A generic, cost-effective, and scalable cell lineage analysis platform

PubMed Central

Biezuner, Tamir; Spiro, Adam; Raz, Ofir; Amir, Shiran; Milo, Lilach; Adar, Rivka; Chapal-Ilani, Noa; Berman, Veronika; Fried, Yael; Ainbinder, Elena; Cohen, Galit; Barr, Haim M.; Halaban, Ruth; Shapiro, Ehud

2016-01-01

Advances in single-cell genomics enable commensurate improvements in methods for uncovering lineage relations among individual cells. Current sequencing-based methods for cell lineage analysis depend on low-resolution bulk analysis or rely on extensive single-cell sequencing, which is not scalable and could be biased by functional dependencies. Here we show an integrated biochemical-computational platform for generic single-cell lineage analysis that is retrospective, cost-effective, and scalable. It consists of a biochemical-computational pipeline that inputs individual cells, produces targeted single-cell sequencing data, and uses it to generate a lineage tree of the input cells. We validated the platform by applying it to cells sampled from an ex vivo grown tree and analyzed its feasibility landscape by computer simulations. We conclude that the platform may serve as a generic tool for lineage analysis and thus pave the way toward large-scale human cell lineage discovery. PMID:27558250

Real-Time Discovery Services over Large, Heterogeneous and Complex Healthcare Datasets Using Schema-Less, Column-Oriented Methods

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

Begoli, Edmon; Dunning, Ted; Charlie, Frasure

We present a service platform for schema-leess exploration of data and discovery of patient-related statistics from healthcare data sets. The architecture of this platform is motivated by the need for fast, schema-less, and flexible approaches to SQL-based exploration and discovery of information embedded in the common, heterogeneously structured healthcare data sets and supporting components (electronic health records, practice management systems, etc.) The motivating use cases described in the paper are clinical trials candidate discovery, and a treatment effectiveness analysis. Following the use cases, we discuss the key features and software architecture of the platform, the underlying core components (Apache Parquet,more » Drill, the web services server), and the runtime profiles and performance characteristics of the platform. We conclude by showing dramatic speedup with some approaches, and the performance tradeoffs and limitations of others.« less

A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine

PubMed Central

Stern, Andrew M.; Schurdak, Mark E.; Bahar, Ivet; Berg, Jeremy M.; Taylor, D. Lansing

2016-01-01

Drug candidates exhibiting well-defined pharmacokinetic and pharmacodynamic profiles that are otherwise safe often fail to demonstrate proof-of-concept in phase II and III trials. Innovation in drug discovery and development has been identified as a critical need for improving the efficiency of drug discovery, especially through collaborations between academia, government agencies, and industry. To address the innovation challenge, we describe a comprehensive, unbiased, integrated, and iterative quantitative systems pharmacology (QSP)–driven drug discovery and development strategy and platform that we have implemented at the University of Pittsburgh Drug Discovery Institute. Intrinsic to QSP is its integrated use of multiscale experimental and computational methods to identify mechanisms of disease progression and to test predicted therapeutic strategies likely to achieve clinical validation for appropriate subpopulations of patients. The QSP platform can address biological heterogeneity and anticipate the evolution of resistance mechanisms, which are major challenges for drug development. The implementation of this platform is dedicated to gaining an understanding of mechanism(s) of disease progression to enable the identification of novel therapeutic strategies as well as repurposing drugs. The QSP platform will help promote the paradigm shift from reactive population-based medicine to proactive personalized medicine by focusing on the patient as the starting and the end point. PMID:26962875

Cell and small animal models for phenotypic drug discovery.

PubMed

Szabo, Mihaly; Svensson Akusjärvi, Sara; Saxena, Ankur; Liu, Jianping; Chandrasekar, Gayathri; Kitambi, Satish S

2017-01-01

The phenotype-based drug discovery (PDD) approach is re-emerging as an alternative platform for drug discovery. This review provides an overview of the various model systems and technical advances in imaging and image analyses that strengthen the PDD platform. In PDD screens, compounds of therapeutic value are identified based on the phenotypic perturbations produced irrespective of target(s) or mechanism of action. In this article, examples of phenotypic changes that can be detected and quantified with relative ease in a cell-based setup are discussed. In addition, a higher order of PDD screening setup using small animal models is also explored. As PDD screens integrate physiology and multiple signaling mechanisms during the screening process, the identified hits have higher biomedical applicability. Taken together, this review highlights the advantages gained by adopting a PDD approach in drug discovery. Such a PDD platform can complement target-based systems that are currently in practice to accelerate drug discovery.

A Preparation of (−)-Nutlin-3 Using Enantioselective Organocatalysis at Decagram Scale

PubMed Central

Davis, Tyler A.; Vilgelm, Anna E.; Richmond, Ann; Johnston, Jeffrey N.

2013-01-01

Chiral nonracemic cis-4,5-bis(aryl) imidazolines have emerged as a powerful platform for the development of cancer chemotherapeutics, stimulated by the Hoffmann-La Roche discovery that Nutlin-3 can restore apoptosis in cells with wild-type p53. The lack of efficient methods for the enantioselective synthesis of cis-imidazolines, however, has limited their more general use. Our disclosure of the first enantioselective synthesis of (−)-Nutlin-3 provided a basis to prepare larger amounts of this tool used widely in cancer biology. Key to the decagram-scale synthesis described here was the discovery of a novel bis(amidine) organocatalyst that provides high enantioselectivity at warmer reaction temperature (−20 °C) and low catalyst loadings. Further refinements to the procedure led to the synthesis of (−)-Nutlin-3 in a 17 gram batch, and elimination of all but three chromatographic purifications. PMID:24127627

Integration of lyoplate based flow cytometry and computational analysis for standardized immunological biomarker discovery.

PubMed

Villanova, Federica; Di Meglio, Paola; Inokuma, Margaret; Aghaeepour, Nima; Perucha, Esperanza; Mollon, Jennifer; Nomura, Laurel; Hernandez-Fuentes, Maria; Cope, Andrew; Prevost, A Toby; Heck, Susanne; Maino, Vernon; Lord, Graham; Brinkman, Ryan R; Nestle, Frank O

2013-01-01

Discovery of novel immune biomarkers for monitoring of disease prognosis and response to therapy in immune-mediated inflammatory diseases is an important unmet clinical need. Here, we establish a novel framework for immunological biomarker discovery, comparing a conventional (liquid) flow cytometry platform (CFP) and a unique lyoplate-based flow cytometry platform (LFP) in combination with advanced computational data analysis. We demonstrate that LFP had higher sensitivity compared to CFP, with increased detection of cytokines (IFN-γ and IL-10) and activation markers (Foxp3 and CD25). Fluorescent intensity of cells stained with lyophilized antibodies was increased compared to cells stained with liquid antibodies. LFP, using a plate loader, allowed medium-throughput processing of samples with comparable intra- and inter-assay variability between platforms. Automated computational analysis identified novel immunophenotypes that were not detected with manual analysis. Our results establish a new flow cytometry platform for standardized and rapid immunological biomarker discovery with wide application to immune-mediated diseases.

Integration of Lyoplate Based Flow Cytometry and Computational Analysis for Standardized Immunological Biomarker Discovery

PubMed Central

Villanova, Federica; Di Meglio, Paola; Inokuma, Margaret; Aghaeepour, Nima; Perucha, Esperanza; Mollon, Jennifer; Nomura, Laurel; Hernandez-Fuentes, Maria; Cope, Andrew; Prevost, A. Toby; Heck, Susanne; Maino, Vernon; Lord, Graham; Brinkman, Ryan R.; Nestle, Frank O.

2013-01-01

Discovery of novel immune biomarkers for monitoring of disease prognosis and response to therapy in immune-mediated inflammatory diseases is an important unmet clinical need. Here, we establish a novel framework for immunological biomarker discovery, comparing a conventional (liquid) flow cytometry platform (CFP) and a unique lyoplate-based flow cytometry platform (LFP) in combination with advanced computational data analysis. We demonstrate that LFP had higher sensitivity compared to CFP, with increased detection of cytokines (IFN-γ and IL-10) and activation markers (Foxp3 and CD25). Fluorescent intensity of cells stained with lyophilized antibodies was increased compared to cells stained with liquid antibodies. LFP, using a plate loader, allowed medium-throughput processing of samples with comparable intra- and inter-assay variability between platforms. Automated computational analysis identified novel immunophenotypes that were not detected with manual analysis. Our results establish a new flow cytometry platform for standardized and rapid immunological biomarker discovery with wide application to immune-mediated diseases. PMID:23843942

Company profile: Complete Genomics Inc.

PubMed

Reid, Clifford

2011-02-01

Complete Genomics Inc. is a life sciences company that focuses on complete human genome sequencing. It is taking a completely different approach to DNA sequencing than other companies in the industry. Rather than building a general-purpose platform for sequencing all organisms and all applications, it has focused on a single application - complete human genome sequencing. The company's Complete Genomics Analysis Platform (CGA™ Platform) comprises an integrated package of biochemistry, instrumentation and software that sequences human genomes at the highest quality, lowest cost and largest scale available. Complete Genomics offers a turnkey service that enables customers to outsource their human genome sequencing to the company's genome sequencing center in Mountain View, CA, USA. Customers send in their DNA samples, the company does all the library preparation, DNA sequencing, assembly and variant analysis, and customers receive research-ready data that they can use for biological discovery.

Continental-scale, data-driven predictive assessment of eliminating the vector-borne disease, lymphatic filariasis, in sub-Saharan Africa by 2020.

PubMed

Michael, Edwin; Singh, Brajendra K; Mayala, Benjamin K; Smith, Morgan E; Hampton, Scott; Nabrzyski, Jaroslaw

2017-09-27

There are growing demands for predicting the prospects of achieving the global elimination of neglected tropical diseases as a result of the institution of large-scale nation-wide intervention programs by the WHO-set target year of 2020. Such predictions will be uncertain due to the impacts that spatial heterogeneity and scaling effects will have on parasite transmission processes, which will introduce significant aggregation errors into any attempt aiming to predict the outcomes of interventions at the broader spatial levels relevant to policy making. We describe a modeling platform that addresses this problem of upscaling from local settings to facilitate predictions at regional levels by the discovery and use of locality-specific transmission models, and we illustrate the utility of using this approach to evaluate the prospects for eliminating the vector-borne disease, lymphatic filariasis (LF), in sub-Saharan Africa by the WHO target year of 2020 using currently applied or newly proposed intervention strategies. METHODS AND RESULTS: We show how a computational platform that couples site-specific data discovery with model fitting and calibration can allow both learning of local LF transmission models and simulations of the impact of interventions that take a fuller account of the fine-scale heterogeneous transmission of this parasitic disease within endemic countries. We highlight how such a spatially hierarchical modeling tool that incorporates actual data regarding the roll-out of national drug treatment programs and spatial variability in infection patterns into the modeling process can produce more realistic predictions of timelines to LF elimination at coarse spatial scales, ranging from district to country to continental levels. Our results show that when locally applicable extinction thresholds are used, only three countries are likely to meet the goal of LF elimination by 2020 using currently applied mass drug treatments, and that switching to more intensive drug regimens, increasing the frequency of treatments, or switching to new triple drug regimens will be required if LF elimination is to be accelerated in Africa. The proportion of countries that would meet the goal of eliminating LF by 2020 may, however, reach up to 24/36 if the WHO 1% microfilaremia prevalence threshold is used and sequential mass drug deliveries are applied in countries. We have developed and applied a data-driven spatially hierarchical computational platform that uses the discovery of locally applicable transmission models in order to predict the prospects for eliminating the macroparasitic disease, LF, at the coarser country level in sub-Saharan Africa. We show that fine-scale spatial heterogeneity in local parasite transmission and extinction dynamics, as well as the exact nature of intervention roll-outs in countries, will impact the timelines to achieving national LF elimination on this continent.

A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine.

PubMed

Stern, Andrew M; Schurdak, Mark E; Bahar, Ivet; Berg, Jeremy M; Taylor, D Lansing

2016-07-01

Drug candidates exhibiting well-defined pharmacokinetic and pharmacodynamic profiles that are otherwise safe often fail to demonstrate proof-of-concept in phase II and III trials. Innovation in drug discovery and development has been identified as a critical need for improving the efficiency of drug discovery, especially through collaborations between academia, government agencies, and industry. To address the innovation challenge, we describe a comprehensive, unbiased, integrated, and iterative quantitative systems pharmacology (QSP)-driven drug discovery and development strategy and platform that we have implemented at the University of Pittsburgh Drug Discovery Institute. Intrinsic to QSP is its integrated use of multiscale experimental and computational methods to identify mechanisms of disease progression and to test predicted therapeutic strategies likely to achieve clinical validation for appropriate subpopulations of patients. The QSP platform can address biological heterogeneity and anticipate the evolution of resistance mechanisms, which are major challenges for drug development. The implementation of this platform is dedicated to gaining an understanding of mechanism(s) of disease progression to enable the identification of novel therapeutic strategies as well as repurposing drugs. The QSP platform will help promote the paradigm shift from reactive population-based medicine to proactive personalized medicine by focusing on the patient as the starting and the end point. © 2016 Society for Laboratory Automation and Screening.

Advances in microfluidics for drug discovery.

PubMed

Lombardi, Dario; Dittrich, Petra S

2010-11-01

Microfluidics is considered as an enabling technology for the development of unconventional and innovative methods in the drug discovery process. The concept of micrometer-sized reaction systems in the form of continuous flow reactors, microdroplets or microchambers is intriguing, and the versatility of the technology perfectly fits with the requirements of drug synthesis, drug screening and drug testing. In this review article, we introduce key microfluidic approaches to the drug discovery process, highlighting the latest and promising achievements in this field, mainly from the years 2007 - 2010. Despite high expectations of microfluidic approaches to several stages of the drug discovery process, up to now microfluidic technology has not been able to significantly replace conventional drug discovery platforms. Our aim is to identify bottlenecks that have impeded the transfer of microfluidics into routine platforms for drug discovery and show some recent solutions to overcome these hurdles. Although most microfluidic approaches are still applied only for proof-of-concept studies, thanks to creative microfluidic research in the past years unprecedented novel capabilities of microdevices could be demonstrated, and general applicable, robust and reliable microfluidic platforms seem to be within reach.

Development of a gene synthesis platform for the efficient large scale production of small genes encoding animal toxins.

PubMed

Sequeira, Ana Filipa; Brás, Joana L A; Guerreiro, Catarina I P D; Vincentelli, Renaud; Fontes, Carlos M G A

2016-12-01

Gene synthesis is becoming an important tool in many fields of recombinant DNA technology, including recombinant protein production. De novo gene synthesis is quickly replacing the classical cloning and mutagenesis procedures and allows generating nucleic acids for which no template is available. In addition, when coupled with efficient gene design algorithms that optimize codon usage, it leads to high levels of recombinant protein expression. Here, we describe the development of an optimized gene synthesis platform that was applied to the large scale production of small genes encoding venom peptides. This improved gene synthesis method uses a PCR-based protocol to assemble synthetic DNA from pools of overlapping oligonucleotides and was developed to synthesise multiples genes simultaneously. This technology incorporates an accurate, automated and cost effective ligation independent cloning step to directly integrate the synthetic genes into an effective Escherichia coli expression vector. The robustness of this technology to generate large libraries of dozens to thousands of synthetic nucleic acids was demonstrated through the parallel and simultaneous synthesis of 96 genes encoding animal toxins. An automated platform was developed for the large-scale synthesis of small genes encoding eukaryotic toxins. Large scale recombinant expression of synthetic genes encoding eukaryotic toxins will allow exploring the extraordinary potency and pharmacological diversity of animal venoms, an increasingly valuable but unexplored source of lead molecules for drug discovery.

Crops In Silico: Generating Virtual Crops Using an Integrative and Multi-scale Modeling Platform.

PubMed

Marshall-Colon, Amy; Long, Stephen P; Allen, Douglas K; Allen, Gabrielle; Beard, Daniel A; Benes, Bedrich; von Caemmerer, Susanne; Christensen, A J; Cox, Donna J; Hart, John C; Hirst, Peter M; Kannan, Kavya; Katz, Daniel S; Lynch, Jonathan P; Millar, Andrew J; Panneerselvam, Balaji; Price, Nathan D; Prusinkiewicz, Przemyslaw; Raila, David; Shekar, Rachel G; Shrivastava, Stuti; Shukla, Diwakar; Srinivasan, Venkatraman; Stitt, Mark; Turk, Matthew J; Voit, Eberhard O; Wang, Yu; Yin, Xinyou; Zhu, Xin-Guang

2017-01-01

Multi-scale models can facilitate whole plant simulations by linking gene networks, protein synthesis, metabolic pathways, physiology, and growth. Whole plant models can be further integrated with ecosystem, weather, and climate models to predict how various interactions respond to environmental perturbations. These models have the potential to fill in missing mechanistic details and generate new hypotheses to prioritize directed engineering efforts. Outcomes will potentially accelerate improvement of crop yield, sustainability, and increase future food security. It is time for a paradigm shift in plant modeling, from largely isolated efforts to a connected community that takes advantage of advances in high performance computing and mechanistic understanding of plant processes. Tools for guiding future crop breeding and engineering, understanding the implications of discoveries at the molecular level for whole plant behavior, and improved prediction of plant and ecosystem responses to the environment are urgently needed. The purpose of this perspective is to introduce Crops in silico (cropsinsilico.org), an integrative and multi-scale modeling platform, as one solution that combines isolated modeling efforts toward the generation of virtual crops, which is open and accessible to the entire plant biology community. The major challenges involved both in the development and deployment of a shared, multi-scale modeling platform, which are summarized in this prospectus, were recently identified during the first Crops in silico Symposium and Workshop.

Crops In Silico: Generating Virtual Crops Using an Integrative and Multi-scale Modeling Platform

PubMed Central

Marshall-Colon, Amy; Long, Stephen P.; Allen, Douglas K.; Allen, Gabrielle; Beard, Daniel A.; Benes, Bedrich; von Caemmerer, Susanne; Christensen, A. J.; Cox, Donna J.; Hart, John C.; Hirst, Peter M.; Kannan, Kavya; Katz, Daniel S.; Lynch, Jonathan P.; Millar, Andrew J.; Panneerselvam, Balaji; Price, Nathan D.; Prusinkiewicz, Przemyslaw; Raila, David; Shekar, Rachel G.; Shrivastava, Stuti; Shukla, Diwakar; Srinivasan, Venkatraman; Stitt, Mark; Turk, Matthew J.; Voit, Eberhard O.; Wang, Yu; Yin, Xinyou; Zhu, Xin-Guang

2017-01-01

Multi-scale models can facilitate whole plant simulations by linking gene networks, protein synthesis, metabolic pathways, physiology, and growth. Whole plant models can be further integrated with ecosystem, weather, and climate models to predict how various interactions respond to environmental perturbations. These models have the potential to fill in missing mechanistic details and generate new hypotheses to prioritize directed engineering efforts. Outcomes will potentially accelerate improvement of crop yield, sustainability, and increase future food security. It is time for a paradigm shift in plant modeling, from largely isolated efforts to a connected community that takes advantage of advances in high performance computing and mechanistic understanding of plant processes. Tools for guiding future crop breeding and engineering, understanding the implications of discoveries at the molecular level for whole plant behavior, and improved prediction of plant and ecosystem responses to the environment are urgently needed. The purpose of this perspective is to introduce Crops in silico (cropsinsilico.org), an integrative and multi-scale modeling platform, as one solution that combines isolated modeling efforts toward the generation of virtual crops, which is open and accessible to the entire plant biology community. The major challenges involved both in the development and deployment of a shared, multi-scale modeling platform, which are summarized in this prospectus, were recently identified during the first Crops in silico Symposium and Workshop. PMID:28555150

Dereplication of peptidic natural products through database search of mass spectra

PubMed Central

Mohimani, Hosein; Gurevich, Alexey; Mikheenko, Alla; Garg, Neha; Nothias, Louis-Felix; Ninomiya, Akihiro; Takada, Kentaro; Dorrestein, Pieter C.; Pevzner, Pavel A.

