page (NEOCP) until additional observations confirm that the object is a real asteroid rather than an observational artifact or an artificial object. Also, NEOCP objects could have a limited observability window and yet be scientifically interesting, e.g., radar and lightcurve targets, mini-moons (temporary Earth captures), mission accessible targets, close approachers or even impactors. For instance, the only two asteroids discovered before an impact, 2008 TC3 and 2014 AA, both reached the Earth less than a day after discovery. For these reasons we developed Scout, an automated system that provides an orbital and hazard assessment for NEOCP objects within minutes after the observations are available. Scout's rapid analysis increases the chances of securing the trajectory of interesting NEOCP objects before the ephemeris uncertainty grows too large or the observing geometry becomes unfavorable. The generally short observation arcs, perhaps only a few hours or even less, lead severe degeneracies in the orbit estimation process. To overcome these degeneracies Scout relies on systematic ranging, a technique that derives possible orbits by scanning a grid in the poorly constrained space of topocentric range and range rate, while the plane-of-sky position and motion are directly tied to the recorded observations. This scan allows us to derive a distribution of the possible orbits and in turn identify the NEOCP objects of most interest to prioritize followup efforts. In particular, Scout ranks objects according to the likelihood of an impact, estimates the close approach distance, the Earth-relative minimum orbit intersection distance and v-infinity, and computes scores to identify objects more likely to be an NEO, a km-sized NEO, a Potentially Hazardous Asteroid, and those on a geocentric orbit. Moreover, Scout provides an ephemeris service that makes use of the statistical information to support observers in their followup efforts.

Divergence time estimates of mammals from molecular clocks and fossils: relevance of new fossil finds from India.

PubMed

Prasad, G V R

2009-11-01

This paper presents a brief review of recent advances in the classification of mammals at higher levels using fossils and molecular clocks. It also discusses latest fossil discoveries from the Cretaceous - Eocene (66-55 m.y.) rocks of India and their relevance to our current understanding of placental mammal origins and diversifications.

Comparison of two probability distributions used to model sizes of undiscovered oil and gas accumulations: Does the tail wag the assessment?

USGS Publications Warehouse

Attanasi, E.D.; Charpentier, R.R.

2002-01-01

Undiscovered oil and gas assessments are commonly reported as aggregate estimates of hydrocarbon volumes. Potential commercial value and discovery costs are, however, determined by accumulation size, so engineers, economists, decision makers, and sometimes policy analysts are most interested in projected discovery sizes. The lognormal and Pareto distributions have been used to model exploration target sizes. This note contrasts the outcomes of applying these alternative distributions to the play level assessments of the U.S. Geological Survey's 1995 National Oil and Gas Assessment. Using the same numbers of undiscovered accumulations and the same minimum, medium, and maximum size estimates, substitution of the shifted truncated lognormal distribution for the shifted truncated Pareto distribution reduced assessed undiscovered oil by 16% and gas by 15%. Nearly all of the volume differences resulted because the lognormal had fewer larger fields relative to the Pareto. The lognormal also resulted in a smaller number of small fields relative to the Pareto. For the Permian Basin case study presented here, reserve addition costs were 20% higher with the lognormal size assumption. ?? 2002 International Association for Mathematical Geology.

Long-chain fatty acid combustion rate is associated with unique metabolite profiles in skeletal muscle mitochondria.

PubMed

Seifert, Erin L; Fiehn, Oliver; Bezaire, Véronic; Bickel, David R; Wohlgemuth, Gert; Adams, Sean H; Harper, Mary-Ellen

2010-03-24

Incomplete or limited long-chain fatty acid (LCFA) combustion in skeletal muscle has been associated with insulin resistance. Signals that are responsive to shifts in LCFA beta-oxidation rate or degree of intramitochondrial catabolism are hypothesized to regulate second messenger systems downstream of the insulin receptor. Recent evidence supports a causal link between mitochondrial LCFA combustion in skeletal muscle and insulin resistance. We have used unbiased metabolite profiling of mouse muscle mitochondria with the aim of identifying candidate metabolites within or effluxed from mitochondria and that are shifted with LCFA combustion rate. Large-scale unbiased metabolomics analysis was performed using GC/TOF-MS on buffer and mitochondrial matrix fractions obtained prior to and after 20 min of palmitate catabolism (n = 7 mice/condition). Three palmitate concentrations (2, 9 and 19 microM; corresponding to low, intermediate and high oxidation rates) and 9 microM palmitate plus tricarboxylic acid (TCA) cycle and electron transport chain inhibitors were each tested and compared to zero palmitate control incubations. Paired comparisons of the 0 and 20 min samples were made by Student's t-test. False discovery rate were estimated and Type I error rates assigned. Major metabolite groups were organic acids, amines and amino acids, free fatty acids and sugar phosphates. Palmitate oxidation was associated with unique profiles of metabolites, a subset of which correlated to palmitate oxidation rate. In particular, palmitate oxidation rate was associated with distinct changes in the levels of TCA cycle intermediates within and effluxed from mitochondria. This proof-of-principle study establishes that large-scale metabolomics methods can be applied to organelle-level models to discover metabolite patterns reflective of LCFA combustion, which may lead to identification of molecules linking muscle fat metabolism and insulin signaling. Our results suggest that future studies should focus on the fate of effluxed TCA cycle intermediates and on mechanisms ensuring their replenishment during LCFA metabolism in skeletal muscle.

Long-Chain Fatty Acid Combustion Rate Is Associated with Unique Metabolite Profiles in Skeletal Muscle Mitochondria

PubMed Central

Seifert, Erin L.; Fiehn, Oliver; Bezaire, Véronic; Bickel, David R.; Wohlgemuth, Gert; Adams, Sean H.; Harper, Mary-Ellen

2010-01-01

Background/Aim Incomplete or limited long-chain fatty acid (LCFA) combustion in skeletal muscle has been associated with insulin resistance. Signals that are responsive to shifts in LCFA β-oxidation rate or degree of intramitochondrial catabolism are hypothesized to regulate second messenger systems downstream of the insulin receptor. Recent evidence supports a causal link between mitochondrial LCFA combustion in skeletal muscle and insulin resistance. We have used unbiased metabolite profiling of mouse muscle mitochondria with the aim of identifying candidate metabolites within or effluxed from mitochondria and that are shifted with LCFA combustion rate. Methodology/Principal Findings Large-scale unbiased metabolomics analysis was performed using GC/TOF-MS on buffer and mitochondrial matrix fractions obtained prior to and after 20 min of palmitate catabolism (n = 7 mice/condition). Three palmitate concentrations (2, 9 and 19 µM; corresponding to low, intermediate and high oxidation rates) and 9 µM palmitate plus tricarboxylic acid (TCA) cycle and electron transport chain inhibitors were each tested and compared to zero palmitate control incubations. Paired comparisons of the 0 and 20 min samples were made by Student's t-test. False discovery rate were estimated and Type I error rates assigned. Major metabolite groups were organic acids, amines and amino acids, free fatty acids and sugar phosphates. Palmitate oxidation was associated with unique profiles of metabolites, a subset of which correlated to palmitate oxidation rate. In particular, palmitate oxidation rate was associated with distinct changes in the levels of TCA cycle intermediates within and effluxed from mitochondria. Conclusions/Significance This proof-of-principle study establishes that large-scale metabolomics methods can be applied to organelle-level models to discover metabolite patterns reflective of LCFA combustion, which may lead to identification of molecules linking muscle fat metabolism and insulin signaling. Our results suggest that future studies should focus on the fate of effluxed TCA cycle intermediates and on mechanisms ensuring their replenishment during LCFA metabolism in skeletal muscle. PMID:20352092

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.

Development and application of a 6.5 million feature Affymetrix Genechip® for massively parallel discovery of single position polymorphisms in lettuce (Lactuca spp.)

PubMed Central

2012-01-01

Background High-resolution genetic maps are needed in many crops to help characterize the genetic diversity that determines agriculturally important traits. Hybridization to microarrays to detect single feature polymorphisms is a powerful technique for marker discovery and genotyping because of its highly parallel nature. However, microarrays designed for gene expression analysis rarely provide sufficient gene coverage for optimal detection of nucleotide polymorphisms, which limits utility in species with low rates of polymorphism such as lettuce (Lactuca sativa). Results We developed a 6.5 million feature Affymetrix GeneChip® for efficient polymorphism discovery and genotyping, as well as for analysis of gene expression in lettuce. Probes on the microarray were designed from 26,809 unigenes from cultivated lettuce and an additional 8,819 unigenes from four related species (L. serriola, L. saligna, L. virosa and L. perennis). Where possible, probes were tiled with a 2 bp stagger, alternating on each DNA strand; providing an average of 187 probes covering approximately 600 bp for each of over 35,000 unigenes; resulting in up to 13 fold redundancy in coverage per nucleotide. We developed protocols for hybridization of genomic DNA to the GeneChip® and refined custom algorithms that utilized coverage from multiple, high quality probes to detect single position polymorphisms in 2 bp sliding windows across each unigene. This allowed us to detect greater than 18,000 polymorphisms between the parental lines of our core mapping population, as well as numerous polymorphisms between cultivated lettuce and wild species in the lettuce genepool. Using marker data from our diversity panel comprised of 52 accessions from the five species listed above, we were able to separate accessions by species using both phylogenetic and principal component analyses. Additionally, we estimated the diversity between different types of cultivated lettuce and distinguished morphological types. Conclusion By hybridizing genomic DNA to a custom oligonucleotide array designed for maximum gene coverage, we were able to identify polymorphisms using two approaches for pair-wise comparisons, as well as a highly parallel method that compared all 52 genotypes simultaneously. PMID:22583801

Development and application of a 6.5 million feature Affymetrix Genechip® for massively parallel discovery of single position polymorphisms in lettuce (Lactuca spp.).

PubMed

Stoffel, Kevin; van Leeuwen, Hans; Kozik, Alexander; Caldwell, David; Ashrafi, Hamid; Cui, Xinping; Tan, Xiaoping; Hill, Theresa; Reyes-Chin-Wo, Sebastian; Truco, Maria-Jose; Michelmore, Richard W; Van Deynze, Allen

2012-05-14

High-resolution genetic maps are needed in many crops to help characterize the genetic diversity that determines agriculturally important traits. Hybridization to microarrays to detect single feature polymorphisms is a powerful technique for marker discovery and genotyping because of its highly parallel nature. However, microarrays designed for gene expression analysis rarely provide sufficient gene coverage for optimal detection of nucleotide polymorphisms, which limits utility in species with low rates of polymorphism such as lettuce (Lactuca sativa). We developed a 6.5 million feature Affymetrix GeneChip® for efficient polymorphism discovery and genotyping, as well as for analysis of gene expression in lettuce. Probes on the microarray were designed from 26,809 unigenes from cultivated lettuce and an additional 8,819 unigenes from four related species (L. serriola, L. saligna, L. virosa and L. perennis). Where possible, probes were tiled with a 2 bp stagger, alternating on each DNA strand; providing an average of 187 probes covering approximately 600 bp for each of over 35,000 unigenes; resulting in up to 13 fold redundancy in coverage per nucleotide. We developed protocols for hybridization of genomic DNA to the GeneChip® and refined custom algorithms that utilized coverage from multiple, high quality probes to detect single position polymorphisms in 2 bp sliding windows across each unigene. This allowed us to detect greater than 18,000 polymorphisms between the parental lines of our core mapping population, as well as numerous polymorphisms between cultivated lettuce and wild species in the lettuce genepool. Using marker data from our diversity panel comprised of 52 accessions from the five species listed above, we were able to separate accessions by species using both phylogenetic and principal component analyses. Additionally, we estimated the diversity between different types of cultivated lettuce and distinguished morphological types. By hybridizing genomic DNA to a custom oligonucleotide array designed for maximum gene coverage, we were able to identify polymorphisms using two approaches for pair-wise comparisons, as well as a highly parallel method that compared all 52 genotypes simultaneously.

Sex-Specific Associations between Particulate Matter Exposure and Gene Expression in Independent Discovery and Validation Cohorts of Middle-Aged Men and Women

PubMed Central

Vrijens, Karen; Winckelmans, Ellen; Tsamou, Maria; Baeyens, Willy; De Boever, Patrick; Jennen, Danyel; de Kok, Theo M.; Den Hond, Elly; Lefebvre, Wouter; Plusquin, Michelle; Reynders, Hans; Schoeters, Greet; Van Larebeke, Nicolas; Vanpoucke, Charlotte; Kleinjans, Jos; Nawrot, Tim S.

2016-01-01

Background: Particulate matter (PM) exposure leads to premature death, mainly due to respiratory and cardiovascular diseases. Objectives: Identification of transcriptomic biomarkers of air pollution exposure and effect in a healthy adult population. Methods: Microarray analyses were performed in 98 healthy volunteers (48 men, 50 women). The expression of eight sex-specific candidate biomarker genes (significantly associated with PM10 in the discovery cohort and with a reported link to air pollution-related disease) was measured with qPCR in an independent validation cohort (75 men, 94 women). Pathway analysis was performed using Gene Set Enrichment Analysis. Average daily PM2.5 and PM10 exposures over 2-years were estimated for each participant’s residential address using spatiotemporal interpolation in combination with a dispersion model. Results: Average long-term PM10 was 25.9 (± 5.4) and 23.7 (± 2.3) μg/m3 in the discovery and validation cohorts, respectively. In discovery analysis, associations between PM10 and the expression of individual genes differed by sex. In the validation cohort, long-term PM10 was associated with the expression of DNAJB5 and EAPP in men and ARHGAP4 (p = 0.053) in women. AKAP6 and LIMK1 were significantly associated with PM10 in women, although associations differed in direction between the discovery and validation cohorts. Expression of the eight candidate genes in the discovery cohort differentiated between validation cohort participants with high versus low PM10 exposure (area under the receiver operating curve = 0.92; 95% CI: 0.85, 1.00; p = 0.0002 in men, 0.86; 95% CI: 0.76, 0.96; p = 0.004 in women). Conclusions: Expression of the sex-specific candidate genes identified in the discovery population predicted PM10 exposure in an independent cohort of adults from the same area. Confirmation in other populations may further support this as a new approach for exposure assessment, and may contribute to the discovery of molecular mechanisms for PM-induced health effects. Citation: Vrijens K, Winckelmans E, Tsamou M, Baeyens W, De Boever P, Jennen D, de Kok TM, Den Hond E, Lefebvre W, Plusquin M, Reynders H, Schoeters G, Van Larebeke N, Vanpoucke C, Kleinjans J, Nawrot TS. 2017. Sex-specific associations between particulate matter exposure and gene expression in independent discovery and validation cohorts of middle-aged men and women. Environ Health Perspect 125:660–669; http://dx.doi.org/10.1289/EHP370 PMID:27740511

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

Kipping, David M.; Chen, Jingjing; Sandford, Emily

The analysis of Proxima Centauri’s radial velocities recently led Anglada-Escudé et al. to claim the presence of a low-mass planet orbiting the Sun’s nearest star once every 11.2 days. Although the a priori probability that Proxima b transits its parent star is just 1.5%, the potential impact of such a discovery would be considerable. Independent of recent radial velocity efforts, we observed Proxima Centauri for 12.5 days in 2014 and 31 days in 2015 with the Microwave and Oscillations of Stars space telescope. We report here that we cannot make a compelling case that Proxima b transits in our precisemore » photometric time series. Imposing an informative prior on the period and phase, we do detect a candidate signal with the expected depth. However, perturbing the phase prior across 100 evenly spaced intervals reveals one strong false positive and one weaker instance. We estimate a false-positive rate of at least a few percent and a much higher false-negative rate of 20%–40%, likely caused by the very high flare rate of Proxima Centauri. Comparing our candidate signal to HATSouth ground-based photometry reveals that the signal is somewhat, but not conclusively, disfavored (1 σ –2 σ ), leading us to argue that the signal is most likely spurious. We expect that infrared photometric follow-up could more conclusively test the existence of this candidate signal, owing to the suppression of flare activity and the impressive infrared brightness of the parent star.« less

No Conclusive Evidence for Transits of Proxima b in MOST Photometry

NASA Astrophysics Data System (ADS)

Kipping, David M.; Cameron, Chris; Hartman, Joel D.; Davenport, James R. A.; Matthews, Jaymie M.; Sasselov, Dimitar; Rowe, Jason; Siverd, Robert J.; Chen, Jingjing; Sandford, Emily; Bakos, Gáspár Á.; Jordán, Andrés; Bayliss, Daniel; Henning, Thomas; Mancini, Luigi; Penev, Kaloyan; Csubry, Zoltan; Bhatti, Waqas; Da Silva Bento, Joao; Guenther, David B.; Kuschnig, Rainer; Moffat, Anthony F. J.; Rucinski, Slavek M.; Weiss, Werner W.

2017-03-01

The analysis of Proxima Centauri’s radial velocities recently led Anglada-Escudé et al. to claim the presence of a low-mass planet orbiting the Sun’s nearest star once every 11.2 days. Although the a priori probability that Proxima b transits its parent star is just 1.5%, the potential impact of such a discovery would be considerable. Independent of recent radial velocity efforts, we observed Proxima Centauri for 12.5 days in 2014 and 31 days in 2015 with the Microwave and Oscillations of Stars space telescope. We report here that we cannot make a compelling case that Proxima b transits in our precise photometric time series. Imposing an informative prior on the period and phase, we do detect a candidate signal with the expected depth. However, perturbing the phase prior across 100 evenly spaced intervals reveals one strong false positive and one weaker instance. We estimate a false-positive rate of at least a few percent and a much higher false-negative rate of 20%-40%, likely caused by the very high flare rate of Proxima Centauri. Comparing our candidate signal to HATSouth ground-based photometry reveals that the signal is somewhat, but not conclusively, disfavored (1σ-2σ), leading us to argue that the signal is most likely spurious. We expect that infrared photometric follow-up could more conclusively test the existence of this candidate signal, owing to the suppression of flare activity and the impressive infrared brightness of the parent star.

Shotgun Mitogenomics Provides a Reference Phylogenetic Framework and Timescale for Living Xenarthrans

PubMed Central

Gibb, Gillian C.; Condamine, Fabien L.; Kuch, Melanie; Enk, Jacob; Moraes-Barros, Nadia; Superina, Mariella; Poinar, Hendrik N.; Delsuc, Frédéric

2016-01-01

Xenarthra (armadillos, sloths, and anteaters) constitutes one of the four major clades of placental mammals. Despite their phylogenetic distinctiveness in mammals, a reference phylogeny is still lacking for the 31 described species. Here we used Illumina shotgun sequencing to assemble 33 new complete mitochondrial genomes, establishing Xenarthra as the first major placental clade to be fully sequenced at the species level for mitogenomes. The resulting data set allowed the reconstruction of a robust phylogenetic framework and timescale that are consistent with previous studies conducted at the genus level using nuclear genes. Incorporating the full species diversity of extant xenarthrans points to a number of inconsistencies in xenarthran systematics and species definition. We propose to split armadillos into two distinct families Dasypodidae (dasypodines) and Chlamyphoridae (euphractines, chlamyphorines, and tolypeutines) to better reflect their ancient divergence, estimated around 42 Ma. Species delimitation within long-nosed armadillos (genus Dasypus) appeared more complex than anticipated, with the discovery of a divergent lineage in French Guiana. Diversification analyses showed Xenarthra to be an ancient clade with a constant diversification rate through time with a species turnover driven by high but constant extinction. We also detected a significant negative correlation between speciation rate and past temperature fluctuations with an increase in speciation rate corresponding to the general cooling observed during the last 15 My. Biogeographic reconstructions identified the tropical rainforest biome of Amazonia and the Guiana Shield as the cradle of xenarthran evolutionary history with subsequent dispersions into more open and dry habitats. PMID:26556496

Quantifying confidence in density functional theory predictions of magnetic ground states

NASA Astrophysics Data System (ADS)

Houchins, Gregory; Viswanathan, Venkatasubramanian

2017-10-01

Density functional theory (DFT) simulations, at the generalized gradient approximation (GGA) level, are being routinely used for material discovery based on high-throughput descriptor-based searches. The success of descriptor-based material design relies on eliminating bad candidates and keeping good candidates for further investigation. While DFT has been widely successfully for the former, oftentimes good candidates are lost due to the uncertainty associated with the DFT-predicted material properties. Uncertainty associated with DFT predictions has gained prominence and has led to the development of exchange correlation functionals that have built-in error estimation capability. In this work, we demonstrate the use of built-in error estimation capabilities within the BEEF-vdW exchange correlation functional for quantifying the uncertainty associated with the magnetic ground state of solids. We demonstrate this approach by calculating the uncertainty estimate for the energy difference between the different magnetic states of solids and compare them against a range of GGA exchange correlation functionals as is done in many first-principles calculations of materials. We show that this estimate reasonably bounds the range of values obtained with the different GGA functionals. The estimate is determined as a postprocessing step and thus provides a computationally robust and systematic approach to estimating uncertainty associated with predictions of magnetic ground states. We define a confidence value (c-value) that incorporates all calculated magnetic states in order to quantify the concurrence of the prediction at the GGA level and argue that predictions of magnetic ground states from GGA level DFT is incomplete without an accompanying c-value. We demonstrate the utility of this method using a case study of Li-ion and Na-ion cathode materials and the c-value metric correctly identifies that GGA-level DFT will have low predictability for NaFePO4F . Further, there needs to be a systematic test of a collection of plausible magnetic states, especially in identifying antiferromagnetic (AFM) ground states. We believe that our approach of estimating uncertainty can be readily incorporated into all high-throughput computational material discovery efforts and this will lead to a dramatic increase in the likelihood of finding good candidate materials.

Lost Near-Earth Object Candidates

NASA Astrophysics Data System (ADS)

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

2017-10-01

The number of discovered Near-Earth Objects (NEOs) increases rapidly, currently exceeding 16,000 NEOs. 2016 was the most productive year ever with 1,888 NEO discoveries. The NEO discovery process typically begins with three to five detections of a previously unidentified object that are reported to the Minor Planet Center (MPC). According to the plane-of-sky motion, the MPC ranks all of the new candidate discoveries for the likelihood of being NEOs using the so-called digest score. If the digest score is greater than 65 the observations appear on the publicly accessible NEO Confirmation Page (NEOCP). Objects on the NEOCP are followed up in subsequent hours and days. When enough observations are collected to ensure that the object is real and that the orbit is determined, the NEO is officially announced with its new designation by a Minor Planet Electronic Circular. However, 14% of NEO candidates never get confirmed and are therefore lost due to the lack of follow-up observations. We analyzed the lost NEO candidates that appeared on NEOCP in 2013-2016 and investigated the reasons why they were not confirmed. In particular, we studied the properties of the lost NEO candidates with a digest score of 100 that were reported by the two most prolific discovery sites - Pan-STARRS1 (F51) and Mt. Lemmon Survey (G96). We derived their plane-of-sky positions and rates, brightness, and ephemeris uncertainties, and assessed correlations with the phase of the moon and seasonal effects apparent in the given observatory’s data. We concluded that lost NEO candidates typically have a larger rate of motion and larger uncertainties than those of confirmed objects. However, many of the lost candidates could be recovered. In fact, the 1-sigma plane-of-sky uncertainty was still within ±0.5 deg in 79% (F51) and 69% (G96) of the cases 24 hours after discovery and in 31% (F51) and 30% (G96) of the cases 48 hours after discovery. If all of the NEO candidates with a digest score of 100 had been followed up, the number of discovered NEOs would have been larger by 685+/-30 in 2013-2016. The measures to decrease the number of lost NEO candidates include improved uncertainty maps and uncertainties as function of time on the NEOCP.