2016-01-01

Peptidic Natural Products (PNPs) are widely used compounds that include many antibiotics and a variety of other bioactive peptides. While recent breakthroughs in PNP discovery raised the challenge of developing new algorithms for their analysis, identification of PNPs via database search of tandem mass spectra remains an open problem. To address this problem, natural product researchers utilize dereplication strategies that identify known PNPs and lead to the discovery of new ones even in cases when the reference spectra are not present in existing spectral libraries. DEREPLICATOR is a new dereplication algorithm that enabled high-throughput PNP identification and that is compatible with large-scale mass spectrometry-based screening platforms for natural product discovery. After searching nearly one hundred million tandem mass spectra in the Global Natural Products Social (GNPS) molecular networking infrastructure, DEREPLICATOR identified an order of magnitude more PNPs (and their new variants) than any previous dereplication efforts. PMID:27820803

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

Integration of Microfractionation, qNMR and Zebrafish Screening for the In Vivo Bioassay-Guided Isolation and Quantitative Bioactivity Analysis of Natural Products

PubMed Central

Maes, Jan; Siverio-Mota, Dany; Marcourt, Laurence; Munck, Sebastian; Kamuhabwa, Appolinary R.; Moshi, Mainen J.; Esguerra, Camila V.; de Witte, Peter A. M.; Crawford, Alexander D.; Wolfender, Jean-Luc

2013-01-01

Natural products (NPs) are an attractive source of chemical diversity for small-molecule drug discovery. Several challenges nevertheless persist with respect to NP discovery, including the time and effort required for bioassay-guided isolation of bioactive NPs, and the limited biomedical relevance to date of in vitro bioassays used in this context. With regard to bioassays, zebrafish have recently emerged as an effective model system for chemical biology, allowing in vivo high-content screens that are compatible with microgram amounts of compound. For the deconvolution of the complex extracts into their individual constituents, recent progress has been achieved on several fronts as analytical techniques now enable the rapid microfractionation of extracts, and microflow NMR methods have developed to the point of allowing the identification of microgram amounts of NPs. Here we combine advanced analytical methods with high-content screening in zebrafish to create an integrated platform for microgram-scale, in vivo NP discovery. We use this platform for the bioassay-guided fractionation of an East African medicinal plant, Rhynchosia viscosa, resulting in the identification of both known and novel isoflavone derivatives with anti-angiogenic and anti-inflammatory activity. Quantitative microflow NMR is used both to determine the structure of bioactive compounds and to quantify them for direct dose-response experiments at the microgram scale. The key advantages of this approach are (1) the microgram scale at which both biological and analytical experiments can be performed, (2) the speed and the rationality of the bioassay-guided fractionation – generic for NP extracts of diverse origin – that requires only limited sample-specific optimization and (3) the use of microflow NMR for quantification, enabling the identification and dose-response experiments with only tens of micrograms of each compound. This study demonstrates that a complete in vivo bioassay-guided fractionation can be performed with only 20 mg of NP extract within a few days. PMID:23700445

MetaCoMET: a web platform for discovery and visualization of the core microbiome

USDA-ARS?s Scientific Manuscript database

A key component of the analysis of microbiome datasets is the identification of OTUs shared between multiple experimental conditions, commonly referred to as the core microbiome. Results: We present a web platform named MetaCoMET that enables the discovery and visualization of the core microbiome an...

HEx: A heterologous expression platform for the discovery of fungal natural products

PubMed Central

Schlecht, Ulrich; Horecka, Joe; Lin, Hsiao-Ching; Naughton, Brian; Miranda, Molly; Li, Yong Fuga; Hennessy, James R.; Vandova, Gergana A.; Steinmetz, Lars M.; Sattely, Elizabeth; Khosla, Chaitan; Hillenmeyer, Maureen E.

2018-01-01

For decades, fungi have been a source of U.S. Food and Drug Administration–approved natural products such as penicillin, cyclosporine, and the statins. Recent breakthroughs in DNA sequencing suggest that millions of fungal species exist on Earth, with each genome encoding pathways capable of generating as many as dozens of natural products. However, the majority of encoded molecules are difficult or impossible to access because the organisms are uncultivable or the genes are transcriptionally silent. To overcome this bottleneck in natural product discovery, we developed the HEx (Heterologous EXpression) synthetic biology platform for rapid, scalable expression of fungal biosynthetic genes and their encoded metabolites in Saccharomyces cerevisiae. We applied this platform to 41 fungal biosynthetic gene clusters from diverse fungal species from around the world, 22 of which produced detectable compounds. These included novel compounds with unexpected biosynthetic origins, particularly from poorly studied species. This result establishes the HEx platform for rapid discovery of natural products from any fungal species, even those that are uncultivable, and opens the door to discovery of the next generation of natural products. PMID:29651464

BioGraph: unsupervised biomedical knowledge discovery via automated hypothesis generation

PubMed Central

2011-01-01

We present BioGraph, a data integration and data mining platform for the exploration and discovery of biomedical information. The platform offers prioritizations of putative disease genes, supported by functional hypotheses. We show that BioGraph can retrospectively confirm recently discovered disease genes and identify potential susceptibility genes, outperforming existing technologies, without requiring prior domain knowledge. Additionally, BioGraph allows for generic biomedical applications beyond gene discovery. BioGraph is accessible at http://www.biograph.be. PMID:21696594

Organs-on-a-chip for drug discovery.

PubMed

Selimović, Seila; Dokmeci, Mehmet R; Khademhosseini, Ali

2013-10-01

The current drug discovery process is arduous and costly, and a majority of the drug candidates entering clinical trials fail to make it to the marketplace. The standard static well culture approaches, although useful, do not fully capture the intricate in vivo environment. By merging the advances in microfluidics with microfabrication technologies, novel platforms are being introduced that lead to the creation of organ functions on a single chip. Within these platforms, microengineering enables precise control over the cellular microenvironment, whereas microfluidics provides an ability to perfuse the constructs on a chip and to connect individual sections with each other. This approach results in microsystems that may better represent the in vivo environment. These organ-on-a-chip platforms can be utilized for developing disease models as well as for conducting drug testing studies. In this article, we highlight several key developments in these microscale platforms for drug discovery applications. Copyright © 2013 Elsevier Ltd. All rights reserved.

Large-scale high-throughput computer-aided discovery of advanced materials using cloud computing

NASA Astrophysics Data System (ADS)

Bazhirov, Timur; Mohammadi, Mohammad; Ding, Kevin; Barabash, Sergey

Recent advances in cloud computing made it possible to access large-scale computational resources completely on-demand in a rapid and efficient manner. When combined with high fidelity simulations, they serve as an alternative pathway to enable computational discovery and design of new materials through large-scale high-throughput screening. Here, we present a case study for a cloud platform implemented at Exabyte Inc. We perform calculations to screen lightweight ternary alloys for thermodynamic stability. Due to the lack of experimental data for most such systems, we rely on theoretical approaches based on first-principle pseudopotential density functional theory. We calculate the formation energies for a set of ternary compounds approximated by special quasirandom structures. During an example run we were able to scale to 10,656 CPUs within 7 minutes from the start, and obtain results for 296 compounds within 38 hours. The results indicate that the ultimate formation enthalpy of ternary systems can be negative for some of lightweight alloys, including Li and Mg compounds. We conclude that compared to traditional capital-intensive approach that requires in on-premises hardware resources, cloud computing is agile and cost-effective, yet scalable and delivers similar performance.

Plenario: An Open Data Discovery and Exploration Platform for Urban Science

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

Catlett, Charlie; Malik, Tanu; Goldstein, Brett J.

2014-12-01

The past decade has seen the widespread release of open data concerning city services, conditions, and activities by government bodies and public institutions of all sizes. Hundreds of open data portals now host thousands of datasets of many different types. These new data sources represent enormous po- tential for improved understanding of urban dynamics and processes—and, ultimately, for more livable, efficient, and prosperous communities. However, those who seek to realize this potential quickly discover that discovering and applying those data relevant to any particular question can be extraordinarily dif- ficult, due to decentralized storage, heterogeneous formats, and poor documentation. Inmore » this context, we introduce Plenario, a platform designed to automating time-consuming tasks associated with the discovery, exploration, and application of open city data—and, in so doing, reduce barriers to data use for researchers, policymakers, service providers, journalists, and members of the general public. Key innovations include a geospatial data warehouse that allows data from many sources to be registered into a common spatial and temporal frame; simple and intuitive interfaces that permit rapid discovery and exploration of data subsets pertaining to a particular area and time, regardless of type and source; easy export of such data subsets for further analysis; a user-configurable data ingest framework for automated importing and periodic updating of new datasets into the data warehouse; cloud hosting for elastic scaling and rapid creation of new Plenario instances; and an open source implementation to enable community contributions. We describe here the architecture and implementation of the Plenario platform, discuss lessons learned from its use by several communities, and outline plans for future work.« less

Plenario: A Spatio-Temporal Platform for Discovery and Exploration of Urban Science Data

NASA Astrophysics Data System (ADS)

Engler, W. H.; Malik, T.; Catlett, C.; Foster, I.; Goldstein, B.

2015-12-01

The past decade has seen the widespread release of open data concerning city services, conditions, and activities by government bodies and public institutions of all sizes. Hundreds of open data portals now host thousands of datasets of many different types. These new data sources represent enormous potential for improved understanding of urban dynamics and processes—and, ultimately, for more livable, efficient, and prosperous communities. However, those who seek to realize this potential quickly discover that discovering and applying those data relevant to any particular question can be extraordinarily difficult, due to decentralized storage, heterogeneous formats, and poor documentation. In this context, we introduce Plenario, a platform designed to automating time-consuming tasks associated with the discovery, exploration, and application of open city data—and, in so doing, reduce barriers to data use for researchers, policymakers, service providers, journalists, and members of the general public. Key innovations include a geospatial data warehouse that allows data from many sources to be registered into a common spatial and temporal frame; simple and intuitive interfaces that permit rapid discovery and exploration of data subsets pertaining to a particular area and time, regardless of type and source; easy export of such data subsets for further analysis; a user-configurable data ingest framework for automated importing and periodic updating of new datasets into the data warehouse; cloud hosting for elastic scaling and rapid creation of new Plenario instances; and an open source implementation to enable community contributions. We describe here the architecture and implementation of the Plenario platform, discuss lessons learned from its use by several communities, and outline plans for future work.

The Aerial Regional-Scale Environmental Surveyor (ARES): New Mars Science to Reduce Human Risk and Prepare for the Human Exploration

NASA Technical Reports Server (NTRS)

Levine, Joel S.; Croom, Mark A.; Wright, Henry S.; Killough, B. D.; Edwards, W. C.

2012-01-01

Obtaining critical measurements for eventual human Mars missions while expanding upon recent Mars scientific discoveries and deriving new scientific knowledge from a unique near surface vantage point is the focus of the Aerial Regional-scale Environmental Surveyor (ARES) exploration mission. The key element of ARES is an instrumented,rocket-powered, well-tested robotic airplane platform, that will fly between one to two kilometers above the surface while traversing hundreds of kilometers to collect and transmit previously unobtainable high spatial measurements relevant to the NASA Mars Exploration Program and the exploration of Mars by humans.

The Cell Collective: Toward an open and collaborative approach to systems biology

PubMed Central

2012-01-01

Background Despite decades of new discoveries in biomedical research, the overwhelming complexity of cells has been a significant barrier to a fundamental understanding of how cells work as a whole. As such, the holistic study of biochemical pathways requires computer modeling. Due to the complexity of cells, it is not feasible for one person or group to model the cell in its entirety. Results The Cell Collective is a platform that allows the world-wide scientific community to create these models collectively. Its interface enables users to build and use models without specifying any mathematical equations or computer code - addressing one of the major hurdles with computational research. In addition, this platform allows scientists to simulate and analyze the models in real-time on the web, including the ability to simulate loss/gain of function and test what-if scenarios in real time. Conclusions The Cell Collective is a web-based platform that enables laboratory scientists from across the globe to collaboratively build large-scale models of various biological processes, and simulate/analyze them in real time. In this manuscript, we show examples of its application to a large-scale model of signal transduction. PMID:22871178

Quantitative Systems Pharmacology: A Case for Disease Models.

PubMed

Musante, C J; Ramanujan, S; Schmidt, B J; Ghobrial, O G; Lu, J; Heatherington, A C

2017-01-01

Quantitative systems pharmacology (QSP) has emerged as an innovative approach in model-informed drug discovery and development, supporting program decisions from exploratory research through late-stage clinical trials. In this commentary, we discuss the unique value of disease-scale "platform" QSP models that are amenable to reuse and repurposing to support diverse clinical decisions in ways distinct from other pharmacometrics strategies. © 2016 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of The American Society for Clinical Pharmacology and Therapeutics.

Open discovery: An integrated live Linux platform of Bioinformatics tools.

PubMed

Vetrivel, Umashankar; Pilla, Kalabharath

2008-01-01

Historically, live linux distributions for Bioinformatics have paved way for portability of Bioinformatics workbench in a platform independent manner. Moreover, most of the existing live Linux distributions limit their usage to sequence analysis and basic molecular visualization programs and are devoid of data persistence. Hence, open discovery - a live linux distribution has been developed with the capability to perform complex tasks like molecular modeling, docking and molecular dynamics in a swift manner. Furthermore, it is also equipped with complete sequence analysis environment and is capable of running windows executable programs in Linux environment. Open discovery portrays the advanced customizable configuration of fedora, with data persistency accessible via USB drive or DVD. The Open Discovery is distributed free under Academic Free License (AFL) and can be downloaded from http://www.OpenDiscovery.org.in.

The Emory Chemical Biology Discovery Center: leveraging academic innovation to advance novel targets through HTS and beyond.

PubMed

Johns, Margaret A; Meyerkord-Belton, Cheryl L; Du, Yuhong; Fu, Haian

2014-03-01

The Emory Chemical Biology Discovery Center (ECBDC) aims to accelerate high throughput biology and translation of biomedical research discoveries into therapeutic targets and future medicines by providing high throughput research platforms to scientific collaborators worldwide. ECBDC research is focused at the interface of chemistry and biology, seeking to fundamentally advance understanding of disease-related biology with its HTS/HCS platforms and chemical tools, ultimately supporting drug discovery. Established HTS/HCS capabilities, university setting, and expertise in diverse assay formats, including protein-protein interaction interrogation, have enabled the ECBDC to contribute to national chemical biology efforts, empower translational research, and serve as a training ground for young scientists. With these resources, the ECBDC is poised to leverage academic innovation to advance biology and therapeutic discovery.

Discovery of DNA repair inhibitors by combinatorial library profiling

PubMed Central

Moeller, Benjamin J.; Sidman, Richard L.; Pasqualini, Renata; Arap, Wadih

2011-01-01

Small molecule inhibitors of DNA repair are emerging as potent and selective anti-cancer therapies, but the sheer magnitude of the protein networks involved in DNA repair processes poses obstacles to discovery of effective candidate drugs. To address this challenge, we used a subtractive combinatorial selection approach to identify a panel of peptide ligands that bind DNA repair complexes. Supporting the concept that these ligands have therapeutic potential, we show that one selected peptide specifically binds and non-competitively inactivates DNA-PKcs, a protein kinase critical in double-strand DNA break repair. In doing so, this ligand sensitizes BRCA-deficient tumor cells to genotoxic therapy. Our findings establish a platform for large-scale parallel screening for ligand-directed DNA repair inhibitors, with immediate applicability to cancer therapy. PMID:21343400

The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology

PubMed Central

Gardner, Eugene J.; Lam, Vincent K.; Harris, Daniel N.; Chuang, Nelson T.; Scott, Emma C.; Pittard, W. Stephen; Mills, Ryan E.; Devine, Scott E.

2017-01-01

Mobile element insertions (MEIs) represent ∼25% of all structural variants in human genomes. Moreover, when they disrupt genes, MEIs can influence human traits and diseases. Therefore, MEIs should be fully discovered along with other forms of genetic variation in whole genome sequencing (WGS) projects involving population genetics, human diseases, and clinical genomics. Here, we describe the Mobile Element Locator Tool (MELT), which was developed as part of the 1000 Genomes Project to perform MEI discovery on a population scale. Using both Illumina WGS data and simulations, we demonstrate that MELT outperforms existing MEI discovery tools in terms of speed, scalability, specificity, and sensitivity, while also detecting a broader spectrum of MEI-associated features. Several run modes were developed to perform MEI discovery on local and cloud systems. In addition to using MELT to discover MEIs in modern humans as part of the 1000 Genomes Project, we also used it to discover MEIs in chimpanzees and ancient (Neanderthal and Denisovan) hominids. We detected diverse patterns of MEI stratification across these populations that likely were caused by (1) diverse rates of MEI production from source elements, (2) diverse patterns of MEI inheritance, and (3) the introgression of ancient MEIs into modern human genomes. Overall, our study provides the most comprehensive map of MEIs to date spanning chimpanzees, ancient hominids, and modern humans and reveals new aspects of MEI biology in these lineages. We also demonstrate that MELT is a robust platform for MEI discovery and analysis in a variety of experimental settings. PMID:28855259

[Structural Study in the Platform for Drug Discovery, Informatics, and Structural Life Science].

PubMed

Senda, Toshiya

2016-01-01

The Platform for Drug Discovery, Informatics, and Structural Life Science (PDIS), which has been launched since FY2012, is a national project in the field of structural biology. The PDIS consists of three cores - structural analysis, control, and informatics - and aims to support life science researchers who are not familiar with structural biology. The PDIS project is able to provide full-scale support for structural biology research. The support provided by the PDIS project includes protein purification with various expression systems, large scale protein crystallization, crystal structure determination, small angle scattering (SAXS), NMR, electron microscopy, bioinformatics, etc. In order to utilize these methods of support, PDIS users need to submit an application form to the one-stop service office. Submitted applications will be reviewed by three referees. It is strongly encouraged that PDIS users have sufficient discussion with researchers in the PDIS project before submitting the application. This discussion is very useful in the process of project design, particularly for beginners in structural biology. In addition to this user support, the PDIS project has conducted R&D, which includes the development of synchrotron beamlines. In the PDIS project, PF and SPring-8 have developed beamlines for micro-crystallography, high-throughput data collection, supramolecular assembly, and native single anomalous dispersion (SAD) phasing. The newly developed beamlines have been open to all users, and have accelerated structural biology research. Beamlines for SAXS have also been developed, which has dramatically increased bio-SAXS users.

Engineering a microbial platform for de novo biosynthesis of diverse methylxanthines

PubMed Central

McKeague, Maureen; Wang, Yen-Hsiang; Cravens, Aaron; Win, Maung Nyan; Smolke, Christina D.