Nova Discovery Efficiency 1890-2014; Only 43%±6% of the Brightest Nova Are Discovered

NASA Astrophysics Data System (ADS)

Schaefer, Bradley E.

2014-06-01

Galactic nova discovery has always been the domain of the best amateur astronomers, with the only substantial exception being the use of the Harvard plates from 1890-1947. (Modern CCD surveys have not produced any significant nova discoveries.) From 1890-1946, novae were discovered by gentlemen who deeply knew the stars in the sky and who checked for new stars on every clear night. This all changed when war surplus binoculars became commonly available, so the various organizations (e.g., AAVSO, BAA) instructed their hunters to use binoculars to regularly search small areas of the Milky Way. In the 1970s the hunters largely switched to blinking photographs, while they switched to CCD images in the 1990s, all exclusively in Milky Way regions. Currently, most hunters use 'go-to' scopes to look deeply only in the Milky Way, use weekly or monthly cadences, never go outside to look up at the light-polluted skies, and do not have the stars memorized at all. This situation is good for catching many faint novae, but is inefficient for catching the more isotropic and systematically-fast bright novae.I have made an exhaustive analysis of all known novae to isolate the effects on the relative discovery efficiency as a function of decade, the elongation from the Sun, the Moon's phase, the declination, the peak magnitude, and the duration of the peak. For example, the relative efficiency for novae south of declination -33° is 0.5 before 1953, 0.2 from 1953-1990, and 0.8 after 1990. My analysis gives the overall discovery efficiency to be 43%±6%, 30%, 22%, 12%, and 6% for novae peaking brighter than 2, 4, 6, 8, and 10 mag. Thus, the majority of first magnitude novae are being missed. The bright novae are lost because they are too close to the Sun, in the far south, and/or very fast. This is illustrated by the discovery rate for Vpeak<2 novae being once every five years before 1946, yet only one such nova (V1500 Cyg) has been seen in the last 68 years. A critical consequence of this result is that the nova rate for our Milky Way has doubled.

Source analysis of alpha rhythm reactivity using LORETA imaging with 64-channel EEG and individual MRI.

PubMed

Cuspineda, E R; Machado, C; Virues, T; Martínez-Montes, E; Ojeda, A; Valdés, P A; Bosch, J; Valdes, L

2009-07-01

Conventional EEG and quantitative EEG visual stimuli (close-open eyes) reactivity analysis have shown their usefulness in clinical practice; however studies at the level of EEG generators are limited. The focus of the study was visual reactivity of cortical resources in healthy subjects and in a stroke patient. The 64 channel EEG and T1 magnetic resonance imaging (MRI) studies were obtained from 32 healthy subjects and a middle cerebral artery stroke patient. Low Resolution Electromagnetic Tomography (LORETA) was used to estimate EEG sources for both close eyes (CE) vs. open eyes (OE) conditions using individual MRI. The t-test was performed between source spectra of the two conditions. Thresholds for statistically significant t values were estimated by the local false discovery rate (lfdr) method. The Z transform was used to quantify the differences in cortical reactivity between the patient and healthy subjects. Closed-open eyes alpha reactivity sources were found mainly in posterior regions (occipito-parietal zones), extended in some cases to anterior and thalamic regions. Significant cortical reactivity sources were found in frequencies different from alpha (lower t-values). Significant changes at EEG reactivity sources were evident in the damaged brain hemisphere. Reactivity changes were also found in the "healthy" hemisphere when compared with the normal population. In conclusion, our study of brain sources of EEG alpha reactivity provides information that is not evident in the usual topographic analysis.

Estimation of Fractal Dimension in Differential Diagnosis of Pigmented Skin Lesions

NASA Astrophysics Data System (ADS)

Aralica, Gorana; Milošević, Danko; Konjevoda, Paško; Seiwerth, Sven; Štambuk, Nikola

Medical differential diagnosis is a method of identifying the presence of a particular entity (disease) within a set of multiple possible alternatives. The significant problem in dermatology and pathology is the differential diagnosis of malignant melanoma and other pigmented skin lesions, especially of dysplastic nevi. Malignant melanoma is the most malignant skin neoplasma, with increasing incidence in various parts of the world. It is hoped that the methods of quantitative pathology, i.e. morphometry, can help objectification of the diagnostic process, since early discovery of melanoma results in 10-year survival rate of 90%. The aim of the study was to use fractal dimension calculated from the perimeter-area relation of the cell nuclei as a tool for the differential diagnosis of pigmented skin lesions. We analyzed hemalaun-eosin stained pathohistological slides of pigmented skin lesions: intradermal naevi (n = 45), dysplastic naevi (n = 47), and malignant melanoma (n = 50). It was found that fractal dimension of malignant melanoma cell nuclei differs significantly from the intradermal and dysplastic naevi (p ≤ 0. 001, Steel-Dwass Multiple Comparison Test). Additionaly, ROC analysis confirmed the value of fractal dimension based evaluation. It is suggested that the estimation of fractal dimension from the perimeter-area relation of the cell nuclei may be a potentially useful morphometric parameter in the medical differential diagnosis of pigmented skin lesions.

Lesion symptom map of cognitive-postural interference in multiple sclerosis.

PubMed

Ruggieri, Serena; Fanelli, Fulvia; Castelli, Letizia; Petsas, Nikolaos; De Giglio, Laura; Prosperini, Luca

2018-04-01

To investigate the disease-altered structure-function relationship underlying the cognitive-postural interference (CPI) phenomenon in multiple sclerosis (MS). We measured postural sway of 96 patients and 48 sex-/age-matched healthy controls by force platform in quiet standing (single-task (ST)) while performing the Stroop test (dual-task (DT)) to estimate the dual-task cost (DTC) of balance. In patient group, binary T2 and T1 lesion masks and their corresponding lesion volumes were obtained from magnetic resonance imaging (MRI) of brain. Normalized brain volume (NBV) was also estimated by SIENAX. Correlations between DTC and lesion location were determined by voxel-based lesion symptom mapping (VLSM) analyses. Patients had greater DTC than controls ( p < 0.001). Among whole brain MRI metrics, only T1 lesion volume correlated with DTC ( r = -0.27; p < 0.01). However, VLSM analysis did not reveal any association with DTC using T1 lesion masks. By contrast, we found clusters of T2 lesions in distinct anatomical regions (anterior and superior corona radiata, bilaterally) to be correlated with DTC ( p < 0.01 false discovery rate (FDR)-corrected). A multivariable stepwise regression model confirmed findings from VLSM analysis. NBV did not contribute to fit the model. Our findings suggest that the CPI phenomenon in MS can be explained by disconnection along specific areas implicated in task-switching abilities and divided attention.

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 .

Fighting obesity with a sugar-based library: discovery of novel MCH-1R antagonists by a new computational-VAST approach for exploration of GPCR binding sites.

PubMed

Heifetz, Alexander; Barker, Oliver; Verquin, Geraldine; Wimmer, Norbert; Meutermans, Wim; Pal, Sandeep; Law, Richard J; Whittaker, Mark

2013-05-24

Obesity is an increasingly common disease. While antagonism of the melanin-concentrating hormone-1 receptor (MCH-1R) has been widely reported as a promising therapeutic avenue for obesity treatment, no MCH-1R antagonists have reached the market. Discovery and optimization of new chemical matter targeting MCH-1R is hindered by reduced HTS success rates and a lack of structural information about the MCH-1R binding site. X-ray crystallography and NMR, the major experimental sources of structural information, are very slow processes for membrane proteins and are not currently feasible for every GPCR or GPCR-ligand complex. This situation significantly limits the ability of these methods to impact the drug discovery process for GPCR targets in "real-time", and hence, there is an urgent need for other practical and cost-efficient alternatives. We present here a conceptually pioneering approach that integrates GPCR modeling with design, synthesis, and screening of a diverse library of sugar-based compounds from the VAST technology (versatile assembly on stable templates) to provide structural insights on the MCH-1R binding site. This approach creates a cost-efficient new avenue for structure-based drug discovery (SBDD) against GPCR targets. In our work, a primary VAST hit was used to construct a high-quality MCH-1R model. Following model validation, a structure-based virtual screen yielded a 14% hit rate and 10 novel chemotypes of potent MCH-1R antagonists, including EOAI3367472 (IC50 = 131 nM) and EOAI3367474 (IC50 = 213 nM).

ARQiv-HTS, a versatile whole-organism screening platform enabling in vivo drug discovery at high-throughput rates

PubMed Central

White, David T; Eroglu, Arife Unal; Wang, Guohua; Zhang, Liyun; Sengupta, Sumitra; Ding, Ding; Rajpurohit, Surendra K; Walker, Steven L; Ji, Hongkai; Qian, Jiang; Mumm, Jeff S

2017-01-01

The zebrafish has emerged as an important model for whole-organism small-molecule screening. However, most zebrafish-based chemical screens have achieved only mid-throughput rates. Here we describe a versatile whole-organism drug discovery platform that can achieve true high-throughput screening (HTS) capacities. This system combines our automated reporter quantification in vivo (ARQiv) system with customized robotics, and is termed ‘ARQiv-HTS’. We detail the process of establishing and implementing ARQiv-HTS: (i) assay design and optimization, (ii) calculation of sample size and hit criteria, (iii) large-scale egg production, (iv) automated compound titration, (v) dispensing of embryos into microtiter plates, and (vi) reporter quantification. We also outline what we see as best practice strategies for leveraging the power of ARQiv-HTS for zebrafish-based drug discovery, and address technical challenges of applying zebrafish to large-scale chemical screens. Finally, we provide a detailed protocol for a recently completed inaugural ARQiv-HTS effort, which involved the identification of compounds that elevate insulin reporter activity. Compounds that increased the number of insulin-producing pancreatic beta cells represent potential new therapeutics for diabetic patients. For this effort, individual screening sessions took 1 week to conclude, and sessions were performed iteratively approximately every other day to increase throughput. At the conclusion of the screen, more than a half million drug-treated larvae had been evaluated. Beyond this initial example, however, the ARQiv-HTS platform is adaptable to almost any reporter-based assay designed to evaluate the effects of chemical compounds in living small-animal models. ARQiv-HTS thus enables large-scale whole-organism drug discovery for a variety of model species and from numerous disease-oriented perspectives. PMID:27831568

Mutation discovery for Mendelian traits in non-laboratory animals: a review of achievements up to 2012

PubMed Central

Nicholas, Frank W; Hobbs, Matthew

2014-01-01

Within two years of the re-discovery of Mendelism, Bateson and Saunders had described six traits in non-laboratory animals (five in chickens and one in cattle) that show single-locus (Mendelian) inheritance. In the ensuing decades, much progress was made in documenting an ever-increasing number of such traits. In 1987 came the first discovery of a causal mutation for a Mendelian trait in non-laboratory animals: a non-sense mutation in the thyroglobulin gene (TG), causing familial goitre in cattle. In the years that followed, the rate of discovery of causal mutations increased, aided mightily by the creation of genome-wide microsatellite maps in the 1990s and even more mightily by genome assemblies and single-nucleotide polymorphism (SNP) chips in the 2000s. With sequencing costs decreasing rapidly, by 2012 causal mutations were being discovered in non-laboratory animals at a rate of more than one per week. By the end of 2012, the total number of Mendelian traits in non-laboratory animals with known causal mutations had reached 499, which was half the number of published single-locus (Mendelian) traits in those species. The distribution of types of mutations documented in non-laboratory animals is fairly similar to that in humans, with almost half being missense or non-sense mutations. The ratio of missense to non-sense mutations in non-laboratory animals to the end of 2012 was 193:78. The fraction of non-sense mutations (78/271 = 0.29) was not very different from the fraction of non-stop codons that are just one base substitution away from a stop codon (21/61 = 0.34). PMID:24372556

The ROTSE Supernova Verification Project (RSVP): Status and Early Discoveries

NASA Astrophysics Data System (ADS)

Yuan, Fang; Akerlof, C.; Quimby, R.; Aretakis, J.; McKay, T.; Miller, J. M.; Rykoff, E. S.; Swan, H. F.; Wheeler, J. C.

2007-12-01

The goal of the ROTSE Supernova Verification Project is the discovery of nearby supernova shortly after shock breakout followed by multi-epoch spectral observations as the lightcurves evolve. The very early spectra effectively constrain the progenitor properties and explosion models, but only a few such observations exist for SN Ia. The sequence of spectral observations reveals deeper and deeper layers of the explosion over time that can be used to construct a detailed picture of the burning process. This program follows the concept of the Texas Supernova Search initiated and executed successfully by Robert Quimby using ROTSE-IIIb at McDonald Observatory. To enlarge the discovery rate, we have developed image subtraction code to be installed on all four ROTSE-III telescopes. By monitoring selected fields nightly to a typical limiting magnitude of 18.5, ROTSE-III is able to discover a nearby supernova earlier than many similar searches. The expected discovery rate is 3 per month at one dedicated site. Since August 2007, our pipeline has been fully operational on ROTSE-IIIb and has discovered 5 supernovae, 3 of which we reported as ATELs and CBETs while the remaining two were found concurrently and reported by others. Among these, SN 2007if is a particularly interesting example of an apparent SN Ia involving the destruction of a super-Chandrasekhar mass system. Its spectrum closely matches that of SN 2003fg which was the first such case that has been observed. Our photometry data show a lightcurve that is a factor of 2 overluminous for a SN Ia, consistent with this interpretation. This work has been supported by NASA grants NNG-04WC41G and NNX-07AF02G.

19 CFR 159.38 - Rates for estimated duties.

Code of Federal Regulations, 2010 CFR

2010-04-01

... TREASURY (CONTINUED) LIQUIDATION OF DUTIES Conversion of Foreign Currency § 159.38 Rates for estimated duties. For purposes of calculating estimated duties, the port director shall use the rate or rates... 19 Customs Duties 2 2010-04-01 2010-04-01 false Rates for estimated duties. 159.38 Section 159.38...

2010 updated assessment of undiscovered oil and gas resources of the National Petroleum Reserve in Alaska (NPRA)

USGS Publications Warehouse

Houseknecht, D.W.; Bird, K.J.; Schuenemeyer, J.H.; Attanasi, E.D.; Garrity, C.P.; Schenk, C.J.; Charpentier, R.R.; Pollastro, R.M.; Cook, T.A.; and Klett, T.R.

2010-01-01

Using a geology-based assessment methodology, the U.S. Geological Survey estimated mean volumes of 896 million barrels of oil (MMBO) and about 53 trillion cubic feet (TCFG) of nonassociated natural gas in conventional, undiscovered accumulations within the National Petroleum Reserve in Alaska and adjacent State waters. The estimated volume of undiscovered oil is significantly lower than estimates released in 2002, owing primarily to recent exploration drilling that revealed an abrupt transition from oil to gas and reduced reservoir quality in the Alpine sandstone 15-20 miles west of the giant Alpine oil field. The National Petroleum Reserve in Alaska (NPRA) has been the focus of oil exploration during the past decade, stimulated by the mid-1990s discovery of the adjacent Alpine field-the largest onshore oil discovery in the United States during the past 25 years. Recent activities in NPRA, including extensive 3-D seismic surveys, six Federal lease sales totaling more than $250 million in bonus bids, and completion of more than 30 exploration wells on Federal and Native lands, indicate in key formations more gas than oil and poorer reservoir quality than anticipated. In the absence of a gas pipeline from northern Alaska, exploration has waned and several petroleum companies have relinquished assets in the NPRA. This fact sheet updates U.S. Geological Survey (USGS) estimates of undiscovered oil and gas in NPRA, based on publicly released information from exploration wells completed during the past decade and on the results of research that documents significant Cenozoic uplift and erosion in NPRA. The results included in this fact sheet-released in October 2010-supersede those of a previous assessment completed by the USGS in 2002.

Egret-Hibernia(!), a significant petroleum system, northern Grand Banks area, offshore eastern Canada

USGS Publications Warehouse

Magoon, L.B.; Hudson, T.L.; Peters, K.E.

2005-01-01

Egret-Hibernia(!) is a well-explored petroleum system (3.25 billion barrels oil equivalent [BOE]) located in the Jeanne d'Arc Basin on the Labrador - Newfoundland shelf. Rifting and sediment fill began in the Late Triassic. Egret source rock was deposited in the Late Jurassic at about 153 Ma. After this time, alternating reservoir rock and seal rock were deposited with some syndepositional faulting. By the end of the Early Cretaceous, faults and folds had formed numerous structural traps. For the next 100 m.y., overburden rock thermally matured the source rock when it reached almost 4 km (2.5 mi) burial depth. For 2 km (1.25 mi) below this depth, oil and gas were expelled, until the source was depleted. The expelled petroleum migrated updip to nearby faulted, anticlinal traps, where much of it migrated across faults and upsection to the Hibernia Formation (44% recoverable oil) and Avalon Formation (28%). Accumulation size decreased, and gas content increased from west to east, independent of trap size. These changes correspond to a decrease in source rock richness and quality from west to east. Almost all (96%) of the discovered petroleum resides in the Lower Cretaceous or older reservoir rock units. All accumulations found to date are normally pressured in structural traps. Fifty-two exploration wells found eighteen discoveries. Their size ranges from 1.2 to 0.01 billion BOE. Most discoveries were made between 1979 and 1991. The discovery cycle began with larger accumulations and progressed to smaller accumulations. The estimated sizes of the larger accumulations have grown since 1990. Estimated mean value for undiscovered hydrocarbons is 3.8 billion BOE, thereby raising the ultimate size of Egret-Hibernia(!) to 6.19 billion BOE. Copyright ?? 2005. The American Association of Petroleum Geologists. All rights reserved.

Arecibo Pulsar Survey Using ALFA. IV. Mock Spectrometer Data Analysis, Survey Sensitivity, and the Discovery of 40 Pulsars

NASA Astrophysics Data System (ADS)

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

2015-10-01

The on-going Arecibo Pulsar-ALFA (PALFA) survey began in 2004 and is searching for radio pulsars in the Galactic plane at 1.4 GHz. Here we present a comprehensive description of one of its main data reduction pipelines that is based on the PRESTO software and includes new interference-excision algorithms and candidate selection heuristics. This pipeline has been used to discover 40 pulsars, bringing the survey’s discovery total to 144 pulsars. Of the new discoveries, eight are millisecond pulsars (MSPs; P\\lt 10 ms) and one is a Fast Radio Burst (FRB). This pipeline has also re-detected 188 previously known pulsars, 60 of them previously discovered by the other PALFA pipelines. We present a novel method for determining the survey sensitivity that accurately takes into account the effects of interference and red noise: we inject synthetic pulsar signals with various parameters into real survey observations and then attempt to recover them with our pipeline. We find that the PALFA survey achieves the sensitivity to MSPs predicted by theoretical models but suffers a degradation for P≳ 100 ms that gradually becomes up to ˜10 times worse for P\\gt 4 {{s}} at {DM}\\lt 150 pc cm-3. We estimate 33 ± 3% of the slower pulsars are missed, largely due to red noise. A population synthesis analysis using the sensitivity limits we measured suggests the PALFA survey should have found 224 ± 16 un-recycled pulsars in the data set analyzed, in agreement with the 241 actually detected. The reduced sensitivity could have implications on estimates of the number of long-period pulsars in the Galaxy.

PHYSICAL PROPERTIES OF THE CURRENT CENSUS OF NORTHERN WHITE DWARFS WITHIN 40 pc OF THE SUN

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

Limoges, M.-M.; Bergeron, P.; Lépine, S., E-mail: limoges@astro.umontreal.ca, E-mail: bergeron@astro.umontreal.ca, E-mail: slepine@chara.gsu.edu

We present a detailed description of the physical properties of our current census of white dwarfs within 40 pc of the Sun, based on an exhaustive spectroscopic survey of northern hemisphere candidates from the SUPERBLINK proper motion database. Our method for selecting white dwarf candidates is based on a combination of theoretical color–magnitude relations and reduced proper motion diagrams. We reported in an earlier publication the discovery of nearly 200 new white dwarfs, and we present here the discovery of an additional 133 new white dwarfs, among which we identify 96 DA, 3 DB, 24 DC, 3 DQ, and 7more » DZ stars. We further identify 178 white dwarfs that lie within 40 pc of the Sun, representing a 40% increase of the current census, which now includes 492 objects. We estimate the completeness of our survey at between 66% and 78%, allowing for uncertainties in the distance estimates. We also perform a homogeneous model atmosphere analysis of this 40 pc sample and find a large fraction of massive white dwarfs, indicating that we are successfully recovering the more massive, and less luminous objects often missed in other surveys. We also show that the 40 pc sample is dominated by cool and old white dwarfs, which populate the faint end of the luminosity function, although trigonometric parallaxes will be needed to shape this part of the luminosity function more accurately. Finally, we identify 4 probable members of the 20 pc sample, 4 suspected double degenerate binaries, and we also report the discovery of two new ZZ Ceti pulsators.« less

What Will Science Gain From Mapping the World Ocean Floor?

NASA Astrophysics Data System (ADS)

Jakobsson, M.

2017-12-01

It is difficult to estimate how much of the World Ocean floor topography (bathymetry) that has been mapped. Estimates range from a few to more than ten percent of the World Ocean area. The most recent version of the bathymetric grid compiled by the General Bathymetric Chart of the Oceans (GEBCO) has bathymetric control points in 18% of the 30 x 30 arc second large grid cells. The depth values for the rest of the cells are obtained through interpolation guided by satellite altimetry in deep water. With this statistic at hand, it seems tenable to suggest that there are many scientific discoveries to be made from a complete high-resolution mapping of the World Ocean floor. In this presentation, some of our recent scientific discoveries based on modern multibeam bathymetric mapping will be highlighted and discussed. For example, how multibeam mapping provided evidence for a km-thick ice shelf covering the entire Arctic Ocean during peak glacial conditions, a hypothesis proposed nearly half a century ago, and how groundwater escape features are visible in high-resolution bathymetry in the Baltic Sea, with potential implications for the freshwater budget and distribution of nutrients and pollutants. Presented examples will be placed in the context of mapping resolution, systematic surveys versus mapping along transits, and scientific hypothesis driven mapping versus ocean exploration. The newly announced Nippon Foundation - GEBCO Seabed 2030 project has the vision to map 100% of the World Ocean floor mapped by 2030. Are there specific scientific areas where we can expect new discoveries from all mapping data collected through the Seabed 2030 project? Are there outstanding hypothesis that can be tested from a fully mapped World Ocean floor?

Zebrafish xenograft models of cancer and metastasis for drug discovery.

PubMed

Brown, Hannah K; Schiavone, Kristina; Tazzyman, Simon; Heymann, Dominique; Chico, Timothy Ja

2017-04-01

Patients with metastatic cancer suffer the highest rate of cancer-related death, but existing animal models of metastasis have disadvantages that limit our ability to understand this process. The zebrafish is increasingly used for cancer modelling, particularly xenografting of human cancer cell lines, and drug discovery, and may provide novel scientific and therapeutic insights. However, this model system remains underexploited. Areas covered: The authors discuss the advantages and disadvantages of the zebrafish xenograft model for the study of cancer, metastasis and drug discovery. They summarise previous work investigating the metastatic cascade, such as tumour-induced angiogenesis, intravasation, extravasation, dissemination and homing, invasion at secondary sites, assessing metastatic potential and evaluation of cancer stem cells in zebrafish. Expert opinion: The practical advantages of zebrafish for basic biological study and drug discovery are indisputable. However, their ability to sufficiently reproduce and predict the behaviour of human cancer and metastasis remains unproven. For this to be resolved, novel mechanisms must to be discovered in zebrafish that are subsequently validated in humans, and for therapeutic interventions that modulate cancer favourably in zebrafish to successfully translate to human clinical studies. In the meantime, more work is required to establish the most informative methods in zebrafish.