2016-01-01

Engineered microbial biosynthesis of plant natural products can support manufacturing of complex bioactive molecules and enable discovery of non-naturally occurring derivatives. Purine alkaloids, including caffeine (coffee), theophylline (antiasthma drug), theobromine (chocolate), and other methylxanthines, play a significant role in pharmacology and food chemistry. Here, we engineered the eukaryotic microbial host Saccharomyces cerevisiae for the de novo biosynthesis of methylxanthines. We constructed a xanthine-to-xanthosine conversion pathway in native yeast central metabolism to increase endogenous purine flux for the production of 7-methylxanthine, a key intermediate in caffeine biosynthesis. Yeast strains were further engineered to produce caffeine through expression of several enzymes from the coffee plant. By expressing combinations of different N-methyltransferases, we were able to demonstrate re-direction of flux to an alternate pathway and develop strains that support the production of diverse methylxanthines. We achieved production of 270 μg/L, 61 μg/L, and 3700 μg/L of caffeine, theophylline, and 3-methylxanthine, respectively, in 0.3-L bench-scale batch fermentations. The constructed strains provide an early platform for de novo production of methylxanthines and with further development will advance the discovery and synthesis of xanthine derivatives. PMID:27519552

Open discovery: An integrated live Linux platform of Bioinformatics tools

PubMed Central

Vetrivel, Umashankar; Pilla, Kalabharath

2008-01-01

Historically, live linux distributions for Bioinformatics have paved way for portability of Bioinformatics workbench in a platform independent manner. Moreover, most of the existing live Linux distributions limit their usage to sequence analysis and basic molecular visualization programs and are devoid of data persistence. Hence, open discovery ‐ a live linux distribution has been developed with the capability to perform complex tasks like molecular modeling, docking and molecular dynamics in a swift manner. Furthermore, it is also equipped with complete sequence analysis environment and is capable of running windows executable programs in Linux environment. Open discovery portrays the advanced customizable configuration of fedora, with data persistency accessible via USB drive or DVD. Availability The Open Discovery is distributed free under Academic Free License (AFL) and can be downloaded from http://www.OpenDiscovery.org.in PMID:19238235

Development and validation of panoptic Meso scale discovery assay to quantify total systemic interleukin-6

PubMed Central

Chaturvedi, Shalini; Siegel, Derick; Wagner, Carrie L; Park, Jaehong; van de Velde, Helgi; Vermeulen, Jessica; Fung, Man-Cheong; Reddy, Manjula; Hall, Brett; Sasser, Kate

2015-01-01

Aim Interleukin-6 (IL-6), a multifunctional cytokine, exists in several forms ranging from a low molecular weight (MW 20–30 kDa) non-complexed form to high MW (200–450 kDa), complexes. Accurate baseline IL-6 assessment is pivotal to understand clinical responses to IL-6-targeted treatments. Existing assays measure only the low MW, non-complexed IL-6 form. The present work aimed to develop a validated assay to measure accurately total IL-6 (complexed and non-complexed) in serum or plasma as matrix in a high throughput and easily standardized format for clinical testing. Methods Commercial capture and detection antibodies were screened against humanized IL-6 and evaluated in an enzyme-linked immunosorbent assay format. The best antibody combinations were screened to identify an antibody pair that gave minimum background and maximum recovery of IL-6 in the presence of 100% serum matrix. A plate-based total IL-6 assay was developed and transferred to the Meso Scale Discovery (MSD) platform for large scale clinical testing. Results The top-performing antibody pair from 36 capture and four detection candidates was validated on the MSD platform. The lower limit of quantification in human serum samples (n = 6) was 9.77 pg l–1, recovery ranged from 93.13–113.27%, the overall pooled coefficients of variation were 20.12% (inter-assay) and 8.67% (intra-assay). High MW forms of IL-6, in size fractionated serum samples from myelodysplastic syndrome and rheumatoid arthritis patients, were detected by the assay but not by a commercial kit. Conclusion This novel panoptic (sees all forms) IL-6 MSD assay that measures both high and low MW forms may have clinical utility. PMID:25847183

Orbiter processing facility service platform failure and redesign

NASA Technical Reports Server (NTRS)

Harris, Jesse L.

1988-01-01

In a high bay of the Orbiter Processing Facility (OPF) at the Kennedy Space Center, technicians were preparing the space shuttle orbiter Discovery for rollout to the Vehicle Assembly Building (VAB). A service platform, commonly referred to as an OPF Bucket, was being retracted when it suddenly fell, striking a technician and impacting Discovery's payload bay door. A critical component in the OPF Bucket hoist system had failed, allowing the platform to fall. The incident was thoroughly investigated by both NASA and Lockheed, revealing many design deficiencies within the system. The deficiencies and the design changes made to correct them are reviewed.

High content live cell imaging for the discovery of new antimalarial marine natural products

PubMed Central

2012-01-01

Background The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum. Methods A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope. Results Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts. Conclusion Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials. PMID:22214291

High content live cell imaging for the discovery of new antimalarial marine natural products.

PubMed

Cervantes, Serena; Stout, Paige E; Prudhomme, Jacques; Engel, Sebastian; Bruton, Matthew; Cervantes, Michael; Carter, David; Tae-Chang, Young; Hay, Mark E; Aalbersberg, William; Kubanek, Julia; Le Roch, Karine G

2012-01-03

The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum. A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope. Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts. Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials. © 2011 Cervantes et al; licensee BioMed Central Ltd.

A Collaborative Web-Based Architecture For Sharing ToxCast Data

EPA Science Inventory

Collaborative Drug Discovery (CDD) has created a scalable platform that combines traditional drug discovery informatics with Web2.0 features. Traditional drug discovery capabilities include substructure, similarity searching and export to excel or sdf formats. Web2.0 features inc...

Optimization of oligonucleotide arrays and RNA amplification protocols for analysis of transcript structure and alternative splicing.

PubMed

Castle, John; Garrett-Engele, Phil; Armour, Christopher D; Duenwald, Sven J; Loerch, Patrick M; Meyer, Michael R; Schadt, Eric E; Stoughton, Roland; Parrish, Mark L; Shoemaker, Daniel D; Johnson, Jason M

2003-01-01

Microarrays offer a high-resolution means for monitoring pre-mRNA splicing on a genomic scale. We have developed a novel, unbiased amplification protocol that permits labeling of entire transcripts. Also, hybridization conditions, probe characteristics, and analysis algorithms were optimized for detection of exons, exon-intron edges, and exon junctions. These optimized protocols can be used to detect small variations and isoform mixtures, map the tissue specificity of known human alternative isoforms, and provide a robust, scalable platform for high-throughput discovery of alternative splicing.

Optimization of oligonucleotide arrays and RNA amplification protocols for analysis of transcript structure and alternative splicing

PubMed Central

Castle, John; Garrett-Engele, Phil; Armour, Christopher D; Duenwald, Sven J; Loerch, Patrick M; Meyer, Michael R; Schadt, Eric E; Stoughton, Roland; Parrish, Mark L; Shoemaker, Daniel D; Johnson, Jason M

2003-01-01

Microarrays offer a high-resolution means for monitoring pre-mRNA splicing on a genomic scale. We have developed a novel, unbiased amplification protocol that permits labeling of entire transcripts. Also, hybridization conditions, probe characteristics, and analysis algorithms were optimized for detection of exons, exon-intron edges, and exon junctions. These optimized protocols can be used to detect small variations and isoform mixtures, map the tissue specificity of known human alternative isoforms, and provide a robust, scalable platform for high-throughput discovery of alternative splicing. PMID:14519201

Implementing WebGL and HTML5 in Macromolecular Visualization and Modern Computer-Aided Drug Design.

PubMed

Yuan, Shuguang; Chan, H C Stephen; Hu, Zhenquan

2017-06-01

Web browsers have long been recognized as potential platforms for remote macromolecule visualization. However, the difficulty in transferring large-scale data to clients and the lack of native support for hardware-accelerated applications in the local browser undermine the feasibility of such utilities. With the introduction of WebGL and HTML5 technologies in recent years, it is now possible to exploit the power of a graphics-processing unit (GPU) from a browser without any third-party plugin. Many new tools have been developed for biological molecule visualization and modern drug discovery. In contrast to traditional offline tools, real-time computing, interactive data analysis, and cross-platform analyses feature WebGL- and HTML5-based tools, facilitating biological research in a more efficient and user-friendly way. Copyright © 2017 Elsevier Ltd. All rights reserved.

Scientific workflows as productivity tools for drug discovery.

PubMed

Shon, John; Ohkawa, Hitomi; Hammer, Juergen

2008-05-01

Large pharmaceutical companies annually invest tens to hundreds of millions of US dollars in research informatics to support their early drug discovery processes. Traditionally, most of these investments are designed to increase the efficiency of drug discovery. The introduction of do-it-yourself scientific workflow platforms has enabled research informatics organizations to shift their efforts toward scientific innovation, ultimately resulting in a possible increase in return on their investments. Unlike the handling of most scientific data and application integration approaches, researchers apply scientific workflows to in silico experimentation and exploration, leading to scientific discoveries that lie beyond automation and integration. This review highlights some key requirements for scientific workflow environments in the pharmaceutical industry that are necessary for increasing research productivity. Examples of the application of scientific workflows in research and a summary of recent platform advances are also provided.

Role of Open Source Tools and Resources in Virtual Screening for Drug Discovery.

PubMed

Karthikeyan, Muthukumarasamy; Vyas, Renu

2015-01-01

Advancement in chemoinformatics research in parallel with availability of high performance computing platform has made handling of large scale multi-dimensional scientific data for high throughput drug discovery easier. In this study we have explored publicly available molecular databases with the help of open-source based integrated in-house molecular informatics tools for virtual screening. The virtual screening literature for past decade has been extensively investigated and thoroughly analyzed to reveal interesting patterns with respect to the drug, target, scaffold and disease space. The review also focuses on the integrated chemoinformatics tools that are capable of harvesting chemical data from textual literature information and transform them into truly computable chemical structures, identification of unique fragments and scaffolds from a class of compounds, automatic generation of focused virtual libraries, computation of molecular descriptors for structure-activity relationship studies, application of conventional filters used in lead discovery along with in-house developed exhaustive PTC (Pharmacophore, Toxicophores and Chemophores) filters and machine learning tools for the design of potential disease specific inhibitors. A case study on kinase inhibitors is provided as an example.

Constructing a Foundational Platform Driven by Japan's K Supercomputer for Next-Generation Drug Design.

PubMed

Brown, J B; Nakatsui, Masahiko; Okuno, Yasushi

2014-12-01

The cost of pharmaceutical R&D has risen enormously, both worldwide and in Japan. However, Japan faces a particularly difficult situation in that its population is aging rapidly, and the cost of pharmaceutical R&D affects not only the industry but the entire medical system as well. To attempt to reduce costs, the newly launched K supercomputer is available for big data drug discovery and structural simulation-based drug discovery. We have implemented both primary (direct) and secondary (infrastructure, data processing) methods for the two types of drug discovery, custom tailored to maximally use the 88 128 compute nodes/CPUs of K, and evaluated the implementations. We present two types of results. In the first, we executed the virtual screening of nearly 19 billion compound-protein interactions, and calculated the accuracy of predictions against publicly available experimental data. In the second investigation, we implemented a very computationally intensive binding free energy algorithm, and found that comparison of our binding free energies was considerably accurate when validated against another type of publicly available experimental data. The common feature of both result types is the scale at which computations were executed. The frameworks presented in this article provide prospectives and applications that, while tuned to the computing resources available in Japan, are equally applicable to any equivalent large-scale infrastructure provided elsewhere. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cardiovascular Organ-on-a-Chip Platforms for Drug Discovery and Development

PubMed Central

Ribas, João; Sadeghi, Hossein; Manbachi, Amir; Leijten, Jeroen; Brinegar, Katelyn; Zhang, Yu Shrike; Ferreira, Lino

2016-01-01

Abstract Cardiovascular diseases are prevalent worldwide and are the most frequent causes of death in the United States. Although spending in drug discovery/development has increased, the amount of drug approvals has seen a progressive decline. Particularly, adverse side effects to the heart and general vasculature have become common causes for preclinical project closures, and preclinical models do not fully recapitulate human in vivo dynamics. Recently, organs-on-a-chip technologies have been proposed to mimic the dynamic conditions of the cardiovascular system—in particular, heart and general vasculature. These systems pay particular attention to mimicking structural organization, shear stress, transmural pressure, mechanical stretching, and electrical stimulation. Heart- and vasculature-on-a-chip platforms have been successfully generated to study a variety of physiological phenomena, model diseases, and probe the effects of drugs. Here, we review and discuss recent breakthroughs in the development of cardiovascular organs-on-a-chip platforms, and their current and future applications in the area of drug discovery and development. PMID:28971113

A Common Platform for Antibiotic Dereplication and Adjuvant Discovery.

PubMed

Cox, Georgina; Sieron, Arthur; King, Andrew M; De Pascale, Gianfranco; Pawlowski, Andrew C; Koteva, Kalinka; Wright, Gerard D

2017-01-19

Solving the antibiotic resistance crisis requires the discovery of new antimicrobial drugs and the preservation of existing ones. The discovery of inhibitors of antibiotic resistance, antibiotic adjuvants, is a proven example of the latter. A major difficulty in identifying new antibiotics is the frequent rediscovery of known compounds, necessitating laborious "dereplication" to identify novel chemical entities. We have developed an antibiotic resistance platform (ARP) that can be used for both the identification of antibiotic adjuvants and for antibiotic dereplication. The ARP is a cell-based array of mechanistically distinct individual resistance elements in an identical genetic background. In dereplication mode, we demonstrate the rapid identification, and thus discrimination, of common antibiotics. In adjuvant discovery mode, we show that the ARP can be harnessed in screens to identify inhibitors of resistance. The ARP is therefore a powerful tool that has broad application in confronting the resistance crisis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Parallel Multivariate Spatio-Temporal Clustering of Large Ecological Datasets on Hybrid Supercomputers

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

Sreepathi, Sarat; Kumar, Jitendra; Mills, Richard T.

A proliferation of data from vast networks of remote sensing platforms (satellites, unmanned aircraft systems (UAS), airborne etc.), observational facilities (meteorological, eddy covariance etc.), state-of-the-art sensors, and simulation models offer unprecedented opportunities for scientific discovery. Unsupervised classification is a widely applied data mining approach to derive insights from such data. However, classification of very large data sets is a complex computational problem that requires efficient numerical algorithms and implementations on high performance computing (HPC) platforms. Additionally, increasing power, space, cooling and efficiency requirements has led to the deployment of hybrid supercomputing platforms with complex architectures and memory hierarchies like themore » Titan system at Oak Ridge National Laboratory. The advent of such accelerated computing architectures offers new challenges and opportunities for big data analytics in general and specifically, large scale cluster analysis in our case. Although there is an existing body of work on parallel cluster analysis, those approaches do not fully meet the needs imposed by the nature and size of our large data sets. Moreover, they had scaling limitations and were mostly limited to traditional distributed memory computing platforms. We present a parallel Multivariate Spatio-Temporal Clustering (MSTC) technique based on k-means cluster analysis that can target hybrid supercomputers like Titan. We developed a hybrid MPI, CUDA and OpenACC implementation that can utilize both CPU and GPU resources on computational nodes. We describe performance results on Titan that demonstrate the scalability and efficacy of our approach in processing large ecological data sets.« less

Crystalline metamaterials for topological properties at subwavelength scales

PubMed Central

Yves, Simon; Fleury, Romain; Berthelot, Thomas; Fink, Mathias; Lemoult, Fabrice; Lerosey, Geoffroy

2017-01-01

The exciting discovery of topological condensed matter systems has lately triggered a search for their photonic analogues, motivated by the possibility of robust backscattering-immune light transport. However, topological photonic phases have so far only been observed in photonic crystals and waveguide arrays, which are inherently physically wavelength scaled, hindering their application in compact subwavelength systems. In this letter, we tackle this problem by patterning the deep subwavelength resonant elements of metamaterials onto specific lattices, and create crystalline metamaterials that can develop complex nonlocal properties due to multiple scattering, despite their very subwavelength spatial scale that usually implies to disregard their structure. These spatially dispersive systems can support subwavelength topological phases, as we demonstrate at microwaves by direct field mapping. Our approach gives a straightforward tabletop platform for the study of photonic topological phases, and allows to envision applications benefiting the compactness of metamaterials and the amazing potential of topological insulators. PMID:28719573

Crystalline metamaterials for topological properties at subwavelength scales

NASA Astrophysics Data System (ADS)

Yves, Simon; Fleury, Romain; Berthelot, Thomas; Fink, Mathias; Lemoult, Fabrice; Lerosey, Geoffroy

2017-07-01

The exciting discovery of topological condensed matter systems has lately triggered a search for their photonic analogues, motivated by the possibility of robust backscattering-immune light transport. However, topological photonic phases have so far only been observed in photonic crystals and waveguide arrays, which are inherently physically wavelength scaled, hindering their application in compact subwavelength systems. In this letter, we tackle this problem by patterning the deep subwavelength resonant elements of metamaterials onto specific lattices, and create crystalline metamaterials that can develop complex nonlocal properties due to multiple scattering, despite their very subwavelength spatial scale that usually implies to disregard their structure. These spatially dispersive systems can support subwavelength topological phases, as we demonstrate at microwaves by direct field mapping. Our approach gives a straightforward tabletop platform for the study of photonic topological phases, and allows to envision applications benefiting the compactness of metamaterials and the amazing potential of topological insulators.

Synthetic biology platform technologies for antimicrobial applications.

PubMed

Braff, Dana; Shis, David; Collins, James J

2016-10-01

The growing prevalence of antibiotic resistance calls for new approaches in the development of antimicrobial therapeutics. Likewise, improved diagnostic measures are essential in guiding the application of targeted therapies and preventing the evolution of therapeutic resistance. Discovery platforms are also needed to form new treatment strategies and identify novel antimicrobial agents. By applying engineering principles to molecular biology, synthetic biologists have developed platforms that improve upon, supplement, and will perhaps supplant traditional broad-spectrum antibiotics. Efforts in engineering bacteriophages and synthetic probiotics demonstrate targeted antimicrobial approaches that can be fine-tuned using synthetic biology-derived principles. Further, the development of paper-based, cell-free expression systems holds promise in promoting the clinical translation of molecular biology tools for diagnostic purposes. In this review, we highlight emerging synthetic biology platform technologies that are geared toward the generation of new antimicrobial therapies, diagnostics, and discovery channels. Copyright © 2016 Elsevier B.V. All rights reserved.

Discovery of FDA-Approved Drugs that Promote Retinal Cell Survival or Regeneration

DTIC Science & Technology

2015-10-01

1 AD______________ AWARD NUMBER: W81XWH-14-1-0407 TITLE:Discovery of FDA-Approved Drugs that Promote Retinal Cell Survival or Regeneration...SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0407Discovery of FDA-Approved Drugs that Promote Retinal Cell Survival or Regeneration 5c...vivo drug discovery platform named Automated Reporter Quantification in vivo (ARQiv). ARQiv quantifies reporter activity in transgenic zebrafish at

KSC-98pc1180

NASA Image and Video Library

1998-09-28

KENNEDY SPACE CENTER, FLA. -- At left, the payload canister for Space Shuttle Discovery is lifted from its canister movement vehicle to the top of the Rotating Service Structure on Launch Pad 39-B. Discovery (right), sitting atop the Mobile Launch Platform and next to the Fixed Service Structure, is scheduled for launch on Oct. 29, 1998, for the STS-95 mission. That mission includes the International Extreme Ultraviolet Hitchhiker (IEH-3), the Hubble Space Telescope Orbital Systems Test Platform, the Spartan solar-observing deployable spacecraft, and the SPACEHAB single module with experiments on space flight and the aging process

Detail view looking aft along the starboard side of the ...

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

Detail view looking aft along the starboard side of the Orbiter Discovery where the forward section meets the mid-fuselage. Note the head of the jack stand and its mechanism to connect to the one of the forward hoist attach points of the orbiter. Also note the support structure of the service platforms. This view was taken from the service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Measurements from an Aerial Vehicle: A New Tool for Planetary Exploration

NASA Technical Reports Server (NTRS)

Wright, Henry S.; Levine, Joel S.; Croom, Mark A.; Edwards, William C.; Qualls, Garry D.; Gasbarre, Joseph F.

2004-01-01

Aerial vehicles fill a unique planetary science measurement gap, that of regional-scale, near-surface observation, while providing a fresh perspective for potential discovery. Aerial vehicles used in planetary exploration bridge the scale and resolution measurement gaps between orbiters (global perspective with limited spatial resolution) and landers (local perspective with high spatial resolution) thus complementing and extending orbital and landed measurements. Planetary aerial vehicles can also survey scientifically interesting terrain that is inaccessible or hazardous to landed missions. The use of aerial assets for performing observations on Mars, Titan, or Venus will enable direct measurements and direct follow-ons to recent discoveries. Aerial vehicles can be used for remote sensing of the interior, surface and atmosphere of Mars, Venus and Titan. Types of aerial vehicles considered are airplane "heavier than air" and airships and balloons "lighter than air". Interdependencies between the science measurements, science goals and objectives, and platform implementation illustrate how the proper balance of science, engineering, and cost, can be achieved to allow for a successful mission. Classification of measurement types along with how those measurements resolve science questions and how these instruments are accommodated within the mission context are discussed.

Next-generation sequencing in clinical virology: Discovery of new viruses.

PubMed

Datta, Sibnarayan; Budhauliya, Raghvendra; Das, Bidisha; Chatterjee, Soumya; Vanlalhmuaka; Veer, Vijay

2015-08-12

Viruses are a cause of significant health problem worldwide, especially in the developing nations. Due to different anthropological activities, human populations are exposed to different viral pathogens, many of which emerge as outbreaks. In such situations, discovery of novel viruses is utmost important for deciding prevention and treatment strategies. Since last century, a number of different virus discovery methods, based on cell culture inoculation, sequence-independent PCR have been used for identification of a variety of viruses. However, the recent emergence and commercial availability of next-generation sequencers (NGS) has entirely changed the field of virus discovery. These massively parallel sequencing platforms can sequence a mixture of genetic materials from a very heterogeneous mix, with high sensitivity. Moreover, these platforms work in a sequence-independent manner, making them ideal tools for virus discovery. However, for their application in clinics, sample preparation or enrichment is necessary to detect low abundance virus populations. A number of techniques have also been developed for enrichment or viral nucleic acids. In this manuscript, we review the evolution of sequencing; NGS technologies available today as well as widely used virus enrichment technologies. We also discuss the challenges associated with their applications in the clinical virus discovery.

Advances in fragment-based drug discovery platforms.

PubMed

Orita, Masaya; Warizaya, Masaichi; Amano, Yasushi; Ohno, Kazuki; Niimi, Tatsuya

2009-11-01

Fragment-based drug discovery (FBDD) has been established as a powerful alternative and complement to traditional high-throughput screening techniques for identifying drug leads. At present, this technique is widely used among academic groups as well as small biotech and large pharmaceutical companies. In recent years, > 10 new compounds developed with FBDD have entered clinical development, and more and more attention in the drug discovery field is being focused on this technique. Under the FBDD approach, a fragment library of relatively small compounds (molecular mass = 100 - 300 Da) is screened by various methods and the identified fragment hits which normally weakly bind to the target are used as starting points to generate more potent drug leads. Because FBDD is still a relatively new drug discovery technology, further developments and optimizations in screening platforms and fragment exploitation can be expected. This review summarizes recent advances in FBDD platforms and discusses the factors important for the successful application of this technique. Under the FBDD approach, both identifying the starting fragment hit to be developed and generating the drug lead from that starting fragment hit are important. Integration of various techniques, such as computational technology, X-ray crystallography, NMR, surface plasmon resonance, isothermal titration calorimetry, mass spectrometry and high-concentration screening, must be applied in a situation-appropriate manner.

B-CAN: a resource sharing platform to improve the operation, visualization and integrated analysis of TCGA breast cancer data.

PubMed

Wen, Can-Hong; Ou, Shao-Min; Guo, Xiao-Bo; Liu, Chen-Feng; Shen, Yan-Bo; You, Na; Cai, Wei-Hong; Shen, Wen-Jun; Wang, Xue-Qin; Tan, Hai-Zhu

2017-12-12

Breast cancer is a high-risk heterogeneous disease with myriad subtypes and complicated biological features. The Cancer Genome Atlas (TCGA) breast cancer database provides researchers with the large-scale genome and clinical data via web portals and FTP services. Researchers are able to gain new insights into their related fields, and evaluate experimental discoveries with TCGA. However, it is difficult for researchers who have little experience with database and bioinformatics to access and operate on because of TCGA's complex data format and diverse files. For ease of use, we build the breast cancer (B-CAN) platform, which enables data customization, data visualization, and private data center. The B-CAN platform runs on Apache server and interacts with the backstage of MySQL database by PHP. Users can customize data based on their needs by combining tables from original TCGA database and selecting variables from each table. The private data center is applicable for private data and two types of customized data. A key feature of the B-CAN is that it provides single table display and multiple table display. Customized data with one barcode corresponding to many records and processed customized data are allowed in Multiple Tables Display. The B-CAN is an intuitive and high-efficient data-sharing platform.

Transgenic mouse strains as platforms for the successful discovery and development of human therapeutic monoclonal antibodies.

PubMed

Green, Larry L

2014-03-01

Transgenic mice have yielded seven of the ten currently-approved human antibody drugs, making them the most successful platform for the discovery of fully human antibody therapeutics. The use of the in vivo immune system helps drive this success by taking advantage of the natural selection process that produces antibodies with desirable characteristics. Appropriately genetically-engineered mice act as robust engines for the generation of diverse repertoires of affinity- matured fully human variable regions with intrinsic properties necessary for successful antibody drug development including high potency, specificity, manufacturability, solubility and low risk of immunogenicity. A broad range of mAb drug targets are addressable in these mice, comprising both secreted and transmembrane targets, including membrane multi-spanning targets, as well as human target antigens that share high sequence identity with their mouse orthologue. Transgenic mice can routinely yield antibodies with sub-nanomolar binding affinity for their antigen, with lead candidate mAbs frequently possessing affinities for binding to their target of less than 100 picomolar, without requiring any ex vivo affinity optimization. While the originator transgenic mice platforms are no longer broadly available, a new generation of transgenic platforms is in development for discovery of the next wave of human therapeutic antibodies.

Development of Transcriptomics-based Biomarkers for Selected Endocrine Disrupting Chemicals in Zebrafish (Danio rerio)

EPA Science Inventory

Genome-wide transcriptional profiling by microarrays provides a powerful platform for gene expression-based biomarker discovery. After their wide acceptance in human disease diagnosis, prognosis, and drug discovery, these gene signatures are increasingly being adopted for environ...

Development of transcriptomics-based biomarkers for selected endocrine disrupting chemicals in zebrafish (Danio rerio)

EPA Science Inventory

Genome-wide transcriptional profiling by microarrays provides a powerful platform for gene expression-based biomarker discovery. After their wide acceptance in human disease diagnosis, prognosis, and drug discovery, these gene signatures are increasingly being adopted for environ...

Discovering System Health Anomalies Using Data Mining Techniques

NASA Technical Reports Server (NTRS)

Sriastava, Ashok, N.

2005-01-01

We present a data mining framework for the analysis and discovery of anomalies in high-dimensional time series of sensor measurements that would be found in an Integrated System Health Monitoring system. We specifically treat the problem of discovering anomalous features in the time series that may be indicative of a system anomaly, or in the case of a manned system, an anomaly due to the human. Identification of these anomalies is crucial to building stable, reusable, and cost-efficient systems. The framework consists of an analysis platform and new algorithms that can scale to thousands of sensor streams to discovers temporal anomalies. We discuss the mathematical framework that underlies the system and also describe in detail how this framework is general enough to encompass both discrete and continuous sensor measurements. We also describe a new set of data mining algorithms based on kernel methods and hidden Markov models that allow for the rapid assimilation, analysis, and discovery of system anomalies. We then describe the performance of the system on a real-world problem in the aircraft domain where we analyze the cockpit data from aircraft as well as data from the aircraft propulsion, control, and guidance systems. These data are discrete and continuous sensor measurements and are dealt with seamlessly in order to discover anomalous flights. We conclude with recommendations that describe the tradeoffs in building an integrated scalable platform for robust anomaly detection in ISHM applications.

Tissue constructs: platforms for basic research and drug discovery.

PubMed

Elson, Elliot L; Genin, Guy M

2016-02-06

The functions, form and mechanical properties of cells are inextricably linked to their extracellular environment. Cells from solid tissues change fundamentally when, isolated from this environment, they are cultured on rigid two-dimensional substrata. These changes limit the significance of mechanical measurements on cells in two-dimensional culture and motivate the development of constructs with cells embedded in three-dimensional matrices that mimic the natural tissue. While measurements of cell mechanics are difficult in natural tissues, they have proven effective in engineered tissue constructs, especially constructs that emphasize specific cell types and their functions, e.g. engineered heart tissues. Tissue constructs developed as models of disease also have been useful as platforms for drug discovery. Underlying the use of tissue constructs as platforms for basic research and drug discovery is integration of multiscale biomaterials measurement and computational modelling to dissect the distinguishable mechanical responses separately of cells and extracellular matrix from measurements on tissue constructs and to quantify the effects of drug treatment on these responses. These methods and their application are the main subjects of this review.

Tissue constructs: platforms for basic research and drug discovery

PubMed Central

Elson, Elliot L.; Genin, Guy M.

2016-01-01

The functions, form and mechanical properties of cells are inextricably linked to their extracellular environment. Cells from solid tissues change fundamentally when, isolated from this environment, they are cultured on rigid two-dimensional substrata. These changes limit the significance of mechanical measurements on cells in two-dimensional culture and motivate the development of constructs with cells embedded in three-dimensional matrices that mimic the natural tissue. While measurements of cell mechanics are difficult in natural tissues, they have proven effective in engineered tissue constructs, especially constructs that emphasize specific cell types and their functions, e.g. engineered heart tissues. Tissue constructs developed as models of disease also have been useful as platforms for drug discovery. Underlying the use of tissue constructs as platforms for basic research and drug discovery is integration of multiscale biomaterials measurement and computational modelling to dissect the distinguishable mechanical responses separately of cells and extracellular matrix from measurements on tissue constructs and to quantify the effects of drug treatment on these responses. These methods and their application are the main subjects of this review. PMID:26855763

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

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

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

High-throughput platform assay technology for the discovery of pre-microrna-selective small molecule probes.

PubMed

Lorenz, Daniel A; Song, James M; Garner, Amanda L

2015-01-21

MicroRNAs (miRNA) play critical roles in human development and disease. As such, the targeting of miRNAs is considered attractive as a novel therapeutic strategy. A major bottleneck toward this goal, however, has been the identification of small molecule probes that are specific for select RNAs and methods that will facilitate such discovery efforts. Using pre-microRNAs as proof-of-concept, herein we report a conceptually new and innovative approach for assaying RNA-small molecule interactions. Through this platform assay technology, which we term catalytic enzyme-linked click chemistry assay or cat-ELCCA, we have designed a method that can be implemented in high throughput, is virtually free of false readouts, and is general for all nucleic acids. Through cat-ELCCA, we envision the discovery of selective small molecule ligands for disease-relevant miRNAs to promote the field of RNA-targeted drug discovery and further our understanding of the role of miRNAs in cellular biology.

STS-29 Discovery, Orbiter Vehicle (OV) 103, roll out to KSC LC Pad 39B

NASA Technical Reports Server (NTRS)

1989-01-01

In the early morning hours, STS-29 Discovery, Orbiter Vehicle (OV) 103, mated to the external tank (ET) and solid rocket boosters (SRBs) is rolled out to Kennedy Space Center (KSC) Launch Complex (LC) Pad 39B atop the mobile launcher platform. Trees, shrubs, and a light mist surround the mobile launcher platform as it makes its way to LC Pad 39B. OV-103 will fly on Mission STS-29 scheduled for launch in mid-March. View provided by KSC with alternate KSC number KSC-89PC-50.

STS-95 Space Shuttle Discovery rollout to Launch Pad 39B

NASA Technical Reports Server (NTRS)

1998-01-01

Perched on the Mobile Launch Platform, in the early morning hours Space Shuttle Discovery approaches Launch Complex Pad 39B after a 6-hour, 4.2-mile trip from the Vehicle Assembly Building. At the launch pad, the orbiter, external tank and solid rocket boosters will undergo final preparations for the launch, scheduled to lift off Oct. 29. The mission includes research payloads such as the Spartan solar-observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process.

Computational drug discovery

PubMed Central

Ou-Yang, Si-sheng; Lu, Jun-yan; Kong, Xiang-qian; Liang, Zhong-jie; Luo, Cheng; Jiang, Hualiang

2012-01-01

Computational drug discovery is an effective strategy for accelerating and economizing drug discovery and development process. Because of the dramatic increase in the availability of biological macromolecule and small molecule information, the applicability of computational drug discovery has been extended and broadly applied to nearly every stage in the drug discovery and development workflow, including target identification and validation, lead discovery and optimization and preclinical tests. Over the past decades, computational drug discovery methods such as molecular docking, pharmacophore modeling and mapping, de novo design, molecular similarity calculation and sequence-based virtual screening have been greatly improved. In this review, we present an overview of these important computational methods, platforms and successful applications in this field. PMID:22922346

GAP Final Technical Report 12-14-04

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

Andrew J. Bordner, PhD, Senior Research Scientist

2004-12-14

The Genomics Annotation Platform (GAP) was designed to develop new tools for high throughput functional annotation and characterization of protein sequences and structures resulting from genomics and structural proteomics, benchmarking and application of those tools. Furthermore, this platform integrated the genomic scale sequence and structural analysis and prediction tools with the advanced structure prediction and bioinformatics environment of ICM. The development of GAP was primarily oriented towards the annotation of new biomolecular structures using both structural and sequence data. Even though the amount of protein X-ray crystal data is growing exponentially, the volume of sequence data is growing even moremore » rapidly. This trend was exploited by leveraging the wealth of sequence data to provide functional annotation for protein structures. The additional information provided by GAP is expected to assist the majority of the commercial users of ICM, who are involved in drug discovery, in identifying promising drug targets as well in devising strategies for the rational design of therapeutics directed at the protein of interest. The GAP also provided valuable tools for biochemistry education, and structural genomics centers. In addition, GAP incorporates many novel prediction and analysis methods not available in other molecular modeling packages. This development led to signing the first Molsoft agreement in the structural genomics annotation area with the University of oxford Structural Genomics Center. This commercial agreement validated the Molsoft efforts under the GAP project and provided the basis for further development of the large scale functional annotation platform.« less

Consolidation of cloud computing in ATLAS

NASA Astrophysics Data System (ADS)

Taylor, Ryan P.; Domingues Cordeiro, Cristovao Jose; Giordano, Domenico; Hover, John; Kouba, Tomas; Love, Peter; McNab, Andrew; Schovancova, Jaroslava; Sobie, Randall; ATLAS Collaboration

2017-10-01

Throughout the first half of LHC Run 2, ATLAS cloud computing has undergone a period of consolidation, characterized by building upon previously established systems, with the aim of reducing operational effort, improving robustness, and reaching higher scale. This paper describes the current state of ATLAS cloud computing. Cloud activities are converging on a common contextualization approach for virtual machines, and cloud resources are sharing monitoring and service discovery components. We describe the integration of Vacuum resources, streamlined usage of the Simulation at Point 1 cloud for offline processing, extreme scaling on Amazon compute resources, and procurement of commercial cloud capacity in Europe. Finally, building on the previously established monitoring infrastructure, we have deployed a real-time monitoring and alerting platform which coalesces data from multiple sources, provides flexible visualization via customizable dashboards, and issues alerts and carries out corrective actions in response to problems.

System Architecture Development for Energy and Water Infrastructure Data Management and Geovisual Analytics

NASA Astrophysics Data System (ADS)

Berres, A.; Karthik, R.; Nugent, P.; Sorokine, A.; Myers, A.; Pang, H.

2017-12-01

Building an integrated data infrastructure that can meet the needs of a sustainable energy-water resource management requires a robust data management and geovisual analytics platform, capable of cross-domain scientific discovery and knowledge generation. Such a platform can facilitate the investigation of diverse complex research and policy questions for emerging priorities in Energy-Water Nexus (EWN) science areas. Using advanced data analytics, machine learning techniques, multi-dimensional statistical tools, and interactive geovisualization components, such a multi-layered federated platform is being developed, the Energy-Water Nexus Knowledge Discovery Framework (EWN-KDF). This platform utilizes several enterprise-grade software design concepts and standards such as extensible service-oriented architecture, open standard protocols, event-driven programming model, enterprise service bus, and adaptive user interfaces to provide a strategic value to the integrative computational and data infrastructure. EWN-KDF is built on the Compute and Data Environment for Science (CADES) environment in Oak Ridge National Laboratory (ORNL).

Technical issues in the conduct of large space platform experiments in plasma physics and geoplasma sciences

NASA Technical Reports Server (NTRS)

Szuszczewicz, Edward P.

1986-01-01

Large, permanently-manned space platforms can provide exciting opportunities for discoveries in basic plasma and geoplasma sciences. The potential for these discoveries will depend very critically on the properties of the platform, its subsystems, and their abilities to fulfill a spectrum of scientific requirements. With this in mind, the planning of space station research initiatives and the development of attendant platform engineering should allow for the identification of critical science and technology issues that must be clarified far in advance of space station program implementation. An attempt is made to contribute to that process, with a perspective that looks to the development of the space station as a permanently-manned Spaceborne Ionospheric Weather Station. The development of this concept requires a synergism of science and technology which leads to several critical design issues. To explore the identification of these issues, the development of the concept of an Ionospheric Weather Station will necessarily touch upon a number of diverse areas. These areas are discussed.

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.

KSC-2009-2938

NASA Image and Video Library

2009-05-05

CAPE CANAVERAL, Fla. – In the Space Station Processing Facility at NASA's Kennedy Space Center in Florida, technicians place equipment in the Resupply Stowage Platform, or RSP, to be installed in the multi-purpose logistics module Leonardo. The module is part of the payload for space shuttle Discovery's STS-128 mission. Discovery will carry science and storage racks to the International Space Station . Launch of Discovery is targeted for Aug. 6. Photo credit: NASA/Kim Shiflett

Integration, Networking, and Global Biobanking in the Age of New Biology.