On the validity of time-dependent AUC estimators.

PubMed

Schmid, Matthias; Kestler, Hans A; Potapov, Sergej

2015-01-01

Recent developments in molecular biology have led to the massive discovery of new marker candidates for the prediction of patient survival. To evaluate the predictive value of these markers, statistical tools for measuring the performance of survival models are needed. We consider estimators of discrimination measures, which are a popular approach to evaluate survival predictions in biomarker studies. Estimators of discrimination measures are usually based on regularity assumptions such as the proportional hazards assumption. Based on two sets of molecular data and a simulation study, we show that violations of the regularity assumptions may lead to over-optimistic estimates of prediction accuracy and may therefore result in biased conclusions regarding the clinical utility of new biomarkers. In particular, we demonstrate that biased medical decision making is possible even if statistical checks indicate that all regularity assumptions are satisfied. © The Author 2013. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Upper limits to the reaction rate coefficients of C(n)(-) and C(n)H(-) (n = 2, 4, 6) with molecular hydrogen.

PubMed

Endres, Eric S; Lakhmanskaya, Olga; Hauser, Daniel; Huber, Stefan E; Best, Thorsten; Kumar, Sunil S; Probst, Michael; Wester, Roland

2014-08-21

In the interstellar medium (ISM) ion–molecule reactions play a key role in forming complex molecules. Since 2006, after the radioastronomical discovery of the first of by now six interstellar anions, interest has grown in understanding the formation and destruction pathways of negative ions in the ISM. Experiments have focused on reactions and photodetachment of the identified negatively charged ions. Hints were found that the reactions of CnH(–) with H2 may proceed with a low (<10(–13) cm(3) s(–1)), but finite rate [Eichelberger, B.; et al. Astrophys. J. 2007, 667, 1283]. Because of the high abundance of molecular hydrogen in the ISM, a precise knowledge of the reaction rate is needed for a better understanding of the low-temperature chemistry in the ISM. A suitable tool to analyze rare reactions is the 22-pole radiofrequency ion trap. Here, we report on reaction rates for Cn(–) and CnH(–) (n = 2, 4, 6) with buffer gas temperatures of H2 at 12 and 300 K. Our experiments show the absence of these reactions with an upper limit to the rate coefficients between 4 × 10(–16) and 5 × 10(–15) cm(3) s(–1), except for the case of C2(–), which does react with a finite rate with H2 at low temperatures. For the cases of C2H(–) and C4H(–), the experimental results were confirmed with quantum chemical calculations. In addition, the possible influence of a residual reactivity on the abundance of C4H(–) and C6H(–) in the ISM were estimated on the basis of a gas-phase chemical model based on the KIDA database. We found that the simulated ion abundances are already unaffected if reaction rate coefficients with H2 were below 10(–14) cm(3) s(–1).

Estimation of rates-across-sites distributions in phylogenetic substitution models.

PubMed

Susko, Edward; Field, Chris; Blouin, Christian; Roger, Andrew J

2003-10-01

Previous work has shown that it is often essential to account for the variation in rates at different sites in phylogenetic models in order to avoid phylogenetic artifacts such as long branch attraction. In most current models, the gamma distribution is used for the rates-across-sites distributions and is implemented as an equal-probability discrete gamma. In this article, we introduce discrete distribution estimates with large numbers of equally spaced rate categories allowing us to investigate the appropriateness of the gamma model. With large numbers of rate categories, these discrete estimates are flexible enough to approximate the shape of almost any distribution. Likelihood ratio statistical tests and a nonparametric bootstrap confidence-bound estimation procedure based on the discrete estimates are presented that can be used to test the fit of a parametric family. We applied the methodology to several different protein data sets, and found that although the gamma model often provides a good parametric model for this type of data, rate estimates from an equal-probability discrete gamma model with a small number of categories will tend to underestimate the largest rates. In cases when the gamma model assumption is in doubt, rate estimates coming from the discrete rate distribution estimate with a large number of rate categories provide a robust alternative to gamma estimates. An alternative implementation of the gamma distribution is proposed that, for equal numbers of rate categories, is computationally more efficient during optimization than the standard gamma implementation and can provide more accurate estimates of site rates.

Chevron starts U.S. gulf`s first Lower Cretaceous flow

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

Petzet, G.A.

1998-06-15

Chevron plans to start production from its Mobile 991 No. 1 well this month. The trend`s first producer is the Viosca Knoll 68 No. 2 well, which went on line April 26 at the anticipated rate of about 15 MMcfd of gas. Chevron has also tested its Viosca Knoll 114 discovery well, drilled in August 1997. Five gas discoveries since 1994 in a trend that extends now Mobile Block 991 to Viosca Knoll Block 252 have recoverable reserve potential of over 600 bcf (gross trend) of natural gas. The paper describes the carbonate trend and exploring the Lower Cretaceous Jamesmore » deposit.« less

Designing biomedical proteomics experiments: state-of-the-art and future perspectives.

PubMed

Maes, Evelyne; Kelchtermans, Pieter; Bittremieux, Wout; De Grave, Kurt; Degroeve, Sven; Hooyberghs, Jef; Mertens, Inge; Baggerman, Geert; Ramon, Jan; Laukens, Kris; Martens, Lennart; Valkenborg, Dirk

2016-05-01

With the current expanded technical capabilities to perform mass spectrometry-based biomedical proteomics experiments, an improved focus on the design of experiments is crucial. As it is clear that ignoring the importance of a good design leads to an unprecedented rate of false discoveries which would poison our results, more and more tools are developed to help researchers designing proteomic experiments. In this review, we apply statistical thinking to go through the entire proteomics workflow for biomarker discovery and validation and relate the considerations that should be made at the level of hypothesis building, technology selection, experimental design and the optimization of the experimental parameters.

Uncertainty of exploitation estimates made from tag returns

USGS Publications Warehouse

Miranda, L.E.; Brock, R.E.; Dorr, B.S.

2002-01-01

Over 6,000 crappies Pomoxis spp. were tagged in five water bodies to estimate exploitation rates by anglers. Exploitation rates were computed as the percentage of tags returned after adjustment for three sources of uncertainty: postrelease mortality due to the tagging process, tag loss, and the reporting rate of tagged fish. Confidence intervals around exploitation rates were estimated by resampling from the probability distributions of tagging mortality, tag loss, and reporting rate. Estimates of exploitation rates ranged from 17% to 54% among the five study systems. Uncertainty around estimates of tagging mortality, tag loss, and reporting resulted in 90% confidence intervals around the median exploitation rate as narrow as 15 percentage points and as broad as 46 percentage points. The greatest source of estimation error was uncertainty about tag reporting. Because the large investments required by tagging and reward operations produce imprecise estimates of the exploitation rate, it may be worth considering other approaches to estimating it or simply circumventing the exploitation question altogether.

Program CONTRAST--A general program for the analysis of several survival or recovery rate estimates

USGS Publications Warehouse

Hines, J.E.; Sauer, J.R.

1989-01-01

This manual describes the use of program CONTRAST, which implements a generalized procedure for the comparison of several rate estimates. This method can be used to test both simple and composite hypotheses about rate estimates, and we discuss its application to multiple comparisons of survival rate estimates. Several examples of the use of program CONTRAST are presented. Program CONTRAST will run on IBM-cimpatible computers, and requires estimates of the rates to be tested, along with associated variance and covariance estimates.

VizieR Online Data Catalog: New proper motion stars with pm>=0.18"/yr (Boyd+, 2011)

NASA Astrophysics Data System (ADS)

Boyd, M. R.; Henry, T. J.; Jao, W.-C.; Subasavage, J. P.; Hambly, N. C.

2012-11-01

Here we present 1584 new southern proper motion systems with μ>=0.18"/yr and 16.5>R59F>=18.0. This search complements the six previous SuperCOSMOS-RECONS (SCR) proper motion searches of the southern sky for stars within the same proper motion range, but with R59F<=16.5. As in previous papers, we present distance estimates for these systems and find that three systems are estimated to be within 25pc, including one, SCR 1546-5534, possibly within the RECONS 10pc horizon at 6.7pc, making it the second nearest discovery of the searches. We find 97 white dwarf candidates with distance estimates between 10 and 120pc, as well as 557 cool subdwarf candidates. (5 data files).

Accuracy Rates of Ancestry Estimation by Forensic Anthropologists Using Identified Forensic Cases.

PubMed

Thomas, Richard M; Parks, Connie L; Richard, Adam H

2017-07-01

A common task in forensic anthropology involves the estimation of the ancestry of a decedent by comparing their skeletal morphology and measurements to skeletons of individuals from known geographic groups. However, the accuracy rates of ancestry estimation methods in actual forensic casework have rarely been studied. This article uses 99 forensic cases with identified skeletal remains to develop accuracy rates for ancestry estimations conducted by forensic anthropologists. The overall rate of correct ancestry estimation from these cases is 90.9%, which is comparable to most research-derived rates and those reported by individual practitioners. Statistical tests showed no significant difference in accuracy rates depending on examiner education level or on the estimated or identified ancestry. More recent cases showed a significantly higher accuracy rate. The incorporation of metric analyses into the ancestry estimate in these cases led to a higher accuracy rate. © 2017 American Academy of Forensic Sciences.

On new physics searches with multidimensional differential shapes

NASA Astrophysics Data System (ADS)

Ferreira, Felipe; Fichet, Sylvain; Sanz, Veronica

2018-03-01

In the context of upcoming new physics searches at the LHC, we investigate the impact of multidimensional differential rates in typical LHC analyses. We discuss the properties of shape information, and argue that multidimensional rates bring limited information in the scope of a discovery, but can have a large impact on model discrimination. We also point out subtleties about systematic uncertainties cancellations and the Cauchy-Schwarz bound on interference terms.

Finding novel pharmaceuticals in the systems biology era using multiple effective drug targets, phenotypic screening and knowledge of transporters: where drug discovery went wrong and how to fix it.

PubMed

Kell, Douglas B

2013-12-01

Despite the sequencing of the human genome, the rate of innovative and successful drug discovery in the pharmaceutical industry has continued to decrease. Leaving aside regulatory matters, the fundamental and interlinked intellectual issues proposed to be largely responsible for this are: (a) the move from 'function-first' to 'target-first' methods of screening and drug discovery; (b) the belief that successful drugs should and do interact solely with single, individual targets, despite natural evolution's selection for biochemical networks that are robust to individual parameter changes; (c) an over-reliance on the rule-of-5 to constrain biophysical and chemical properties of drug libraries; (d) the general abandoning of natural products that do not obey the rule-of-5; (e) an incorrect belief that drugs diffuse passively into (and presumably out of) cells across the bilayers portions of membranes, according to their lipophilicity; (f) a widespread failure to recognize the overwhelmingly important role of proteinaceous transporters, as well as their expression profiles, in determining drug distribution in and between different tissues and individual patients; and (g) the general failure to use engineering principles to model biology in parallel with performing 'wet' experiments, such that 'what if?' experiments can be performed in silico to assess the likely success of any strategy. These facts/ideas are illustrated with a reasonably extensive literature review. Success in turning round drug discovery consequently requires: (a) decent systems biology models of human biochemical networks; (b) the use of these (iteratively with experiments) to model how drugs need to interact with multiple targets to have substantive effects on the phenotype; (c) the adoption of polypharmacology and/or cocktails of drugs as a desirable goal in itself; (d) the incorporation of drug transporters into systems biology models, en route to full and multiscale systems biology models that incorporate drug absorption, distribution, metabolism and excretion; (e) a return to 'function-first' or phenotypic screening; and (f) novel methods for inferring modes of action by measuring the properties on system variables at all levels of the 'omes. Such a strategy offers the opportunity of achieving a state where we can hope to predict biological processes and the effect of pharmaceutical agents upon them. Consequently, this should both lower attrition rates and raise the rates of discovery of effective drugs substantially. © 2013 The Author Journal compilation © 2013 FEBS.