PubMed

Karimi-Busheri, Feridoun; Rasouli-Nia, Aghdass

2015-01-01

Scientific revolution is changing the world forever. Many new disciplines and fields have emerged with unlimited possibilities and opportunities. Biobanking is one of many that is benefiting from revolutionary milestones in human genome, post-genomic, and computer and bioinformatics discoveries. The storage, management, and analysis of massive clinical and biological data sets cannot be achieved without a global collaboration and networking. At the same time, biobanking is facing many significant challenges that need to be addressed and solved including dealing with an ever increasing complexity of sample storage and retrieval, data management and integration, and establishing common platforms in a global context. The overall picture of the biobanking of the future, however, is promising. Many population-based biobanks have been formed, and more are under development. It is certain that amazing discoveries will emerge from this large-scale method of preserving and accessing human samples. Signs of a healthy collaboration between industry, academy, and government are encouraging.

Payload canister for Discovery is lifted in place for transfer

NASA Technical Reports Server (NTRS)

1998-01-01

At left, the payload canister for Space Shuttle Discovery is lifted from its canister movement vehicle to the top of the Rotating Service Structure on Launch Pad 39-B. Discovery (right), sitting atop the Mobile Launch Platform and next to the Fixed Service Structure (FSS), is scheduled for launch on Oct. 29, 1998, for the STS-95 mission. That mission includes the International Extreme Ultraviolet Hitchhiker (IEH-3), the Hubble Space Telescope Orbital Systems Test Platform, the Spartan solar- observing deployable spacecraft, and the SPACEHAB single module with experiments on space flight and the aging process. At the top of the FSS can be seen the 80-foot lightning mast . The 4- foot-high lightning rod on top helps prevent lightning current from passing directly through the Space Shuttle and the structures on the pad.

An automated Genomes-to-Natural Products platform (GNP) for the discovery of modular natural products.

PubMed

Johnston, Chad W; Skinnider, Michael A; Wyatt, Morgan A; Li, Xiang; Ranieri, Michael R M; Yang, Lian; Zechel, David L; Ma, Bin; Magarvey, Nathan A

2015-09-28

Bacterial natural products are a diverse and valuable group of small molecules, and genome sequencing indicates that the vast majority remain undiscovered. The prediction of natural product structures from biosynthetic assembly lines can facilitate their discovery, but highly automated, accurate, and integrated systems are required to mine the broad spectrum of sequenced bacterial genomes. Here we present a genome-guided natural products discovery tool to automatically predict, combinatorialize and identify polyketides and nonribosomal peptides from biosynthetic assembly lines using LC-MS/MS data of crude extracts in a high-throughput manner. We detail the directed identification and isolation of six genetically predicted polyketides and nonribosomal peptides using our Genome-to-Natural Products platform. This highly automated, user-friendly programme provides a means of realizing the potential of genetically encoded natural products.

Annotation-based genome-wide SNP discovery in the large and complex Aegilops tauschii genome using next-generation sequencing without a reference genome sequence

PubMed Central

2011-01-01

Background Many plants have large and complex genomes with an abundance of repeated sequences. Many plants are also polyploid. Both of these attributes typify the genome architecture in the tribe Triticeae, whose members include economically important wheat, rye and barley. Large genome sizes, an abundance of repeated sequences, and polyploidy present challenges to genome-wide SNP discovery using next-generation sequencing (NGS) of total genomic DNA by making alignment and clustering of short reads generated by the NGS platforms difficult, particularly in the absence of a reference genome sequence. Results An annotation-based, genome-wide SNP discovery pipeline is reported using NGS data for large and complex genomes without a reference genome sequence. Roche 454 shotgun reads with low genome coverage of one genotype are annotated in order to distinguish single-copy sequences and repeat junctions from repetitive sequences and sequences shared by paralogous genes. Multiple genome equivalents of shotgun reads of another genotype generated with SOLiD or Solexa are then mapped to the annotated Roche 454 reads to identify putative SNPs. A pipeline program package, AGSNP, was developed and used for genome-wide SNP discovery in Aegilops tauschii-the diploid source of the wheat D genome, and with a genome size of 4.02 Gb, of which 90% is repetitive sequences. Genomic DNA of Ae. tauschii accession AL8/78 was sequenced with the Roche 454 NGS platform. Genomic DNA and cDNA of Ae. tauschii accession AS75 was sequenced primarily with SOLiD, although some Solexa and Roche 454 genomic sequences were also generated. A total of 195,631 putative SNPs were discovered in gene sequences, 155,580 putative SNPs were discovered in uncharacterized single-copy regions, and another 145,907 putative SNPs were discovered in repeat junctions. These SNPs were dispersed across the entire Ae. tauschii genome. To assess the false positive SNP discovery rate, DNA containing putative SNPs was amplified by PCR from AL8/78 and AS75 and resequenced with the ABI 3730 xl. In a sample of 302 randomly selected putative SNPs, 84.0% in gene regions, 88.0% in repeat junctions, and 81.3% in uncharacterized regions were validated. Conclusion An annotation-based genome-wide SNP discovery pipeline for NGS platforms was developed. The pipeline is suitable for SNP discovery in genomic libraries of complex genomes and does not require a reference genome sequence. The pipeline is applicable to all current NGS platforms, provided that at least one such platform generates relatively long reads. The pipeline package, AGSNP, and the discovered 497,118 Ae. tauschii SNPs can be accessed at (http://avena.pw.usda.gov/wheatD/agsnp.shtml). PMID:21266061

KENNEDY SPACE CENTER, FLA. - This bird's-eye view of a high bay in the Orbiter Processing Facility (OPF) shows the open payload bay of Space Shuttle Discovery surrounded by the standard platforms and equipment required to process a Space Shuttle orbiter. The high bay is 197 feet (60 meters) long, 150 feet (46 meters) wide, 95 feet (29 meters) high, and encompasses a 29,000-square-foot (2,694-meter) area. The 30-ton (27-metric-ton) bridge crane (yellow device, right) has a hook height of approximately 66 feet (20 meters). Platforms, a main access bridge, and two rolling bridges with trucks provide access to various parts of the orbiter. In addition to routine servicing and checkout, the inspections and modifications made to enhance Discovery's performance and upgrade its systems were performed in the OPF during its recently completed Orbiter Major Modification (OMM) period.

NASA Image and Video Library

2003-09-02

KENNEDY SPACE CENTER, FLA. - This bird's-eye view of a high bay in the Orbiter Processing Facility (OPF) shows the open payload bay of Space Shuttle Discovery surrounded by the standard platforms and equipment required to process a Space Shuttle orbiter. The high bay is 197 feet (60 meters) long, 150 feet (46 meters) wide, 95 feet (29 meters) high, and encompasses a 29,000-square-foot (2,694-meter) area. The 30-ton (27-metric-ton) bridge crane (yellow device, right) has a hook height of approximately 66 feet (20 meters). Platforms, a main access bridge, and two rolling bridges with trucks provide access to various parts of the orbiter. In addition to routine servicing and checkout, the inspections and modifications made to enhance Discovery's performance and upgrade its systems were performed in the OPF during its recently completed Orbiter Major Modification (OMM) period.

Integrated Platform for Expedited Synthesis–Purification–Testing of Small Molecule Libraries

PubMed Central

2017-01-01

The productivity of medicinal chemistry programs can be significantly increased through the introduction of automation, leading to shortened discovery cycle times. Herein, we describe a platform that consolidates synthesis, purification, quantitation, dissolution, and testing of small molecule libraries. The system was validated through the synthesis and testing of two libraries of binders of polycomb protein EED, and excellent correlation of obtained data with results generated through conventional approaches was observed. The fully automated and integrated platform enables batch-supported compound synthesis based on a broad array of chemical transformations with testing in a variety of biochemical assay formats. A library turnaround time of between 24 and 36 h was achieved, and notably, each library synthesis produces sufficient amounts of compounds for further evaluation in secondary assays thereby contributing significantly to the shortening of medicinal chemistry discovery cycles. PMID:28435537

Validation of a multiplex electrochemiluminescent immunoassay platform in human and mouse samples

PubMed Central

Bastarache, J.A.; Koyama, T.; Wickersham, N.E; Ware, L.B.

2014-01-01

Despite the widespread use of multiplex immunoassays, there are very few scientific reports that test the accuracy and reliability of a platform prior to publication of experimental data. Our laboratory has previously demonstrated the need for new assay platform validation prior to use of biologic samples from large studies in order to optimize sample handling and assay performance. In this study, our goal was to test the accuracy and reproducibility of an electrochemiluminescent multiplex immunoassay platform (Meso Scale Discovery, MSD®) and compare this platform to validated, singleplex immunoassays (R&D Systems®) using actual study subject (human plasma and mouse bronchoalveolar lavage fluid (BALF) and plasma) samples. We found that the MSD platform performed well on intra- and inter-assay comparisons, spike and recovery and cross-platform comparisons. The mean intra-assay CV% and range for MSD was 3.49 (0.0-10.4) for IL-6 and 2.04 (0.1-7.9) for IL-8. The correlation between values for identical samples measured on both MSD and R&D was R=0.97 for both analytes. The mouse MSD assay had a broader range of CV% with means ranging from 9.5-28.5 depending on the analyte. The range of mean CV% was similar for single plex ELISAs at 4.3-23.7 depending on the analyte. Regardless of species or sample type, CV% was more variable at lower protein concentrations. In conclusion, we validated a multiplex electrochemiluminscent assay system and found that it has superior test characteristics in human plasma compared to mouse BALF and plasma. Both human and MSD assays compared favorably to well-validated singleplex ELISA's PMID:24768796

Network-based drug discovery by integrating systems biology and computational technologies

PubMed Central

Leung, Elaine L.; Cao, Zhi-Wei; Jiang, Zhi-Hong; Zhou, Hua

2013-01-01

Network-based intervention has been a trend of curing systemic diseases, but it relies on regimen optimization and valid multi-target actions of the drugs. The complex multi-component nature of medicinal herbs may serve as valuable resources for network-based multi-target drug discovery due to its potential treatment effects by synergy. Recently, robustness of multiple systems biology platforms shows powerful to uncover molecular mechanisms and connections between the drugs and their targeting dynamic network. However, optimization methods of drug combination are insufficient, owning to lacking of tighter integration across multiple ‘-omics’ databases. The newly developed algorithm- or network-based computational models can tightly integrate ‘-omics’ databases and optimize combinational regimens of drug development, which encourage using medicinal herbs to develop into new wave of network-based multi-target drugs. However, challenges on further integration across the databases of medicinal herbs with multiple system biology platforms for multi-target drug optimization remain to the uncertain reliability of individual data sets, width and depth and degree of standardization of herbal medicine. Standardization of the methodology and terminology of multiple system biology and herbal database would facilitate the integration. Enhance public accessible databases and the number of research using system biology platform on herbal medicine would be helpful. Further integration across various ‘-omics’ platforms and computational tools would accelerate development of network-based drug discovery and network medicine. PMID:22877768

Microbial Efflux Systems and Inhibitors: Approaches to Drug Discovery and the Challenge of Clinical Implementation

PubMed Central

Kourtesi, Christina; Ball, Anthony R; Huang, Ying-Ying; Jachak, Sanjay M; Vera, D Mariano A; Khondkar, Proma; Gibbons, Simon; Hamblin, Michael R; Tegos, George P

2013-01-01

Conventional antimicrobials are increasingly ineffective due to the emergence of multidrug-resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered exploration for novel and unconventional approaches to controlling microbial infections. Multidrug efflux systems (MES) have been a profound obstacle in the successful deployment of antimicrobials. The discovery of small molecule efflux system blockers has been an active and rapidly expanding research discipline. A major theme in this platform involves efflux pump inhibitors (EPIs) from natural sources. The discovery methodologies and the available number of natural EPI-chemotypes are increasing. Advances in our understanding of microbial physiology have shed light on a series of pathways and phenotypes where the role of efflux systems is pivotal. Complementing existing antimicrobial discovery platforms such as photodynamic therapy (PDT) with efflux inhibition is a subject under investigation. This core information is a stepping stone in the challenge of highlighting an effective drug development path for EPIs since the puzzle of clinical implementation remains unsolved. This review summarizes advances in the path of EPI discovery, discusses potential avenues of EPI implementation and development, and underlines the need for highly informative and comprehensive translational approaches. PMID:23569468

Colloquium : Emergent properties in plane view: Strong correlations at oxide interfaces

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

Chakhalian, Jak; Freeland, John W.; Millis, Andrew J.

2014-10-01

Finding new collective electronic states in materials is one of the fundamental goals of condensed matter physics. Atomic-scale superlattices formed from transition metal oxides are a particularly appealing hunting ground for new physics. In bulk form, transition metal oxides exhibit a remarkable range of magnetic, superconducting, and multiferroic phases that are of great scientific interest and are potentially capable of providing innovative energy, security, electronics, and medical technology platforms. In superlattices new states may emerge at the interfaces where dissimilar materials meet. This Colloquium illustrates the essential features that make transition metal oxide-based heterostructures an appealing discovery platform for emergentmore » properties with a few selected examples, showing how charge redistributes, magnetism and orbital polarization arises, and ferroelectric order emerges from heterostructures comprised of oxide components with nominally contradictory behavior with the aim providing insight into the creation and control of novel behavior at oxide interfaces by suitable mechanical, electrical, or optical boundary conditions and excitations.« less

Next-generation sequencing in the clinic: promises and challenges.

PubMed

Xuan, Jiekun; Yu, Ying; Qing, Tao; Guo, Lei; Shi, Leming

2013-11-01

The advent of next generation sequencing (NGS) technologies has revolutionized the field of genomics, enabling fast and cost-effective generation of genome-scale sequence data with exquisite resolution and accuracy. Over the past years, rapid technological advances led by academic institutions and companies have continued to broaden NGS applications from research to the clinic. A recent crop of discoveries have highlighted the medical impact of NGS technologies on Mendelian and complex diseases, particularly cancer. However, the ever-increasing pace of NGS adoption presents enormous challenges in terms of data processing, storage, management and interpretation as well as sequencing quality control, which hinder the translation from sequence data into clinical practice. In this review, we first summarize the technical characteristics and performance of current NGS platforms. We further highlight advances in the applications of NGS technologies towards the development of clinical diagnostics and therapeutics. Common issues in NGS workflows are also discussed to guide the selection of NGS platforms and pipelines for specific research purposes. Published by Elsevier Ireland Ltd.

ATOM - Accelerating therapeutics through opportunities in medicine

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

Mcmahon, Benjamin Hamilton; Dotson, Paul Jeffrey

Create a new paradigm of drug discovery that would reduce the time from an identified drug target to clinical candidate from the current ~6 years to just 12 months. ATOM will develop, test, and validate a multidisciplinary approach to drug discovery in which modern science, technology and engineering, supercomputing, simulations, data science, and artificial intelligence are highly integrated into a single drug-discovery platform that can ultimately be shared with the drug development community at-large.

Development of an Automated Microfluidic Reaction Platform for Multidimensional Screening: Reaction Discovery Employing Bicyclo[3.2.1]octanoid Scaffolds

PubMed Central

Goodell, John R.; McMullen, Jonathan P.; Zaborenko, Nikolay; Maloney, Jason R.; Ho, Chuan-Xing; Jensen, Klavs F.; Porco, John A.

2010-01-01

An automated, silicon-based microreactor system has been developed for rapid, low-volume, multidimensional reaction screening. Use of the microfluidic platform to identify transformations of densely functionalized bicyclo[3.2.1]octanoid scaffolds will be described. PMID:20560568

ACTIVIS: Visual Exploration of Industry-Scale Deep Neural Network Models.

PubMed

Kahng, Minsuk; Andrews, Pierre Y; Kalro, Aditya; Polo Chau, Duen Horng

2017-08-30

While deep learning models have achieved state-of-the-art accuracies for many prediction tasks, understanding these models remains a challenge. Despite the recent interest in developing visual tools to help users interpret deep learning models, the complexity and wide variety of models deployed in industry, and the large-scale datasets that they used, pose unique design challenges that are inadequately addressed by existing work. Through participatory design sessions with over 15 researchers and engineers at Facebook, we have developed, deployed, and iteratively improved ACTIVIS, an interactive visualization system for interpreting large-scale deep learning models and results. By tightly integrating multiple coordinated views, such as a computation graph overview of the model architecture, and a neuron activation view for pattern discovery and comparison, users can explore complex deep neural network models at both the instance- and subset-level. ACTIVIS has been deployed on Facebook's machine learning platform. We present case studies with Facebook researchers and engineers, and usage scenarios of how ACTIVIS may work with different models.

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons.

PubMed

Ali, Yousuf O; Bradley, Gillian; Lu, Hui-Chen

2017-03-07

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer's, Huntington's, Parkinson's diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons.

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

PubMed Central

Ali, Yousuf O.; Bradley, Gillian; Lu, Hui-Chen

2017-01-01

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer’s, Huntington’s, Parkinson’s diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons. PMID:28266613

B-CAN: a resource sharing platform to improve the operation, visualization and integrated analysis of TCGA breast cancer data

PubMed Central

Wen, Can-Hong; Ou, Shao-Min; Guo, Xiao-Bo; Liu, Chen-Feng; Shen, Yan-Bo; You, Na; Cai, Wei-Hong; Shen, Wen-Jun; Wang, Xue-Qin; Tan, Hai-Zhu

2017-01-01

Breast cancer is a high-risk heterogeneous disease with myriad subtypes and complicated biological features. The Cancer Genome Atlas (TCGA) breast cancer database provides researchers with the large-scale genome and clinical data via web portals and FTP services. Researchers are able to gain new insights into their related fields, and evaluate experimental discoveries with TCGA. However, it is difficult for researchers who have little experience with database and bioinformatics to access and operate on because of TCGA’s complex data format and diverse files. For ease of use, we build the breast cancer (B-CAN) platform, which enables data customization, data visualization, and private data center. The B-CAN platform runs on Apache server and interacts with the backstage of MySQL database by PHP. Users can customize data based on their needs by combining tables from original TCGA database and selecting variables from each table. The private data center is applicable for private data and two types of customized data. A key feature of the B-CAN is that it provides single table display and multiple table display. Customized data with one barcode corresponding to many records and processed customized data are allowed in Multiple Tables Display. The B-CAN is an intuitive and high-efficient data-sharing platform. PMID:29312567

Clinical analysis of genome next-generation sequencing data using the Omicia platform

PubMed Central

Coonrod, Emily M; Margraf, Rebecca L; Russell, Archie; Voelkerding, Karl V; Reese, Martin G

2013-01-01

Aims Next-generation sequencing is being implemented in the clinical laboratory environment for the purposes of candidate causal variant discovery in patients affected with a variety of genetic disorders. The successful implementation of this technology for diagnosing genetic disorders requires a rapid, user-friendly method to annotate variants and generate short lists of clinically relevant variants of interest. This report describes Omicia’s Opal platform, a new software tool designed for variant discovery and interpretation in a clinical laboratory environment. The software allows clinical scientists to process, analyze, interpret and report on personal genome files. Materials & Methods To demonstrate the software, the authors describe the interactive use of the system for the rapid discovery of disease-causing variants using three cases. Results & Conclusion Here, the authors show the features of the Opal system and their use in uncovering variants of clinical significance. PMID:23895124

Stem cells: a model for screening, discovery and development of drugs.

PubMed

Kitambi, Satish Srinivas; Chandrasekar, Gayathri

2011-01-01

The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficacy studies using stem cells offers a reliable platform for the drug discovery process. Advances made in the generation of induced pluripotent stem cells from normal or diseased tissue serves as a platform to perform drug screens aimed at developing cell-based therapies against conditions like Parkinson's disease and diabetes. This review discusses the application of stem cells and cancer stem cells in drug screening and their role in complementing, reducing, and replacing animal testing. In addition to this, target identification and major advances in the field of personalized medicine using induced pluripotent cells are also discussed.