Optical sensing method to analyze germination rate of Capsicum annum seeds treated with growth-promoting chemical compounds using optical coherence tomography

NASA Astrophysics Data System (ADS)

Wijesinghe, Ruchire Eranga; Lee, Seung-Yeol; Kim, Pilun; Jung, Hee-Young; Jeon, Mansik; Kim, Jeehyun

2017-09-01

Seed germination rate differs based on chemical treatments, and nondestructive measurements of germination rate have become an essential requirement in the field of agriculture. Seed scientists and other biologists are interested in optical sensing technologies-based biological discoveries due to nondestructive detection capability. Optical coherence tomography (OCT) has recently emerged as a powerful method for biological and plant material discoveries. We report an extended application of OCT by monitoring the germination rate acceleration of chemically primed seeds. To validate the versatility of the method, Capsicum annum seeds were primed using three chemical compounds: sterile distilled water (SDW), butandiol, and 1-hexadecene. Monitoring was performed using a 1310-nm swept source OCT system. The results confirmed more rapid morphological variations in the seeds treated with 1-hexadecene medium than the seeds treated with SDW and butandiol within 8 consecutive days. In addition, fresh weight measurements (gold standard) of seeds were monitored for 15 days, and the obtained results were correlated with the OCT results. Thus, such a method can be used in various agricultural fields, and OCT shows potential as a rigorous sensing method for selecting the optimal plant growth-promoting chemical compounds rapidly, when compared with the gold standard methods.

The Quirky Collider Signals of Folded Supersymmetry

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

Burdman, Gustavo; Chacko, Z.; Goh, Hock-Seng

2008-08-01

We investigate the collider signals associated with scalar quirks ('squirks') in folded supersymmetric models. As opposed to regular superpartners in supersymmetric models these particles are uncolored, but are instead charged under a new confining group, leading to radically different collider signals. Due to the new strong dynamics, squirks that are pair produced do not hadronize separately, but rather form a highly excited bound state. The excited 'squirkonium' loses energy to radiation before annihilating back into Standard Model particles. We calculate the branching fractions into various channels for this process, which is prompt on collider time-scales. The most promising annihilation channelmore » for discovery is W+photon which dominates for squirkonium near its ground state. We demonstrate the feasibility of the LHC search, showing that the mass peak is visible above the SM continuum background and estimate the discovery reach.« less

LSST Astroinformatics And Astrostatistics: Data-oriented Astronomical Research

NASA Astrophysics Data System (ADS)

Borne, Kirk D.; Stassun, K.; Brunner, R. J.; Djorgovski, S. G.; Graham, M.; Hakkila, J.; Mahabal, A.; Paegert, M.; Pesenson, M.; Ptak, A.; Scargle, J.; Informatics, LSST; Statistics Team

2011-01-01

The LSST Informatics and Statistics Science Collaboration (ISSC) focuses on research and scientific discovery challenges posed by the very large and complex data collection that LSST will generate. Application areas include astroinformatics, machine learning, data mining, astrostatistics, visualization, scientific data semantics, time series analysis, and advanced signal processing. Research problems to be addressed with these methodologies include transient event characterization and classification, rare class discovery, correlation mining, outlier/anomaly/surprise detection, improved estimators (e.g., for photometric redshift or early onset supernova classification), exploration of highly dimensional (multivariate) data catalogs, and more. We present sample science results from these data-oriented approaches to large-data astronomical research. We present results from LSST ISSC team members, including the EB (Eclipsing Binary) Factory, the environmental variations in the fundamental plane of elliptical galaxies, and outlier detection in multivariate catalogs.

Exoplanet Science in the Classroom: Learning Activities for an Introductory Physics Course

NASA Astrophysics Data System (ADS)

Della-Rose, Devin; Carlson, Randall; de La Harpe, Kimberly; Novotny, Steven; Polsgrove, Daniel

2018-03-01

Discovery of planets outside our solar system, known as extra-solar planets or exoplanets for short, has been at the forefront of astronomical research for over 25 years. Reports of new discoveries have almost become routine; however, the excitement surrounding them has not. Amazingly, as groundbreaking as exoplanet science is, the basic physics is quite accessible to first-year physics students, as discussed in previous TPT articles. To further illustrate this point, we developed an iOS application that generates synthetic exoplanet data to provide students and teachers with interactive learning activities. Using introductory physics concepts, we demonstrate how to estimate exoplanet mass, radius, and density from the app output. These calculations form the basis for a diverse range of classroom activities. We conclude with a summary of exoplanet science resources for teachers.

[Evaluation of performance of five bioinformatics software for the prediction of missense mutations].

PubMed

Chen, Qianting; Dai, Congling; Zhang, Qianjun; Du, Juan; Li, Wen

2016-10-01

To study the prediction performance evaluation with five kinds of bioinformatics software (SIFT, PolyPhen2, MutationTaster, Provean, MutationAssessor). From own database for genetic mutations collected over the past five years, Chinese literature database, Human Gene Mutation Database, and dbSNP, 121 missense mutations confirmed by functional studies, and 121 missense mutations suspected to be pathogenic by pedigree analysis were used as positive gold standard, while 242 missense mutations with minor allele frequency (MAF)>5% in dominant hereditary diseases were used as negative gold standard. The selected mutations were predicted with the five software. Based on the results, the performance of the five software was evaluated for their sensitivity, specificity, positive predict value, false positive rate, negative predict value, false negative rate, false discovery rate, accuracy, and receiver operating characteristic curve (ROC). In terms of sensitivity, negative predictive value and false negative rate, the rank was MutationTaster, PolyPhen2, Provean, SIFT, and MutationAssessor. For specificity and false positive rate, the rank was MutationTaster, Provean, MutationAssessor, SIFT, and PolyPhen2. For positive predict value and false discovery rate, the rank was MutationTaster, Provean, MutationAssessor, PolyPhen2, and SIFT. For area under the ROC curve (AUC) and accuracy, the rank was MutationTaster, Provean, PolyPhen2, MutationAssessor, and SIFT. The prediction performance of software may be different when using different parameters. Among the five software, MutationTaster has the best prediction performance.

Lightcurve Analysis of the NEA Binary Asteroid 5381 Sekhmet

NASA Astrophysics Data System (ADS)

Warner, Brian D.; Harris, Alan W.

2014-10-01

Radar observations in 2003 (Nolan et al., 2003) showed that the near-Earth asteroid (NEA) 5381 Sekhmet was a binary. CCD photometry observations made from the Center for Solar System Studies-Palmer Divide Station (CS3-PDS) during the 2014 apparition confirmed the discovery and found the first precise values for the primary rotation period, P1 = 2.8233 ± 0.0001 h, and the orbital period of the satellite, P_ORB = 12.379 ± 0.004 h. The estimated effective size ratio of the two bodies is Ds/Dp ≥ 0.25 ± 0.02, which is in good agreement with the sizes estimated by radar.

Supernovae as Cosmological Probes

NASA Astrophysics Data System (ADS)

Cappellaro, E.

I review the use of SN Ia as distance indicators for measuring H 0, the Hubble constant, and the expansion history of the Universe. Most current estimates of H 0 are in the range 74-76 km s^{-1}Mpc^{-1}, in significant disagreement with the PLANCK's CMB estimate that is 10 % smaller. The main issues for SN Ia calibration, namely the luminosity vs. light curve shape relation and the correction for dust extinction are briefly addressed. SN Ia have been the key for the discovery of the acceleration of the cosmic expansion and in the near future they are expected to give a significant contribution to reveal the nature of dark energy.

Estimation of the object orientation and location with the use of MEMS sensors

NASA Astrophysics Data System (ADS)

Sawicki, Aleksander; Walendziuk, Wojciech; Idzkowski, Adam

2015-09-01

The article presents the implementation of the estimation algorithms of orientation in 3D space and the displacement of an object in a 2D space. Moreover, a general orientation storage methods using Euler angles, quaternion and rotation matrix are presented. The experimental part presents the results of the complementary filter implementation. In the study experimental microprocessor module based on STM32f4 Discovery system and myRIO hardware platform equipped with FPGA were used. The attempt to track an object in two-dimensional space, which are showed in the final part of this article, were made with the use of the equipment mentioned above.

Discovery of a transiting planet near the snow-line

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

Kipping, D. M.; Torres, G.; Buchhave, L. A.

2014-11-01

In most theories of planet formation, the snow-line represents a boundary between the emergence of the interior rocky planets and the exterior ice giants. The wide separation of the snow-line makes the discovery of transiting worlds challenging, yet transits would allow for detailed subsequent characterization. We present the discovery of Kepler-421b, a Uranus-sized exoplanet transiting a G9/K0 dwarf once every 704.2 days in a near-circular orbit. Using public Kepler photometry, we demonstrate that the two observed transits can be uniquely attributed to the 704.2 day period. Detailed light curve analysis with BLENDER validates the planetary nature of Kepler-421b to >4σmore » confidence. Kepler-421b receives the same insolation as a body at ∼2 AU in the solar system, as well as a Uranian albedo, which would have an effective temperature of ∼180 K. Using a time-dependent model for the protoplanetary disk, we estimate that Kepler-421b's present semi-major axis was beyond the snow-line after ∼3 Myr, indicating that Kepler-421b may have formed at its observed location.« less

Advances in immobilized artificial membrane (IAM) chromatography for novel drug discovery.

PubMed

Tsopelas, Fotios; Vallianatou, Theodosia; Tsantili-Kakoulidou, Anna

2016-01-01

The development of immobilized artificial membrane (IAM) chromatography has unfolded new perspectives for the use of chromatographic techniques in drug discovery, combining simulation of the environment of cell membranes with rapid measurements. The present review describes the characteristics of phosphatidylcholine-based stationary phases and analyses the molecular factors governing IAM retention in comparison to n-octanol-water and liposomes partitioning systems as well as to reversed phase chromatography. Other biomimetic stationary phases are also briefly discussed. The potential of IAM chromatography to model permeability through the main physiological barriers and drug membrane interactions is outlined. Further applications to calculate complex pharmacokinetic properties, related to tissue binding, and to screen drug candidates for phospholipidosis, as well as to estimate cell accumulation/retention are surveyed. The ambivalent nature of IAM chromatography, as a border case between passive diffusion and binding, defines its multiple potential applications. However, despite its successful performance in many permeability and drug-membrane interactions studies, IAM chromatography is still used as a supportive and not a stand-alone technique. Further studies looking at IAM chromatography in different biological processes are still required if this technique is to have a more focused and consistent application in drug discovery.