The STS-93 external tank and booster stack sits at the Mobile Launcher Platform park site

NASA Technical Reports Server (NTRS)

1999-01-01

The STS-93 stack of solid rocket boosters and external tank sits at the Mobile Launcher Platform park site waiting for lightning shield wires to be installed on the Vehicle Assembly Building (VAB) in the background. The stack is being temporarily stored outside the VAB while Space Shuttle Discovery undergoes repair to hail damage in High Bay 1. Discovery was rolled back from Pad 39B to the VAB for repairs because access to all of the damaged areas was not possible at the pad. The STS-93 stack will be moved under the wires at the VAB for protection until Discovery returns to the pad, later this week. The scheduled date for launch of mission STS-96 is no earlier than May 27. STS-93 is targeted for launch on July 22, carrying the Chandra X-ray Observatory.

A Road Map for Precision Medicine in the Epilepsies

PubMed Central

2015-01-01

Summary Technological advances have paved the way for accelerated genomic discovery and are bringing precision medicine clearly into view. Epilepsy research in particular is well-suited to serve as a model for the development and deployment of targeted therapeutics in precision medicine because of the rapidly expanding genetic knowledge base in epilepsy, the availability of good in vitro and in vivo model systems to efficiently study the biological consequences of genetic mutations, the ability to turn these models into effective drug screening platforms, and the establishment of collaborative research groups. Moving forward, it is critical that we strengthen these collaborations, particularly through integrated research platforms to provide robust analyses both for accurate personal genome analysis and gene and drug discovery. Similarly, the implementation of clinical trial networks will allow the expansion of patient sample populations with genetically defined epilepsy so that drug discovery can be translated into clinical practice. PMID:26416172

The EGS Data Collaboration Platform: Enabling Scientific Discovery

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

Weers, Jonathan D; Johnston, Henry; Huggins, Jay V

Collaboration in the digital age has been stifled in recent years. Reasonable responses to legitimate security concerns have created a virtual landscape of silos and fortified castles incapable of sharing information efficiently. This trend is unfortunately opposed to the geothermal scientific community's migration toward larger, more collaborative projects. To facilitate efficient sharing of information between team members from multiple national labs, universities, and private organizations, the 'EGS Collab' team has developed a universally accessible, secure data collaboration platform and has fully integrated it with the U.S. Department of Energy's (DOE) Geothermal Data Repository (GDR) and the National Geothermal Data Systemmore » (NGDS). This paper will explore some of the challenges of collaboration in the modern digital age, highlight strategies for active data management, and discuss the integration of the EGS Collab data management platform with the GDR to enable scientific discovery through the timely dissemination of information.« less

A method for the isolation and characterization of functional murine monoclonal antibodies by single B cell cloning.

PubMed

Carbonetti, Sara; Oliver, Brian G; Vigdorovich, Vladimir; Dambrauskas, Nicholas; Sack, Brandon; Bergl, Emilee; Kappe, Stefan H I; Sather, D Noah

2017-09-01

Monoclonal antibody technologies have enabled dramatic advances in immunology, the study of infectious disease, and modern medicine over the past 40years. However, many monoclonal antibody discovery procedures are labor- and time-intensive, low efficiency, and expensive. Here we describe an optimized mAb discovery platform for the rapid and efficient isolation, cloning and characterization of monoclonal antibodies in murine systems. In this platform, antigen-binding splenic B cells from immunized mice are isolated by FACS and cocultured with CD40L positive cells to induce proliferation and mAb production. After 12days of coculture, cell culture supernatants are screened for antigen, and IgG positivity and RNA is isolated for reverse-transcription. Positive-well cDNA is then amplified by PCR and the resulting amplicons can be cloned into ligation-independent expression vectors, which are then used directly to transfect HEK293 cells for recombinant antibody production. After 4days of growth, conditioned medium can be screened using biolayer interferometry for antigen binding and affinity measurements. Using this method, we were able to isolate six unique, functional monoclonal antibodies against an antigen of the human malaria parasite Plasmodium falciparum. Importantly, this method incorporates several important advances that circumvent the need for single-cell PCR, restriction cloning, and large scale protein production, and can be applied to a wide array of protein antigens. Copyright © 2017 Elsevier B.V. All rights reserved.

High-content screening in microfluidic devices.

PubMed

Cheong, Raymond; Paliwal, Saurabh; Levchenko, Andre

2010-08-01

Miniaturization is the key to advancing the state of the art in high-content screening (HCS) in order to enable dramatic cost savings through reduced usage of expensive biochemical reagents and to enable large-scale screening on primary cells. Microfluidic technology offers the potential to enable HCS to be performed with an unprecedented degree of miniaturization. This perspective highlights a real-world example from the authors’ work of HCS assays implemented in a highly miniaturized microfluidic format. The advantages of this technology are discussed, including cost savings, high-throughput screening on primary cells, improved accuracy, the ability to study complex time-varying stimuli, and ease of automation, integration and scaling. The reader will understand the capabilities of anew microfluidics-based platform for HCS and the advantages it provides over conventional plate-based HCS. Microfluidics technology will drive significant advancements and broader usage and applicability of HCS in drug discovery.

Transcriptome sequencing and annotation of the halophytic microalga Dunaliella salina * #

PubMed Central

Hong, Ling; Liu, Jun-li; Midoun, Samira Z.; Miller, Philip C.

2017-01-01

The unicellular green alga Dunaliella salina is well adapted to salt stress and contains compounds (including β-carotene and vitamins) with potential commercial value. A large transcriptome database of D. salina during the adjustment, exponential and stationary growth phases was generated using a high throughput sequencing platform. We characterized the metabolic processes in D. salina with a focus on valuable metabolites, with the aim of manipulating D. salina to achieve greater economic value in large-scale production through a bioengineering strategy. Gene expression profiles under salt stress verified using quantitative polymerase chain reaction (qPCR) implied that salt can regulate the expression of key genes. This study generated a substantial fraction of D. salina transcriptional sequences for the entire growth cycle, providing a basis for the discovery of novel genes. This first full-scale transcriptome study of D. salina establishes a foundation for further comparative genomic studies. PMID:28990374

Large-scale production of human pluripotent stem cell derived cardiomyocytes.

PubMed

Kempf, Henning; Andree, Birgit; Zweigerdt, Robert

2016-01-15

Regenerative medicine, including preclinical studies in large animal models and tissue engineering approaches as well as innovative assays for drug discovery, will require the constant supply of hPSC-derived cardiomyocytes and other functional progenies. Respective cell production processes must be robust, economically viable and ultimately GMP-compliant. Recent research has enabled transition of lab scale protocols for hPSC expansion and cardiomyogenic differentiation towards more controlled processing in industry-compatible culture platforms. Here, advanced strategies for the cultivation and differentiation of hPSCs will be reviewed by focusing on stirred bioreactor-based techniques for process upscaling. We will discuss how cardiomyocyte mass production might benefit from recent findings such as cell expansion at the cardiovascular progenitor state. Finally, remaining challenges will be highlighted, specifically regarding three dimensional (3D) hPSC suspension culture and critical safety issues ahead of clinical translation. Copyright © 2015 Elsevier B.V. All rights reserved.

Large Scale Mass Spectrometry-based Identifications of Enzyme-mediated Protein Methylation Are Subject to High False Discovery Rates*

PubMed Central

Hart-Smith, Gene; Yagoub, Daniel; Tay, Aidan P.; Pickford, Russell; Wilkins, Marc R.

2016-01-01

All large scale LC-MS/MS post-translational methylation site discovery experiments require methylpeptide spectrum matches (methyl-PSMs) to be identified at acceptably low false discovery rates (FDRs). To meet estimated methyl-PSM FDRs, methyl-PSM filtering criteria are often determined using the target-decoy approach. The efficacy of this methyl-PSM filtering approach has, however, yet to be thoroughly evaluated. Here, we conduct a systematic analysis of methyl-PSM FDRs across a range of sample preparation workflows (each differing in their exposure to the alcohols methanol and isopropyl alcohol) and mass spectrometric instrument platforms (each employing a different mode of MS/MS dissociation). Through 13CD3-methionine labeling (heavy-methyl SILAC) of Saccharomyces cerevisiae cells and in-depth manual data inspection, accurate lists of true positive methyl-PSMs were determined, allowing methyl-PSM FDRs to be compared with target-decoy approach-derived methyl-PSM FDR estimates. These results show that global FDR estimates produce extremely unreliable methyl-PSM filtering criteria; we demonstrate that this is an unavoidable consequence of the high number of amino acid combinations capable of producing peptide sequences that are isobaric to methylated peptides of a different sequence. Separate methyl-PSM FDR estimates were also found to be unreliable due to prevalent sources of false positive methyl-PSMs that produce high peptide identity score distributions. Incorrect methylation site localizations, peptides containing cysteinyl-S-β-propionamide, and methylated glutamic or aspartic acid residues can partially, but not wholly, account for these false positive methyl-PSMs. Together, these results indicate that the target-decoy approach is an unreliable means of estimating methyl-PSM FDRs and methyl-PSM filtering criteria. We suggest that orthogonal methylpeptide validation (e.g. heavy-methyl SILAC or its offshoots) should be considered a prerequisite for obtaining high confidence methyl-PSMs in large scale LC-MS/MS methylation site discovery experiments and make recommendations on how to reduce methyl-PSM FDRs in samples not amenable to heavy isotope labeling. Data are available via ProteomeXchange with the data identifier PXD002857. PMID:26699799

Multiscale Modelling of Relationships between Protein Classes and Drug Behavior Across all Diseases Using the CANDO Platform

PubMed Central

Samudrala, Ram

2015-01-01

We have examined the effect of eight different protein classes (channels, GPCRs, kinases, ligases, nuclear receptors, proteases, phosphatases, transporters) on the benchmarking performance of the CANDO drug discovery and repurposing platform (http://protinfo.org/cando). The first version of the CANDO platform utilizes a matrix of predicted interactions between 48278 proteins and 3733 human ingestible compounds (including FDA approved drugs and supplements) that map to 2030 indications/diseases using a hierarchical chem and bio-informatic fragment based docking with dynamics protocol (> one billion predicted interactions considered). The platform uses similarity of compound-proteome interaction signatures as indicative of similar functional behavior and benchmarking accuracy is calculated across 1439 indications/diseases with more than one approved drug. The CANDO platform yields a significant correlation (0.99, p-value < 0.0001) between the number of proteins considered and benchmarking accuracy obtained indicating the importance of multitargeting for drug discovery. Average benchmarking accuracies range from 6.2 % to 7.6 % for the eight classes when the top 10 ranked compounds are considered, in contrast to a range of 5.5 % to 11.7 % obtained for the comparison/control sets consisting of 10, 100, 1000, and 10000 single best performing proteins. These results are generally two orders of magnitude better than the average accuracy of 0.2% obtained when randomly generated (fully scrambled) matrices are used. Different indications perform well when different classes are used but the best accuracies (up to 11.7% for the top 10 ranked compounds) are achieved when a combination of classes are used containing the broadest distribution of protein folds. Our results illustrate the utility of the CANDO approach and the consideration of different protein classes for devising indication specific protocols for drug repurposing as well as drug discovery. PMID:25694071

Targeted proteomics guided by label-free global proteome analysis in saliva reveal transition signatures from health to periodontal disease.

PubMed

Bostanci, Nagihan; Selevsek, Nathalie; Wolski, Witold; Grossmann, Jonas; Bao, Kai; Wahlander, Asa; Trachsel, Christian; Schlapbach, Ralph; Özturk, Veli Özgen; Afacan, Beral; Emingil, Gulnur; Belibasakis, Georgios N

2018-04-02

Periodontal diseases are among the most prevalent worldwide, but largely silent, chronic diseases. They affect the tooth-supporting tissues with multiple ramifications on life quality. Their early diagnosis is still challenging, due to lack of appropriate molecular diagnostic methods. Saliva offers a non-invasively collectable reservoir of clinically relevant biomarkers, which, if utilized efficiently, could facilitate early diagnosis and monitoring of ongoing disease. Despite several novel protein markers being recently enlisted by discovery proteomics, their routine diagnostic application is hampered by the lack of validation platforms that allow for rapid, accurate and simultaneous quantification of multiple proteins in large cohorts. We carried out a pipeline of two proteomic platforms; firstly, we applied open ended label-free quantitative (LFQ) proteomics for discovery in saliva (n=67, health, gingivitis, and periodontitis), followed by selected-reaction monitoring (SRM)-targeted proteomics for validation in an independent cohort (n=82). The LFQ platform led to the discovery of 119 proteins with at least two-fold significant difference between health and disease. The 65 proteins chosen for the subsequent SRM platform included 50 related proteins derived from the significantly enriched processes of the LFQ data, 11 from literature-mining, and four house-keeping ones. Among those, 60 were reproducibly quantifiable proteins (92% success rate), represented by a total of 143 peptides. Machine-learning modeling led to a narrowed-down panel of five proteins of high predictive value for periodontal diseases (higher in disease: Matrix metalloproteinase-9, Ras-related protein-1, Actin-related protein 2/3 complex subunit 5; lower in disease: Clusterin, Deleted in Malignant Brain Tumors 1), with maximum area under the receiver operating curve >0.97. This panel enriches the pool of credible clinical biomarker candidates for diagnostic assay development. Yet, the quantum leap brought in periodontal diagnostics by this study lies in the introduction of the well established discovery-through-verification pipeline for periodontal biomarker discovery and validation in further periodontal patient cohorts. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

3D cell culture systems--towards primary drug discovery platforms: an interview with Heinz Ruffner (Novartis) and Jan Lichtenberg (InSphero).

PubMed

Ruffner, Heinz; Lichtenberg, Jan

2012-07-01

Advanced cell culture systems for regenerative medicine, drug efficacy and toxicity testing, enabling technologies to create and analyze 3D cell culture systems were the topics of the 3D cell culture meeting taking place in March 14-16, 2012 at the Technopark in Zurich, Switzerland. At this meeting Biotechnology Journal had the pleasure to talk to Dr. Heinz Ruffner, Novartis AG, and Dr. Jan Lichtenberg, co-founder and CEO of InSphero AG, about challenges and perspectives in using 3D cell culture systems as primary drug discovery platforms. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

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

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

Discovery touches down after successful mission STS-95

NASA Technical Reports Server (NTRS)

1998-01-01

Orbiter Discovery smokes its tires as it touches down on runway 33 at the Shuttle Landing Facility. Discovery returns to Earth with its crew of seven after a successful mission STS-95 lasting nearly nine days and 3.6 million miles. The mission included research payloads such as the Spartan solar-observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process.

Discovery touches down after successful mission STS-95

NASA Technical Reports Server (NTRS)

1998-01-01

Orbiter Discovery startles a great white egret next to runway 33 as it touches down at the Shuttle Landing Facility. Discovery returns to Earth with its crew of seven after a successful mission STS-95 lasting nearly nine days and 3.6 million miles. The mission included research payloads such as the Spartan solar- observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process.

IMG-ABC: A Knowledge Base To Fuel Discovery of Biosynthetic Gene Clusters and Novel Secondary Metabolites.

PubMed

Hadjithomas, Michalis; Chen, I-Min Amy; Chu, Ken; Ratner, Anna; Palaniappan, Krishna; Szeto, Ernest; Huang, Jinghua; Reddy, T B K; Cimermančič, Peter; Fischbach, Michael A; Ivanova, Natalia N; Markowitz, Victor M; Kyrpides, Nikos C; Pati, Amrita

2015-07-14

In the discovery of secondary metabolites, analysis of sequence data is a promising exploration path that remains largely underutilized due to the lack of computational platforms that enable such a systematic approach on a large scale. In this work, we present IMG-ABC (https://img.jgi.doe.gov/abc), an atlas of biosynthetic gene clusters within the Integrated Microbial Genomes (IMG) system, which is aimed at harnessing the power of "big" genomic data for discovering small molecules. IMG-ABC relies on IMG's comprehensive integrated structural and functional genomic data for the analysis of biosynthetic gene clusters (BCs) and associated secondary metabolites (SMs). SMs and BCs serve as the two main classes of objects in IMG-ABC, each with a rich collection of attributes. A unique feature of IMG-ABC is the incorporation of both experimentally validated and computationally predicted BCs in genomes as well as metagenomes, thus identifying BCs in uncultured populations and rare taxa. We demonstrate the strength of IMG-ABC's focused integrated analysis tools in enabling the exploration of microbial secondary metabolism on a global scale, through the discovery of phenazine-producing clusters for the first time in Alphaproteobacteria. IMG-ABC strives to fill the long-existent void of resources for computational exploration of the secondary metabolism universe; its underlying scalable framework enables traversal of uncovered phylogenetic and chemical structure space, serving as a doorway to a new era in the discovery of novel molecules. IMG-ABC is the largest publicly available database of predicted and experimental biosynthetic gene clusters and the secondary metabolites they produce. The system also includes powerful search and analysis tools that are integrated with IMG's extensive genomic/metagenomic data and analysis tool kits. As new research on biosynthetic gene clusters and secondary metabolites is published and more genomes are sequenced, IMG-ABC will continue to expand, with the goal of becoming an essential component of any bioinformatic exploration of the secondary metabolism world. Copyright © 2015 Hadjithomas et al.

Games as a Platform for Student Participation in Authentic Scientific Research

ERIC Educational Resources Information Center

Magnussen, Rikke; Hansen, Sidse Damgaard; Planke, Tilo; Sherson, Jacob Friis

2014-01-01

This paper presents results from the design and testing of an educational version of Quantum Moves, a Scientific Discovery Game that allows players to help solve authentic scientific challenges in the effort to develop a quantum computer. The primary aim of developing a game-based platform for student-research collaboration is to investigate if…

Enhancing Mobility: Integrating New Services into Your Library's Mobile Platform to Increase Traffic

ERIC Educational Resources Information Center

Felts, John W., Jr.

2014-01-01

Kimbel Library launched its mobile environment and ran it in full production for several months yet usage patterns were quite low and flat. The library only saw a substantial increase in usage when new, value-added services were integrated into this platform. Upon implementing and integrating discovery services, chat and SMS capabilities, and…

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

Ma, Biao; Yamaguchi, Keiichi; Fukuoka, Mayuko

To accelerate the logical drug design procedure, we created the program “NAGARA,” a plugin for PyMOL, and applied it to the discovery of small compounds called medical chaperones (MCs) that stabilize the cellular form of a prion protein (PrP{sup C}). In NAGARA, we constructed a single platform to unify the docking simulation (DS), free energy calculation by molecular dynamics (MD) simulation, and interfragment interaction energy (IFIE) calculation by quantum chemistry (QC) calculation. NAGARA also enables large-scale parallel computing via a convenient graphical user interface. Here, we demonstrated its performance and its broad applicability from drug discovery to lead optimization withmore » full compatibility with various experimental methods including Western blotting (WB) analysis, surface plasmon resonance (SPR), and nuclear magnetic resonance (NMR) measurements. Combining DS and WB, we discovered anti-prion activities for two compounds and tegobuvir (TGV), a non-nucleoside non-structural protein NS5B polymerase inhibitor showing activity against hepatitis C virus genotype 1. Binding profiles predicted by MD and QC are consistent with those obtained by SPR and NMR. Free energy analyses showed that these compounds stabilize the PrP{sup C} conformation by decreasing the conformational fluctuation of the PrP{sup C}. Because TGV has been already approved as a medicine, its extension to prion diseases is straightforward. Finally, we evaluated the affinities of the fragmented regions of TGV using QC and found a clue for its further optimization. By repeating WB, MD, and QC recursively, we were able to obtain the optimum lead structure. - Highlights: • NAGARA integrates docking simulation, molecular dynamics, and quantum chemistry. • We found many compounds, e.g., tegobuvir (TGV), that exhibit anti-prion activities. • We obtained insights into the action mechanism of TGV as a medical chaperone. • Using QC, we obtained useful information for optimization of the lead compound, TGV. • NAGARA is a convenient platform for drug discovery and lead optimization.« less

Determining conserved metabolic biomarkers from a million database queries.