The origin and diversification of eukaryotes: problems with molecular phylogenetics and molecular clock estimation

PubMed Central

Roger, Andrew J; Hug, Laura A

2006-01-01

Determining the relationships among and divergence times for the major eukaryotic lineages remains one of the most important and controversial outstanding problems in evolutionary biology. The sequencing and phylogenetic analyses of ribosomal RNA (rRNA) genes led to the first nearly comprehensive phylogenies of eukaryotes in the late 1980s, and supported a view where cellular complexity was acquired during the divergence of extant unicellular eukaryote lineages. More recently, however, refinements in analytical methods coupled with the availability of many additional genes for phylogenetic analysis showed that much of the deep structure of early rRNA trees was artefactual. Recent phylogenetic analyses of a multiple genes and the discovery of important molecular and ultrastructural phylogenetic characters have resolved eukaryotic diversity into six major hypothetical groups. Yet relationships among these groups remain poorly understood because of saturation of sequence changes on the billion-year time-scale, possible rapid radiations of major lineages, phylogenetic artefacts and endosymbiotic or lateral gene transfer among eukaryotes. Estimating the divergence dates between the major eukaryote lineages using molecular analyses is even more difficult than phylogenetic estimation. Error in such analyses comes from a myriad of sources including: (i) calibration fossil dates, (ii) the assumed phylogenetic tree, (iii) the nucleotide or amino acid substitution model, (iv) substitution number (branch length) estimates, (v) the model of how rates of evolution change over the tree, (vi) error inherent in the time estimates for a given model and (vii) how multiple gene data are treated. By reanalysing datasets from recently published molecular clock studies, we show that when errors from these various sources are properly accounted for, the confidence intervals on inferred dates can be very large. Furthermore, estimated dates of divergence vary hugely depending on the methods used and their assumptions. Accurate dating of divergence times among the major eukaryote lineages will require a robust tree of eukaryotes, a much richer Proterozoic fossil record of microbial eukaryotes assignable to extant groups for calibration, more sophisticated relaxed molecular clock methods and many more genes sampled from the full diversity of microbial eukaryotes. PMID:16754613

The IPAC Image Subtraction and Discovery Pipeline for the Intermediate Palomar Transient Factory

NASA Astrophysics Data System (ADS)

Masci, Frank J.; Laher, Russ R.; Rebbapragada, Umaa D.; Doran, Gary B.; Miller, Adam A.; Bellm, Eric; Kasliwal, Mansi; Ofek, Eran O.; Surace, Jason; Shupe, David L.; Grillmair, Carl J.; Jackson, Ed; Barlow, Tom; Yan, Lin; Cao, Yi; Cenko, S. Bradley; Storrie-Lombardi, Lisa J.; Helou, George; Prince, Thomas A.; Kulkarni, Shrinivas R.

2017-01-01

We describe the near real-time transient-source discovery engine for the intermediate Palomar Transient Factory (iPTF), currently in operations at the Infrared Processing and Analysis Center (IPAC), Caltech. We coin this system the IPAC/iPTF Discovery Engine (or IDE). We review the algorithms used for PSF-matching, image subtraction, detection, photometry, and machine-learned (ML) vetting of extracted transient candidates. We also review the performance of our ML classifier. For a limiting signal-to-noise ratio of 4 in relatively unconfused regions, bogus candidates from processing artifacts and imperfect image subtractions outnumber real transients by ≃10:1. This can be considerably higher for image data with inaccurate astrometric and/or PSF-matching solutions. Despite this occasionally high contamination rate, the ML classifier is able to identify real transients with an efficiency (or completeness) of ≃97% for a maximum tolerable false-positive rate of 1% when classifying raw candidates. All subtraction-image metrics, source features, ML probability-based real-bogus scores, contextual metadata from other surveys, and possible associations with known Solar System objects are stored in a relational database for retrieval by the various science working groups. We review our efforts in mitigating false-positives and our experience in optimizing the overall system in response to the multitude of science projects underway with iPTF.

The IPAC Image Subtraction and Discovery Pipeline for the Intermediate Palomar Transient Factory

NASA Technical Reports Server (NTRS)

Masci, Frank J.; Laher, Russ R.; Rebbapragada, Umaa D.; Doran, Gary B.; Miller, Adam A.; Bellm, Eric; Kasliwal, Mansi; Ofek, Eran O.; Surace, Jason; Shupe, David L.;

Astrophysical Implications of the Binary Black-hole Merger GW150914

NASA Astrophysics Data System (ADS)

Abbott, B. P.; Abbott, R.; Abbott, T. D.; Abernathy, M. R.; Acernese, F.; Ackley, K.; Adams, C.; Adams, T.; Addesso, P.; Adhikari, R. X.; Adya, V. B.; Affeldt, C.; Agathos, M.; Agatsuma, K.; Aggarwal, N.; Aguiar, O. D.; Aiello, L.; Ain, A.; Ajith, P.; Allen, B.; Allocca, A.; Altin, P. A.; Anderson, S. B.; Anderson, W. G.; Arai, K.; Araya, M. C.; Arceneaux, C. C.; Areeda, J. S.; Arnaud, N.; Arun, K. G.; Ascenzi, S.; Ashton, G.; Ast, M.; Aston, S. M.; Astone, P.; Aufmuth, P.; Aulbert, C.; Babak, S.; Bacon, P.; Bader, M. K. M.; Baker, P. T.; Baldaccini, F.; Ballardin, G.; Ballmer, S. W.; Barayoga, J. C.; Barclay, S. E.; Barish, B. C.; Barker, D.; Barone, F.; Barr, B.; Barsotti, L.; Barsuglia, M.; Barta, D.; Bartlett, J.; Bartos, I.; Bassiri, R.; Basti, A.; Batch, J. C.; Baune, C.; Bavigadda, V.; Bazzan, M.; Behnke, B.; Bejger, M.; Belczynski, C.; Bell, A. S.; Bell, C. J.; Berger, B. K.; Bergman, J.; Bergmann, G.; Berry, C. P. L.; Bersanetti, D.; Bertolini, A.; Betzwieser, J.; Bhagwat, S.; Bhandare, R.; Bilenko, I. A.; Billingsley, G.; Birch, J.; Birney, R.; Biscans, S.; Bisht, A.; Bitossi, M.; Biwer, C.; Bizouard, M. A.; Blackburn, J. K.; Blair, C. D.; Blair, D. G.; Blair, R. M.; Bloemen, S.; Bock, O.; Bodiya, T. P.; Boer, M.; Bogaert, G.; Bogan, C.; Bohe, A.; Bojtos, P.; Bond, C.; Bondu, F.; Bonnand, R.; Boom, B. A.; Bork, R.; Boschi, V.; Bose, S.; Bouffanais, Y.; Bozzi, A.; Bradaschia, C.; Brady, P. R.; Braginsky, V. B.; Branchesi, M.; Brau, J. E.; Briant, T.; Brillet, A.; Brinkmann, M.; Brisson, V.; Brockill, P.; Brooks, A. F.; Brown, D. A.; Brown, D. D.; Brown, N. M.; Buchanan, C. C.; Buikema, A.; Bulik, T.; Bulten, H. J.; Buonanno, A.; Buskulic, D.; Buy, C.; Byer, R. L.; Cadonati, L.; Cagnoli, G.; Cahillane, C.; Calderón Bustillo, J.; Callister, T.; Calloni, E.; Camp, J. B.; Cannon, K. C.; Cao, J.; Capano, C. D.; Capocasa, E.; Carbognani, F.; Caride, S.; Casanueva Diaz, J.; Casentini, C.; Caudill, S.; Cavaglià, M.; Cavalier, F.; Cavalieri, R.; Cella, G.; Cepeda, C.; Cerboni Baiardi, L.; Cerretani, G.; Cesarini, E.; Chakraborty, R.; Chalermsongsak, T.; Chamberlin, S. J.; Chan, M.; Chao, S.; Charlton, P.; Chassande-Mottin, E.; Chen, H. Y.; Chen, Y.; Cheng, C.; Chincarini, A.; Chiummo, A.; Cho, H. S.; Cho, M.; Chow, J. H.; Christensen, N.; Chu, Q.; Chua, S.; Chung, S.; Ciani, G.; Clara, F.; Clark, J. A.; Cleva, F.; Coccia, E.; Cohadon, P.-F.; Colla, A.; Collette, C. G.; Cominsky, L.; Constancio, M., Jr.; Conte, A.; Conti, L.; Cook, D.; Corbitt, T. R.; Cornish, N.; Corsi, A.; Cortese, S.; Costa, C. A.; Coughlin, M. W.; Coughlin, S. B.; Coulon, J.-P.; Countryman, S. T.; Couvares, P.; Cowan, E. E.; Coward, D. M.; Cowart, M. J.; Coyne, D. C.; Coyne, R.; Craig, K.; Creighton, J. D. E.; Cripe, J.; Crowder, S. G.; Cumming, A.; Cunningham, L.; Cuoco, E.; Dal Canton, T.; Danilishin, S. L.; D'Antonio, S.; Danzmann, K.; Darman, N. S.; Dattilo, V.; Dave, I.; Daveloza, H. P.; Davier, M.; Davies, G. S.; Daw, E. J.; Day, R.; DeBra, D.; Debreczeni, G.; Degallaix, J.; De Laurentis, M.; Deléglise, S.; Del Pozzo, W.; Denker, T.; Dent, T.; Dereli, H.; Dergachev, V.; DeRosa, R.; DeRosa, R. T.; DeSalvo, R.; Dhurandhar, S.; Díaz, M. C.; Di Fiore, L.; Di Giovanni, M.; Di Lieto, A.; Di Pace, S.; Di Palma, I.; Di Virgilio, A.; Dojcinoski, G.; Dolique, V.; Donovan, F.; Dooley, K. L.; Doravari, S.; Douglas, R.; Downes, T. P.; Drago, M.; Drever, R. W. P.; Driggers, J. C.; Du, Z.; Ducrot, M.; Dwyer, S. E.; Edo, T. B.; Edwards, M. C.; Effler, A.; Eggenstein, H.-B.; Ehrens, P.; Eichholz, J.; Eikenberry, S. S.; Engels, W.; Essick, R. C.; Etzel, T.; Evans, M.; Evans, T. M.; Everett, R.; Factourovich, M.; Fafone, V.; Fair, H.; Fairhurst, S.; Fan, X.; Fang, Q.; Farinon, S.; Farr, B.; Farr, W. M.; Favata, M.; Fays, M.; Fehrmann, H.; Fejer, M. M.; Ferrante, I.; Ferreira, E. C.; Ferrini, F.; Fidecaro, F.; Fiori, I.; Fiorucci, D.; Fisher, R. P.; Flaminio, R.; Fletcher, M.; Fournier, J.-D.; Franco, S.; Frasca, S.; Frasconi, F.; Frei, Z.; Freise, A.; Frey, R.; Frey, V.; Fricke, T. T.; Fritschel, P.; Frolov, V. V.; Fulda, P.; Fyffe, M.; Gabbard, H. A. G.; Gair, J. R.; Gammaitoni, L.; Gaonkar, S. G.; Garufi, F.; Gatto, A.; Gaur, G.; Gehrels, N.; Gemme, G.; Gendre, B.; Genin, E.; Gennai, A.; George, J.; Gergely, L.; Germain, V.; Ghosh, Archisman; Ghosh, S.; Giaime, J. A.; Giardina, K. D.; Giazotto, A.; Gill, K.; Glaefke, A.; Goetz, E.; Goetz, R.; Gondan, L.; González, G.; Gonzalez Castro, J. M.; Gopakumar, A.; Gordon, N. A.; Gorodetsky, M. L.; Gossan, S. E.; Gosselin, M.; Gouaty, R.; Graef, C.; Graff, P. B.; Granata, M.; Grant, A.; Gras, S.; Gray, C.; Greco, G.; Green, A. C.; Groot, P.; Grote, H.; Grunewald, S.; Guidi, G. M.; Guo, X.; Gupta, A.; Gupta, M. K.; Gushwa, K. E.; Gustafson, E. K.; Gustafson, R.; Hacker, J. J.; Hall, B. R.; Hall, E. D.; Hammond, G.; Haney, M.; Hanke, M. M.; Hanks, J.; Hanna, C.; Hannam, M. D.; Hanson, J.; Hardwick, T.; Harms, J.; Harry, G. M.; Harry, I. W.; Hart, M. J.; Hartman, M. T.; Haster, C.-J.; Haughian, K.; Heidmann, A.; Heintze, M. C.; Heitmann, H.; Hello, P.; Hemming, G.; Hendry, M.; Heng, I. S.; Hennig, J.; Heptonstall, A. W.; Heurs, M.; Hild, S.; Hoak, D.; Hodge, K. A.; Hofman, D.; Hollitt, S. E.; Holt, K.; Holz, D. E.; Hopkins, P.; Hosken, D. J.; Hough, J.; Houston, E. A.; Howell, E. J.; Hu, Y. M.; Huang, S.; Huerta, E. A.; Huet, D.; Hughey, B.; Husa, S.; Huttner, S. H.; Huynh-Dinh, T.; Idrisy, A.; Indik, N.; Ingram, D. R.; Inta, R.; Isa, H. N.; Isac, J.-M.; Isi, M.; Islas, G.; Isogai, T.; Iyer, B. R.; Izumi, K.; Jacqmin, T.; Jang, H.; Jani, K.; Jaranowski, P.; Jawahar, S.; Jiménez-Forteza, F.; Johnson, W. W.; Jones, D. I.; Jones, R.; Jonker, R. J. G.; Ju, L.; K, Haris; Kalaghatgi, C. V.; Kalogera, V.; Kandhasamy, S.; Kang, G.; Kanner, J. B.; Karki, S.; Kasprzack, M.; Katsavounidis, E.; Katzman, W.; Kaufer, S.; Kaur, T.; Kawabe, K.; Kawazoe, F.; Kéfélian, F.; Kehl, M. S.; Keitel, D.; Kelley, D. B.; Kells, W.; Kennedy, R.; Key, J. S.; Khalaidovski, A.; Khalili, F. Y.; Khan, I.; Khan, S.; Khan, Z.; Khazanov, E. A.; Kijbunchoo, N.; Kim, C.; Kim, J.; Kim, K.; Kim, Nam-Gyu; Kim, Namjun; Kim, Y.-M.; King, E. J.; King, P. J.; Kinzel, D. L.; Kissel, J. S.; Kleybolte, L.; Klimenko, S.; Koehlenbeck, S. M.; Kokeyama, K.; Koley, S.; Kondrashov, V.; Kontos, A.; Korobko, M.; Korth, W. Z.; Kowalska, I.; Kozak, D. B.; Kringel, V.; Krishnan, B.; Królak, A.; Krueger, C.; Kuehn, G.; Kumar, P.; Kuo, L.; Kutynia, A.; Lackey, B. D.; Landry, M.; Lange, J.; Lantz, B.; Lasky, P. D.; Lazzarini, A.; Lazzaro, C.; Leaci, P.; Leavey, S.; Lebigot, E. O.; Lee, C. H.; Lee, H. K.; Lee, H. M.; Lee, K.; Lenon, A.; Leonardi, M.; Leong, J. R.; Leroy, N.; Letendre, N.; Levin, Y.; Levine, B. M.; Li, T. G. F.; Libson, A.; Littenberg, T. B.; Lockerbie, N. A.; Logue, J.; Lombardi, A. L.; Lord, J. E.; Lorenzini, M.; Loriette, V.; Lormand, M.; Losurdo, G.; Lough, J. D.; Lück, H.; Lundgren, A. P.; Luo, J.; Lynch, R.; Ma, Y.; MacDonald, T.; Machenschalk, B.; MacInnis, M.; Macleod, D. M.; Magaña-Sandoval, F.; Magee, R. M.; Mageswaran, M.; Majorana, E.; Maksimovic, I.; Malvezzi, V.; Man, N.; Mandel, I.; Mandic, V.; Mangano, V.; Mansell, G. L.; Manske, M.; Mantovani, M.; Marchesoni, F.; Marion, F.; Márka, S.; Márka, Z.; Markosyan, A. S.; Maros, E.; Martelli, F.; Martellini, L.; Martin, I. W.; Martin, R. M.; Martynov, D. V.; Marx, J. N.; Mason, K.; Masserot, A.; Massinger, T. J.; Masso-Reid, M.; Matichard, F.; Matone, L.; Mavalvala, N.; Mazumder, N.; Mazzolo, G.; McCarthy, R.; McClelland, D. E.; McCormick, S.; McGuire, S. C.; McIntyre, G.; McIver, J.; McManus, D. J.; McWilliams, S. T.; Meacher, D.; Meadors, G. D.; Meidam, J.; Melatos, A.; Mendell, G.; Mendoza-Gandara, D.; Mercer, R. A.; Merilh, E.; Merzougui, M.; Meshkov, S.; Messenger, C.; Messick, C.; Meyers, P. M.; Mezzani, F.; Miao, H.; Michel, C.; Middleton, H.; Mikhailov, E. E.; Milano, L.; Miller, J.; Millhouse, M.; Minenkov, Y.; Ming, J.; Mirshekari, S.; Mishra, C.; Mitra, S.; Mitrofanov, V. P.; Mitselmakher, G.; Mittleman, R.; Moggi, A.; Mohan, M.; Mohapatra, S. R. P.; Montani, M.; Moore, B. C.; Moore, C. J.; Moraru, D.; Moreno, G.; Morriss, S. R.; Mossavi, K.; Mours, B.; Mow-Lowry, C. M.; Mueller, C. L.; Mueller, G.; Muir, A. W.; Mukherjee, Arunava; Mukherjee, D.; Mukherjee, S.; Mukund, N.; Mullavey, A.; Munch, J.; Murphy, D. J.; Murray, P. G.; Mytidis, A.; Nardecchia, I.; Naticchioni, L.; Nayak, R. K.; Necula, V.; Nedkova, K.; Nelemans, G.; Neri, M.; Neunzert, A.; Newton, G.; Nguyen, T. T.; Nielsen, A. B.; Nissanke, S.; Nitz, A.; Nocera, F.; Nolting, D.; Normandin, M. E. N.; Nuttall, L. K.; Oberling, J.; Ochsner, E.; O'Dell, J.; Oelker, E.; Ogin, G. H.; Oh, J. J.; Oh, S. H.; Ohme, F.; Oliver, M.; Oppermann, P.; Oram, Richard J.; O'Reilly, B.; O'Shaughnessy, R.; Ottaway, D. J.; Ottens, R. S.; Overmier, H.; Owen, B. J.; Pai, A.; Pai, S. A.; Palamos, J. R.; Palashov, O.; Palomba, C.; Pal-Singh, A.; Pan, H.; Pankow, C.; Pannarale, F.; Pant, B. C.; Paoletti, F.; Paoli, A.; Papa, M. A.; Paris, H. R.; Parker, W.; Pascucci, D.; Pasqualetti, A.; Passaquieti, R.; Passuello, D.; Patricelli, B.; Patrick, Z.; Pearlstone, B. L.; Pedraza, M.; Pedurand, R.; Pekowsky, L.; Pele, A.; Penn, S.; Perreca, A.; Phelps, M.; Piccinni, O.; Pichot, M.; Piergiovanni, F.; Pierro, V.; Pillant, G.; Pinard, L.; Pinto, I. M.; Pitkin, M.; Poggiani, R.; Popolizio, P.; Post, A.; Powell, J.; Prasad, J.; Predoi, V.; Premachandra, S. S.; Prestegard, T.; Price, L. R.; Prijatelj, M.; Principe, M.; Privitera, S.; Prix, R.; Prodi, G. A.; Prokhorov, L.; Puncken, O.; Punturo, M.; Puppo, P.; Pürrer, M.; Qi, H.; Qin, J.; Quetschke, V.; Quintero, E. A.; Quitzow-James, R.; Raab, F. J.; Rabeling, D. S.; Radkins, H.; Raffai, P.; Raja, S.; Rakhmanov, M.; Rapagnani, P.; Raymond, V.; Razzano, M.; Re, V.; Read, J.; Reed, C. M.; Regimbau, T.; Rei, L.; Reid, S.; Reitze, D. H.; Rew, H.; Reyes, S. D.; Ricci, F.; Riles, K.; Robertson, N. A.; Robie, R.; Robinet, F.; Rocchi, A.; Rolland, L.; Rollins, J. G.; Roma, V. J.; Romano, J. D.; Romano, R.; Romanov, G.; Romie, J. H.; Rosińska, D.; Rowan, S.; Rüdiger, A.; Ruggi, P.; Ryan, K.; Sachdev, S.; Sadecki, T.; Sadeghian, L.; Salconi, L.; Saleem, M.; Salemi, F.; Samajdar, A.; Sammut, L.; Sanchez, E. J.; Sandberg, V.; Sandeen, B.; Sanders, J. R.; Sassolas, B.; Sathyaprakash, B. S.; Saulson, P. R.; Sauter, O.; Savage, R. L.; Sawadsky, A.; Schale, P.; Schilling, R.; Schmidt, J.; Schmidt, P.; Schnabel, R.; Schofield, R. M. S.; Schönbeck, A.; Schreiber, E.; Schuette, D.; Schutz, B. F.; Scott, J.; Scott, S. M.; Sellers, D.; Sentenac, D.; Sequino, V.; Sergeev, A.; Serna, G.; Setyawati, Y.; Sevigny, A.; Shaddock, D. A.; Shah, S.; Shahriar, M. S.; Shaltev, M.; Shao, Z.; Shapiro, B.; Shawhan, P.; Sheperd, A.; Shoemaker, D. H.; Shoemaker, D. M.; Siellez, K.; Siemens, X.; Sigg, D.; Silva, A. D.; Simakov, D.; Singer, A.; Singer, L. P.; Singh, A.; Singh, R.; Singhal, A.; Sintes, A. M.; Slagmolen, B. J. J.; Smith, J. R.; Smith, N. D.; Smith, R. J. E.; Son, E. J.; Sorazu, B.; Sorrentino, F.; Souradeep, T.; Srivastava, A. K.; Staley, A.; Steinke, M.; Steinlechner, J.; Steinlechner, S.; Steinmeyer, D.; Stephens, B. C.; Stevenson, S. P.; Stone, R.; Strain, K. A.; Straniero, N.; Stratta, G.; Strauss, N. A.; Strigin, S.; Sturani, R.; Stuver, A. L.; Summerscales, T. Z.; Sun, L.; Sutton, P. J.; Swinkels, B. L.; Szczepańczyk, M. J.; Tacca, M.; Talukder, D.; Tanner, D. B.; Tápai, M.; Tarabrin, S. P.; Taracchini, A.; Taylor, R.; Theeg, T.; Thirugnanasambandam, M. P.; Thomas, E. G.; Thomas, M.; Thomas, P.; Thorne, K. A.; Thorne, K. S.; Thrane, E.; Tiwari, S.; Tiwari, V.; Tokmakov, K. V.; Tomlinson, C.; Tonelli, M.; Torres, C. V.; Torrie, C. 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F.; Williams, R. D.; Williamson, A. R.; Willis, J. L.; Willke, B.; Wimmer, M. H.; Winkler, W.; Wipf, C. C.; Wittel, H.; Woan, G.; Worden, J.; Wright, J. L.; Wu, G.; Yablon, J.; Yam, W.; Yamamoto, H.; Yancey, C. C.; Yap, M. J.; Yu, H.; Yvert, M.; Zadrożny, A.; Zangrando, L.; Zanolin, M.; Zendri, J.-P.; Zevin, M.; Zhang, F.; Zhang, L.; Zhang, M.; Zhang, Y.; Zhao, C.; Zhou, M.; Zhou, Z.; Zhu, X. J.; Zucker, M. E.; Zuraw, S. E.; and; Zweizig, J.; LIGO Scientific Collaboration; Virgo Collaboration

2016-02-01

The discovery of the gravitational-wave (GW) source GW150914 with the Advanced LIGO detectors provides the first observational evidence for the existence of binary black hole (BH) systems that inspiral and merge within the age of the universe. Such BH mergers have been predicted in two main types of formation models, involving isolated binaries in galactic fields or dynamical interactions in young and old dense stellar environments. The measured masses robustly demonstrate that relatively “heavy” BHs (≳ 25 {M}⊙ ) can form in nature. This discovery implies relatively weak massive-star winds and thus the formation of GW150914 in an environment with a metallicity lower than about 1/2 of the solar value. The rate of binary-BH (BBH) mergers inferred from the observation of GW150914 is consistent with the higher end of rate predictions (≳ 1 Gpc-3 yr-1) from both types of formation models. The low measured redshift (z≃ 0.1) of GW150914 and the low inferred metallicity of the stellar progenitor imply either BBH formation in a low-mass galaxy in the local universe and a prompt merger, or formation at high redshift with a time delay between formation and merger of several Gyr. This discovery motivates further studies of binary-BH formation astrophysics. It also has implications for future detections and studies by Advanced LIGO and Advanced Virgo, and GW detectors in space.