PubMed

Kurczy, Michael E; Ivanisevic, Julijana; Johnson, Caroline H; Uritboonthai, Winnie; Hoang, Linh; Fang, Mingliang; Hicks, Matthew; Aldebot, Anthony; Rinehart, Duane; Mellander, Lisa J; Tautenhahn, Ralf; Patti, Gary J; Spilker, Mary E; Benton, H Paul; Siuzdak, Gary

2015-12-01

Metabolite databases provide a unique window into metabolome research allowing the most commonly searched biomarkers to be catalogued. Omic scale metabolite profiling, or metabolomics, is finding increased utility in biomarker discovery largely driven by improvements in analytical technologies and the concurrent developments in bioinformatics. However, the successful translation of biomarkers into clinical or biologically relevant indicators is limited. With the aim of improving the discovery of translatable metabolite biomarkers, we present search analytics for over one million METLIN metabolite database queries. The most common metabolites found in METLIN were cross-correlated against XCMS Online, the widely used cloud-based data processing and pathway analysis platform. Analysis of the METLIN and XCMS common metabolite data has two primary implications: these metabolites, might indicate a conserved metabolic response to stressors and, this data may be used to gauge the relative uniqueness of potential biomarkers. METLIN can be accessed by logging on to: https://metlin.scripps.edu siuzdak@scripps.edu Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

iClimate: a climate data and analysis portal

NASA Astrophysics Data System (ADS)

Goodman, P. J.; Russell, J. L.; Merchant, N.; Miller, S. J.; Juneja, A.

2015-12-01

We will describe a new climate data and analysis portal called iClimate that facilitates direct comparisons between available climate observations and climate simulations. Modeled after the successful iPlant Collaborative Discovery Environment (www.iplantcollaborative.org) that allows plant scientists to trade and share environmental, physiological and genetic data and analyses, iClimate provides an easy-to-use platform for large-scale climate research, including the storage, sharing, automated preprocessing, analysis and high-end visualization of large and often disparate observational and model datasets. iClimate will promote data exploration and scientific discovery by providing: efficient and high-speed transfer of data from nodes around the globe (e.g. PCMDI and NASA); standardized and customized data/model metrics; efficient subsampling of datasets based on temporal period, geographical region or variable; and collaboration tools for sharing data, workflows, analysis results, and data visualizations with collaborators or with the community at large. We will present iClimate's capabilities, and demonstrate how it will simplify and enhance the ability to do basic or cutting-edge climate research by professionals, laypeople and students.

Cancer in silico drug discovery: a systems biology tool for identifying candidate drugs to target specific molecular tumor subtypes.

PubMed

San Lucas, F Anthony; Fowler, Jerry; Chang, Kyle; Kopetz, Scott; Vilar, Eduardo; Scheet, Paul

2014-12-01

Large-scale cancer datasets such as The Cancer Genome Atlas (TCGA) allow researchers to profile tumors based on a wide range of clinical and molecular characteristics. Subsequently, TCGA-derived gene expression profiles can be analyzed with the Connectivity Map (CMap) to find candidate drugs to target tumors with specific clinical phenotypes or molecular characteristics. This represents a powerful computational approach for candidate drug identification, but due to the complexity of TCGA and technology differences between CMap and TCGA experiments, such analyses are challenging to conduct and reproduce. We present Cancer in silico Drug Discovery (CiDD; scheet.org/software), a computational drug discovery platform that addresses these challenges. CiDD integrates data from TCGA, CMap, and Cancer Cell Line Encyclopedia (CCLE) to perform computational drug discovery experiments, generating hypotheses for the following three general problems: (i) determining whether specific clinical phenotypes or molecular characteristics are associated with unique gene expression signatures; (ii) finding candidate drugs to repress these expression signatures; and (iii) identifying cell lines that resemble the tumors being studied for subsequent in vitro experiments. The primary input to CiDD is a clinical or molecular characteristic. The output is a biologically annotated list of candidate drugs and a list of cell lines for in vitro experimentation. We applied CiDD to identify candidate drugs to treat colorectal cancers harboring mutations in BRAF. CiDD identified EGFR and proteasome inhibitors, while proposing five cell lines for in vitro testing. CiDD facilitates phenotype-driven, systematic drug discovery based on clinical and molecular data from TCGA. ©2014 American Association for Cancer Research.

A platform for the discovery of new macrolide antibiotics

NASA Astrophysics Data System (ADS)

Seiple, Ian B.; Zhang, Ziyang; Jakubec, Pavol; Langlois-Mercier, Audrey; Wright, Peter M.; Hog, Daniel T.; Yabu, Kazuo; Allu, Senkara Rao; Fukuzaki, Takehiro; Carlsen, Peter N.; Kitamura, Yoshiaki; Zhou, Xiang; Condakes, Matthew L.; Szczypiński, Filip T.; Green, William D.; Myers, Andrew G.

2016-05-01

The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.

Developing the Biomolecular Screening Facility at the EPFL into the Chemical Biology Screening Platform for Switzerland.

PubMed

Turcatti, Gerardo

2014-05-01

The Biomolecular Screening Facility (BSF) is a multidisciplinary laboratory created in 2006 at the Ecole Polytechnique Federale de Lausanne (EPFL) to perform medium and high throughput screening in life sciences-related projects. The BSF was conceived and developed to meet the needs of a wide range of researchers, without privileging a particular biological discipline or therapeutic area. The facility has the necessary infrastructure, multidisciplinary expertise and flexibility to perform large screening programs using small interfering RNAs (siRNAs) and chemical collections in the areas of chemical biology, systems biology and drug discovery. In the framework of the National Centres of Competence in Research (NCCR) Chemical Biology, the BSF is hosting 'ACCESS', the Academic Chemical Screening Platform of Switzerland that provides the scientific community with chemical diversity, screening facilities and know-how in chemical genetics. In addition, the BSF started its own applied research axes that are driven by innovation in thematic areas related to preclinical drug discovery and discovery of bioactive probes.

Development of novel IVD assays: a manufacturer's perspective.

PubMed

Metcalfe, Thomas A

2010-01-01

IVD manufacturers are heavily reliant on novel IVD assays to fuel their growth and drive innovation within the industry. They represent a key part of the IVD industry's value proposition to customers and the healthcare industry in general, driving product differentiation, helping to create demand for new systems and generating incremental revenue. However, the discovery of novel biomarkers and their qualification for a specific clinical purpose is a high risk undertaking and the large, risky investments associated with doing this on a large scale are incompatible with IVD manufacturer's business models. This article describes the sources of novel IVD assays, the processes for discovering and qualifying novel assays and the reliance of IVD manufacturers on collaborations and in-licensing to source new IVD assays for their platforms.

Computational, Integrative, and Comparative Methods for the Elucidation of Genetic Coexpression Networks

DOE PAGES

Baldwin, Nicole E.; Chesler, Elissa J.; Kirov, Stefan; ...

2005-01-01

Gene expression microarray data can be used for the assembly of genetic coexpression network graphs. Using mRNA samples obtained from recombinant inbred Mus musculus strains, it is possible to integrate allelic variation with molecular and higher-order phenotypes. The depth of quantitative genetic analysis of microarray data can be vastly enhanced utilizing this mouse resource in combination with powerful computational algorithms, platforms, and data repositories. The resulting network graphs transect many levels of biological scale. This approach is illustrated with the extraction of cliques of putatively co-regulated genes and their annotation using gene ontology analysis and cis -regulatory element discovery. Themore » causal basis for co-regulation is detected through the use of quantitative trait locus mapping.« less

Functional Interaction Network Construction and Analysis for Disease Discovery.

PubMed

Wu, Guanming; Haw, Robin

2017-01-01

Network-based approaches project seemingly unrelated genes or proteins onto a large-scale network context, therefore providing a holistic visualization and analysis platform for genomic data generated from high-throughput experiments, reducing the dimensionality of data via using network modules and increasing the statistic analysis power. Based on the Reactome database, the most popular and comprehensive open-source biological pathway knowledgebase, we have developed a highly reliable protein functional interaction network covering around 60 % of total human genes and an app called ReactomeFIViz for Cytoscape, the most popular biological network visualization and analysis platform. In this chapter, we describe the detailed procedures on how this functional interaction network is constructed by integrating multiple external data sources, extracting functional interactions from human curated pathway databases, building a machine learning classifier called a Naïve Bayesian Classifier, predicting interactions based on the trained Naïve Bayesian Classifier, and finally constructing the functional interaction database. We also provide an example on how to use ReactomeFIViz for performing network-based data analysis for a list of genes.

All the World's a Stage: Facilitating Discovery Science and Improved Cancer Care through the Global Alliance for Genomics and Health.

PubMed

Lawler, Mark; Siu, Lillian L; Rehm, Heidi L; Chanock, Stephen J; Alterovitz, Gil; Burn, John; Calvo, Fabien; Lacombe, Denis; Teh, Bin Tean; North, Kathryn N; Sawyers, Charles L

2015-11-01

The recent explosion of genetic and clinical data generated from tumor genome analysis presents an unparalleled opportunity to enhance our understanding of cancer, but this opportunity is compromised by the reluctance of many in the scientific community to share datasets and the lack of interoperability between different data platforms. The Global Alliance for Genomics and Health is addressing these barriers and challenges through a cooperative framework that encourages "team science" and responsible data sharing, complemented by the development of a series of application program interfaces that link different data platforms, thus breaking down traditional silos and liberating the data to enable new discoveries and ultimately benefit patients. ©2015 American Association for Cancer Research.

Quantitative structure-activity relationship: promising advances in drug discovery platforms.

PubMed

Wang, Tao; Wu, Mian-Bin; Lin, Jian-Ping; Yang, Li-Rong

2015-12-01

Quantitative structure-activity relationship (QSAR) modeling is one of the most popular computer-aided tools employed in medicinal chemistry for drug discovery and lead optimization. It is especially powerful in the absence of 3D structures of specific drug targets. QSAR methods have been shown to draw public attention since they were first introduced. In this review, the authors provide a brief discussion of the basic principles of QSAR, model development and model validation. They also highlight the current applications of QSAR in different fields, particularly in virtual screening, rational drug design and multi-target QSAR. Finally, in view of recent controversies, the authors detail the challenges faced by QSAR modeling and the relevant solutions. The aim of this review is to show how QSAR modeling can be applied in novel drug discovery, design and lead optimization. QSAR should intentionally be used as a powerful tool for fragment-based drug design platforms in the field of drug discovery and design. Although there have been an increasing number of experimentally determined protein structures in recent years, a great number of protein structures cannot be easily obtained (i.e., membrane transport proteins and G-protein coupled receptors). Fragment-based drug discovery, such as QSAR, could be applied further and have a significant role in dealing with these problems. Moreover, along with the development of computer software and hardware, it is believed that QSAR will be increasingly important.

Strategy for Identifying Repurposed Drugs for the Treatment of Cerebral Cavernous Malformation

PubMed Central

Gibson, Christopher C.; Zhu, Weiquan; Davis, Chadwick T.; Bowman-Kirigin, Jay A.; Chan, Aubrey C.; Ling, Jing; Walker, Ashley E.; Goitre, Luca; Monache, Simona Delle; Retta, Saverio Francesco; Shiu, Yan-Ting E.; Grossmann, Allie H.; Thomas, Kirk R.; Donato, Anthony J.; Lesniewski, Lisa A.; Whitehead, Kevin J.; Li, Dean Y.

2014-01-01

Background Cerebral cavernous malformation (CCM) is a hemorrhagic stroke disease affecting up to 0.5% of North Americans with no approved non-surgical treatment. A subset of patients have a hereditary form of the disease due primarily to loss-of-function mutations in KRIT1, CCM2, or PDCD10. We sought to identify known drugs that could be repurposed to treat CCM. Methods and Results We developed an unbiased screening platform based on both cellular and animal models of loss-of-function of CCM2. Our discovery strategy consisted of four steps: an automated immunofluorescence and machine-learning-based primary screen of structural phenotypes in human endothelial cells deficient in CCM2; a secondary screen of functional changes in endothelial stability in these same cells; a rapid in vivo tertiary screen of dermal microvascular leak in mice lacking endothelial Ccm2; and finally a quaternary screen of CCM lesion burden in these same mice. We screened 2,100 known drugs and bioactive compounds, and identified two candidates for further study, cholecalciferol (Vitamin D3) and tempol (a scavenger of superoxide). Each drug decreased lesion burden in a mouse model of CCM vascular disease by approximately 50%. Conclusions By identifying known drugs as potential therapeutics for CCM, we have decreased the time, cost, and risk of bringing treatments to patients. Each drug also prompts additional exploration of biomarkers of CCM disease. We further suggest that the structure-function screening platform presented here may be adapted and scaled to facilitate drug discovery for diverse loss-of-function genetic vascular disease. PMID:25486933

Oligo-Miocene foraminiferal record (Miogypsinidae, Lepidocyclinidae and Nummulitidae) from the Western Taurides (SW Turkey): Biometry and implications for the regional geology

NASA Astrophysics Data System (ADS)

Özcan, Ercan; Less, György; Báldi-Beke, Mária; Kollányi, Katalin; Acar, Ferhat

2009-05-01

The marine Oligo-Miocene units of western Taurides, deposited under different tectonic regimes (in Bey Dağları platform in foreland and coeval sequences in hinterland), were studied to establish a high-resolution biostratigraphic framework. Biometric study of the full spectrum of larger foraminifera in a regional scale allowed us correlating them with the shallow benthic zonation (SBZ) system introduced by [Cahuzac, B., Poignant, A., 1997. Essai de biozonation de l'Oligo-Miocène dans les bassins européens à l'aide des grands foraminifères néritiques. Bulletin de la Société géologique de France 168, 155-169], and to determine the ages of these sites on zonal precision for the first time. In correlating these assemblages to standard shallow benthic zones, planktonic data were also used whenever possible. Taxa, classified under the genera Nummulites, Miogypsina, Miolepidocyclina, Nephrolepidina, Eulepidina, Heterostegina, Operculina and Cycloclypeus (?) and their assemblages, closely resemble to the fauna described from European basins. These groups characterize the SBZ 22B to 25 zones referring to a time interval from early Chattian to Burdigalian. However, a main gap in late Chattian (SBZ 23) and in early part of the Aquitanian (SBZ 24) is also recorded in the platform succession. In the meantime, rare Eulepidina in the Burdigalian levels suggest a clear Indo-Pacific influence. Based on the discovery of early Chattian (SBZ 22B) deposits (previously mapped under Eocene/Miocene units), the Oligo-Miocene stratigraphy of the Bey Dağları platform is also revised. A more precise chronology for regional Miocene transgression is presented based on the miogypsinid evolutionary scale.

Utilizing Social Bookmarking Tag Space for Web Content Discovery: A Social Network Analysis Approach

ERIC Educational Resources Information Center

Wei, Wei

2010-01-01

Social bookmarking has gained popularity since the advent of Web 2.0. Keywords known as tags are created to annotate web content, and the resulting tag space composed of the tags, the resources, and the users arises as a new platform for web content discovery. Useful and interesting web resources can be located through searching and browsing based…

General view taken inside of an assembly bay of the ...

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

General view taken inside of an assembly bay of the Vehicle Assembly Building at the Kennedy Space Center. This view shows the Orbiter Discovery being lowered into position in preparation for being mated to the External Tank/Solid Rocket Booster assembly on the Mobile Launch Platform. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

SSWAP: A Simple Semantic Web Architecture and Protocol for semantic web services

PubMed Central

Gessler, Damian DG; Schiltz, Gary S; May, Greg D; Avraham, Shulamit; Town, Christopher D; Grant, David; Nelson, Rex T

2009-01-01

Background SSWAP (Simple Semantic Web Architecture and Protocol; pronounced "swap") is an architecture, protocol, and platform for using reasoning to semantically integrate heterogeneous disparate data and services on the web. SSWAP was developed as a hybrid semantic web services technology to overcome limitations found in both pure web service technologies and pure semantic web technologies. Results There are currently over 2400 resources published in SSWAP. Approximately two dozen are custom-written services for QTL (Quantitative Trait Loci) and mapping data for legumes and grasses (grains). The remaining are wrappers to Nucleic Acids Research Database and Web Server entries. As an architecture, SSWAP establishes how clients (users of data, services, and ontologies), providers (suppliers of data, services, and ontologies), and discovery servers (semantic search engines) interact to allow for the description, querying, discovery, invocation, and response of semantic web services. As a protocol, SSWAP provides the vocabulary and semantics to allow clients, providers, and discovery servers to engage in semantic web services. The protocol is based on the W3C-sanctioned first-order description logic language OWL DL. As an open source platform, a discovery server running at (as in to "swap info") uses the description logic reasoner Pellet to integrate semantic resources. The platform hosts an interactive guide to the protocol at , developer tools at , and a portal to third-party ontologies at (a "swap meet"). Conclusion SSWAP addresses the three basic requirements of a semantic web services architecture (i.e., a common syntax, shared semantic, and semantic discovery) while addressing three technology limitations common in distributed service systems: i.e., i) the fatal mutability of traditional interfaces, ii) the rigidity and fragility of static subsumption hierarchies, and iii) the confounding of content, structure, and presentation. SSWAP is novel by establishing the concept of a canonical yet mutable OWL DL graph that allows data and service providers to describe their resources, to allow discovery servers to offer semantically rich search engines, to allow clients to discover and invoke those resources, and to allow providers to respond with semantically tagged data. SSWAP allows for a mix-and-match of terms from both new and legacy third-party ontologies in these graphs. PMID:19775460

Modeling congenital disease and inborn errors of development in Drosophila melanogaster

PubMed Central

Moulton, Matthew J.; Letsou, Anthea

2016-01-01

ABSTRACT Fly models that faithfully recapitulate various aspects of human disease and human health-related biology are being used for research into disease diagnosis and prevention. Established and new genetic strategies in Drosophila have yielded numerous substantial successes in modeling congenital disorders or inborn errors of human development, as well as neurodegenerative disease and cancer. Moreover, although our ability to generate sequence datasets continues to outpace our ability to analyze these datasets, the development of high-throughput analysis platforms in Drosophila has provided access through the bottleneck in the identification of disease gene candidates. In this Review, we describe both the traditional and newer methods that are facilitating the incorporation of Drosophila into the human disease discovery process, with a focus on the models that have enhanced our understanding of human developmental disorders and congenital disease. Enviable features of the Drosophila experimental system, which make it particularly useful in facilitating the much anticipated move from genotype to phenotype (understanding and predicting phenotypes directly from the primary DNA sequence), include its genetic tractability, the low cost for high-throughput discovery, and a genome and underlying biology that are highly evolutionarily conserved. In embracing the fly in the human disease-gene discovery process, we can expect to speed up and reduce the cost of this process, allowing experimental scales that are not feasible and/or would be too costly in higher eukaryotes. PMID:26935104

Development of an Interferometric Phased Array Trigger for Balloon-Borne Detection of the Highest Energy Cosmic Particles

NASA Astrophysics Data System (ADS)

Vieregg, Abigail

Through high energy neutrino astrophysics, we explore the structure and evolution of the universe in a unique way and learn about the physics inside of astrophysical sources that drives the acceleration of the highest energy particles. Neutrinos travel virtually unimpeded through the universe, making them unique messenger particles for cosmic sources and carrying information about very distant sources that would otherwise be unavailable. The highest energy neutrinos (E>10^{18} eV), created as a by-product of the interaction of the highest energy cosmic rays with the cosmic microwave background, are an important tool for determining the origin of the highest energy cosmic rays and still await discovery. Balloon-borne and ground-based experiments are poised to discover these ultra-high energy (UHE) cosmogenic neutrinos by looking for radio emission from two different types of neutrino interactions: particle cascades induced by neutrinos in glacial ice, and extensive air showers in the atmosphere induced by the charged-particle by-product of tau neutrinos interacting in the earth. These impulsive radio detectors are also sensitive to radio emission from extensive air showers induced directly by UHE cosmic rays. Balloon-borne experiments are especially well-suited for discovering the highest energy neutrinos, and are the only way to probe the high energy cutoff of the sources themselves to reveal the astrophysics that drives the central engines inside the most energetic accelerators in the universe. Balloon platforms offer the chance to monitor extremely large volumes of ice and atmosphere, but with a higher energy threshold compared to ground-based observatories, since the neutrino interaction happens farther from the detector. This tradeoff means that the sensitivity of balloon-borne experiments, such as the Antarctic Impulsive Transient Antenna (ANITA) or the ExaVolt Antenna, is optimized for discovery of the highest energy neutrinos. We are developing an interferometric phased array trigger for these impulsive radio detectors, a new type of trigger that will improve sensitivity substantially and expedite the discovery of the highest energy particles in our universe. We have developed an 8- channel interferometric trigger board for ground-based applications that will be deployed in December 2017 with the ground-based Askaryan Radio Array (ARA) experiment at the South Pole. Preliminary Monte Carlo simulations indicate that the cosmogenic neutrino event rate will go up by a factor of 3 with the new trigger. The true power of the interferometric trigger is in scaling to large numbers of channels, and the discovery space that is only available from a balloon platform at the highest energies is extremely appealing. We will build on and extend the NASA investment in the ANITA Long Duration Balloon (LDB) mission and the many other complementary particle astrophysics LDB missions by developing the electronics required to bring a large-scale radio interferometric trigger to a balloon platform, extending the scientific reach of any future LDB or Super Pressure Balloon (SPB) mission for radio detection of the highest energy cosmic particles. We will develop an interferometric trigger system that is scalable to O(100) channels and suitable for use on a balloon platform. Under this proposal, we will: 1) Design and fabricate interferometric trigger hardware for balloon-borne cosmic particle detectors that is scalable to large numbers of channels O(100) by reducing the power consumption per channel, increasing the number of channels per board, and developing high-speed communication capability between boards. 2) Perform a trade study and inform design decisions for future balloon missions by further developing our Monte Carlo simulation and adapting it to balloon geometries.

Informatics for neglected diseases collaborations.

PubMed

Bost, Frederic; Jacobs, Robert T; Kowalczyk, Paul

2010-05-01

Many different public and private organizations from across the globe are collaborating on neglected diseases drug-discovery and development projects with the aim of identifying a cure for tropical infectious diseases. These neglected diseases collaborations require a global, secure, multi-organization data-management solution, combined with a platform that facilitates communication and supports collaborative work. This review discusses the solutions offered by 'Software as a Service' (SaaS) web-based platforms, despite notable challenges, and the evolution of these platforms required to foster efficient virtual research efforts by geographically dispersed scientists.

Cloud Computing for Protein-Ligand Binding Site Comparison

PubMed Central

2013-01-01

The proteome-wide analysis of protein-ligand binding sites and their interactions with ligands is important in structure-based drug design and in understanding ligand cross reactivity and toxicity. The well-known and commonly used software, SMAP, has been designed for 3D ligand binding site comparison and similarity searching of a structural proteome. SMAP can also predict drug side effects and reassign existing drugs to new indications. However, the computing scale of SMAP is limited. We have developed a high availability, high performance system that expands the comparison scale of SMAP. This cloud computing service, called Cloud-PLBS, combines the SMAP and Hadoop frameworks and is deployed on a virtual cloud computing platform. To handle the vast amount of experimental data on protein-ligand binding site pairs, Cloud-PLBS exploits the MapReduce paradigm as a management and parallelizing tool. Cloud-PLBS provides a web portal and scalability through which biologists can address a wide range of computer-intensive questions in biology and drug discovery. PMID:23762824

Cloud computing for protein-ligand binding site comparison.

PubMed

Hung, Che-Lun; Hua, Guan-Jie

2013-01-01

The proteome-wide analysis of protein-ligand binding sites and their interactions with ligands is important in structure-based drug design and in understanding ligand cross reactivity and toxicity. The well-known and commonly used software, SMAP, has been designed for 3D ligand binding site comparison and similarity searching of a structural proteome. SMAP can also predict drug side effects and reassign existing drugs to new indications. However, the computing scale of SMAP is limited. We have developed a high availability, high performance system that expands the comparison scale of SMAP. This cloud computing service, called Cloud-PLBS, combines the SMAP and Hadoop frameworks and is deployed on a virtual cloud computing platform. To handle the vast amount of experimental data on protein-ligand binding site pairs, Cloud-PLBS exploits the MapReduce paradigm as a management and parallelizing tool. Cloud-PLBS provides a web portal and scalability through which biologists can address a wide range of computer-intensive questions in biology and drug discovery.

High content screening in microfluidic devices

PubMed Central

Cheong, Raymond; Paliwal, Saurabh; Levchenko, Andre

2011-01-01

Importance of the field Miniaturization is key to advancing the state-of-the-art in high content screening (HCS), in order to enable dramatic cost savings through reduced usage of expensive biochemical reagents and to enable large-scale screening on primary cells. Microfluidic technology offers the potential to enable HCS to be performed with an unprecedented degree of miniaturization. Areas covered in this review This perspective highlights a real-world example from the authors’ work of HCS assays implemented in a highly miniaturized microfluidic format. Advantages of this technology are discussed, including cost savings, high throughput screening on primary cells, improved accuracy, the ability to study complex time-varying stimuli, and ease of automation, integration, and scaling. What the reader will gain The reader will understand the capabilities of a new microfluidics-based platform for HCS, and the advantages it provides over conventional plate-based HCS. Take home message Microfluidics technology will drive significant advancements and broader usage and applicability of HCS in drug discovery. PMID:21852997

STS-95 Space Shuttle Discovery rollout to Launch Pad 39B

NASA Technical Reports Server (NTRS)

1998-01-01

As daylight creeps over the horizon, STS-95 Space Shuttle Discovery, on the Mobile Launch Platform, arrives at Launch Complex Pad 39B after a 4.2-mile trip taking approximately 6 hours. At the left is the 'white room,' attached to the orbiter access arm. The white room is an environmental chamber that mates with the orbiter and holds six persons. At the launch pad, the orbiter, external tank and solid rocket boosters will undergo final preparations for the launch, scheduled to lift off Oct. 29. The mission includes research payloads such as the Spartan solar- observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process.

KENNEDY SPACE CENTER, FLA. - STS-114 Mission Specialist Soichi Noguchi looks at tile on the underside of the orbiter Discovery. Noguchi is with the Japanese Aerospace and Exploration Agency. He and other crew members are at KSC becoming familiar with Shuttle and mission equipment. The mission is Logistics Flight 1, which is scheduled to deliver supplies and equipment plus the external stowage platform to the International Space Station.

NASA Image and Video Library

2004-03-05

KENNEDY SPACE CENTER, FLA. - STS-114 Mission Specialist Soichi Noguchi looks at tile on the underside of the orbiter Discovery. Noguchi is with the Japanese Aerospace and Exploration Agency. He and other crew members are at KSC becoming familiar with Shuttle and mission equipment. The mission is Logistics Flight 1, which is scheduled to deliver supplies and equipment plus the external stowage platform to the International Space Station.

KSC-98pc1179

NASA Image and Video Library

1998-09-28

KENNEDY SPACE CENTER, FLA. -- At left, the payload canister for Space Shuttle Discovery is lifted from its canister movement vehicle to the top of the Rotating Service Structure on Launch Pad 39-B. Discovery (right), sitting atop the Mobile Launch Platform and next to the Fixed Service Structure (FSS), is scheduled for launch on Oct. 29, 1998, for the STS-95 mission. That mission includes the International Extreme Ultraviolet Hitchhiker (IEH-3), the Hubble Space Telescope Orbital Systems Test Platform, the Spartan solar-observing deployable spacecraft, and the SPACEHAB single module with experiments on space flight and the aging process. At the top of the FSS can be seen the 80-foot lightning mast . The 4-foot-high lightning rod on top helps prevent lightning current from passing directly through the Space Shuttle and the structures on the pad

Chemical screening platforms for autophagy drug discovery to identify therapeutic candidates for Huntington's disease and other neurodegenerative disorders.

PubMed

Sarkar, Sovan

2013-01-01

Autophagy is a cellular degradation process involved in the clearance of aggregate-prone proteins associated with neurodegenerative diseases. While the mTOR pathway has been known to be the major regulator of autophagy, recent advancements into the regulation of autophagy have identified mTOR-independent autophagy pathways that are amenable to chemical perturbations. Several chemical and genetic screens have been undertaken to identify small molecule and genetic regulators of autophagy, respectively. The small molecule autophagy enhancers offer great potential as therapeutic candidates not only for neurodegenerative diseases, but also for diverse human diseases where autophagy acts as a protective pathway. This review highlights the various chemical screening platforms for autophagy drug discovery pertinent for the treatment of neurodegenerative diseases.

Drugs for Neglected Diseases initiative model of drug development for neglected diseases: current status and future challenges.

PubMed

Ioset, Jean-Robert; Chang, Shing

2011-09-01

The Drugs for Neglected Diseases initiative (DNDi) is a patients' needs-driven organization committed to the development of new treatments for neglected diseases. Created in 2003, DNDi has delivered four improved treatments for malaria, sleeping sickness and visceral leishmaniasis. A main DNDi challenge is to build a solid R&D portfolio for neglected diseases and to deliver preclinical candidates in a timely manner using an original model based on partnership. To address this challenge DNDi has remodeled its discovery activities from a project-based academic-bound network to a fully integrated process-oriented platform in close collaboration with pharmaceutical companies. This discovery platform relies on dedicated screening capacity and lead-optimization consortia supported by a pragmatic, structured and pharmaceutical-focused compound sourcing strategy.

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

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

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

GWATCH: a web platform for automated gene association discovery analysis.

PubMed

Svitin, Anton; Malov, Sergey; Cherkasov, Nikolay; Geerts, Paul; Rotkevich, Mikhail; Dobrynin, Pavel; Shevchenko, Andrey; Guan, Li; Troyer, Jennifer; Hendrickson, Sher; Dilks, Holli Hutcheson; Oleksyk, Taras K; Donfield, Sharyne; Gomperts, Edward; Jabs, Douglas A; Sezgin, Efe; Van Natta, Mark; Harrigan, P Richard; Brumme, Zabrina L; O'Brien, Stephen J

2014-01-01

As genome-wide sequence analyses for complex human disease determinants are expanding, it is increasingly necessary to develop strategies to promote discovery and validation of potential disease-gene associations. Here we present a dynamic web-based platform - GWATCH - that automates and facilitates four steps in genetic epidemiological discovery: 1) Rapid gene association search and discovery analysis of large genome-wide datasets; 2) Expanded visual display of gene associations for genome-wide variants (SNPs, indels, CNVs), including Manhattan plots, 2D and 3D snapshots of any gene region, and a dynamic genome browser illustrating gene association chromosomal regions; 3) Real-time validation/replication of candidate or putative genes suggested from other sources, limiting Bonferroni genome-wide association study (GWAS) penalties; 4) Open data release and sharing by eliminating privacy constraints (The National Human Genome Research Institute (NHGRI) Institutional Review Board (IRB), informed consent, The Health Insurance Portability and Accountability Act (HIPAA) of 1996 etc.) on unabridged results, which allows for open access comparative and meta-analysis. GWATCH is suitable for both GWAS and whole genome sequence association datasets. We illustrate the utility of GWATCH with three large genome-wide association studies for HIV-AIDS resistance genes screened in large multicenter cohorts; however, association datasets from any study can be uploaded and analyzed by GWATCH.

KSC-2009-4425

NASA Image and Video Library

2009-08-04

CAPE CANAVERAL, Fla. – Sitting on top of the mobile launcher platform, space shuttle Discovery straddles the flame trench, which channels the flames and smoke exhaust of the shuttle's solid rocket boosters away from the space shuttle during liftoff, on Launch Pad 39A at NASA's Kennedy Space Center in Florida. Traveling from the Vehicle Assembly Building, the shuttle took nearly 12 hours on the journey as technicians stopped several times to clear mud from the crawler's treads and bearings caused by the waterlogged crawlerway. First motion out of the VAB was at 2:07 a.m. EDT Aug. 4. Rollout was delayed approximately 2 hours due to lightning in the area. Discovery was secured, or "hard down" to Launch Pad 39A at 1:50 p.m. EDT. "Hard down" means that the mobile launcher platform, or MLP, is sitting on the pedestals on the pad, and the crawler has been jacked down, thus transferring the weight of the MLP from the crawler to the pad pedestals. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the International Space Station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for late August. Photo credit: NASA/Troy Cryder

SpirPep: an in silico digestion-based platform to assist bioactive peptides discovery from a genome-wide database.

PubMed

Anekthanakul, Krittima; Hongsthong, Apiradee; Senachak, Jittisak; Ruengjitchatchawalya, Marasri

2018-04-20

Bioactive peptides, including biological sources-derived peptides with different biological activities, are protein fragments that influence the functions or conditions of organisms, in particular humans and animals. Conventional methods of identifying bioactive peptides are time-consuming and costly. To quicken the processes, several bioinformatics tools are recently used to facilitate screening of the potential peptides prior their activity assessment in vitro and/or in vivo. In this study, we developed an efficient computational method, SpirPep, which offers many advantages over the currently available tools. The SpirPep web application tool is a one-stop analysis and visualization facility to assist bioactive peptide discovery. The tool is equipped with 15 customized enzymes and 1-3 miscleavage options, which allows in silico digestion of protein sequences encoded by protein-coding genes from single, multiple, or genome-wide scaling, and then directly classifies the peptides by bioactivity using an in-house database that contains bioactive peptides collected from 13 public databases. With this tool, the resulting peptides are categorized by each selected enzyme, and shown in a tabular format where the peptide sequences can be tracked back to their original proteins. The developed tool and webpages are coded in PHP and HTML with CSS/JavaScript. Moreover, the tool allows protein-peptide alignment visualization by Generic Genome Browser (GBrowse) to display the region and details of the proteins and peptides within each parameter, while considering digestion design for the desirable bioactivity. SpirPep is efficient; it takes less than 20 min to digest 3000 proteins (751,860 amino acids) with 15 enzymes and three miscleavages for each enzyme, and only a few seconds for single enzyme digestion. Obviously, the tool identified more bioactive peptides than that of the benchmarked tool; an example of validated pentapeptide (FLPIL) from LC-MS/MS was demonstrated. The web and database server are available at http://spirpepapp.sbi.kmutt.ac.th . SpirPep, a web-based bioactive peptide discovery application, is an in silico-based tool with an overview of the results. The platform is a one-stop analysis and visualization facility; and offers advantages over the currently available tools. This tool may be useful for further bioactivity analysis and the quantitative discovery of desirable peptides.

The MaxQuant computational platform for mass spectrometry-based shotgun proteomics.

PubMed

Tyanova, Stefka; Temu, Tikira; Cox, Juergen

2016-12-01

MaxQuant is one of the most frequently used platforms for mass-spectrometry (MS)-based proteomics data analysis. Since its first release in 2008, it has grown substantially in functionality and can be used in conjunction with more MS platforms. Here we present an updated protocol covering the most important basic computational workflows, including those designed for quantitative label-free proteomics, MS1-level labeling and isobaric labeling techniques. This protocol presents a complete description of the parameters used in MaxQuant, as well as of the configuration options of its integrated search engine, Andromeda. This protocol update describes an adaptation of an existing protocol that substantially modifies the technique. Important concepts of shotgun proteomics and their implementation in MaxQuant are briefly reviewed, including different quantification strategies and the control of false-discovery rates (FDRs), as well as the analysis of post-translational modifications (PTMs). The MaxQuant output tables, which contain information about quantification of proteins and PTMs, are explained in detail. Furthermore, we provide a short version of the workflow that is applicable to data sets with simple and standard experimental designs. The MaxQuant algorithms are efficiently parallelized on multiple processors and scale well from desktop computers to servers with many cores. The software is written in C# and is freely available at http://www.maxquant.org.

Teach-Discover-Treat (TDT): Collaborative Computational Drug Discovery for Neglected Diseases

PubMed Central

Jansen, Johanna M.; Cornell, Wendy; Tseng, Y. Jane; Amaro, Rommie E.

2012-01-01

Teach – Discover – Treat (TDT) is an initiative to promote the development and sharing of computational tools solicited through a competition with the aim to impact education and collaborative drug discovery for neglected diseases. Collaboration, multidisciplinary integration, and innovation are essential for successful drug discovery. This requires a workforce that is trained in state-of-the-art workflows and equipped with the ability to collaborate on platforms that are accessible and free. The TDT competition solicits high quality computational workflows for neglected disease targets, using freely available, open access tools. PMID:23085175

An introduction to web scale discovery systems.

PubMed

Hoy, Matthew B

2012-01-01

This article explores the basic principles of web-scale discovery systems and how they are being implemented in libraries. "Web scale discovery" refers to a class of products that index a vast number of resources in a wide variety formats and allow users to search for content in the physical collection, print and electronic journal collections, and other resources from a single search box. Search results are displayed in a manner similar to Internet searches, in a relevance ranked list with links to online content. The advantages and disadvantages of these systems are discussed, and a list of popular discovery products is provided. A list of library websites with discovery systems currently implemented is also provided.

Bringing your tools to CyVerse Discovery Environment using Docker

PubMed Central

Devisetty, Upendra Kumar; Kennedy, Kathleen; Sarando, Paul; Merchant, Nirav; Lyons, Eric

2016-01-01

Docker has become a very popular container-based virtualization platform for software distribution that has revolutionized the way in which scientific software and software dependencies (software stacks) can be packaged, distributed, and deployed. Docker makes the complex and time-consuming installation procedures needed for scientific software a one-time process. Because it enables platform-independent installation, versioning of software environments, and easy redeployment and reproducibility, Docker is an ideal candidate for the deployment of identical software stacks on different compute environments such as XSEDE and Amazon AWS. CyVerse’s Discovery Environment also uses Docker for integrating its powerful, community-recommended software tools into CyVerse’s production environment for public use. This paper will help users bring their tools into CyVerse Discovery Environment (DE) which will not only allows users to integrate their tools with relative ease compared to the earlier method of tool deployment in DE but will also help users to share their apps with collaborators and release them for public use. PMID:27803802

Bringing your tools to CyVerse Discovery Environment using Docker.

PubMed

Devisetty, Upendra Kumar; Kennedy, Kathleen; Sarando, Paul; Merchant, Nirav; Lyons, Eric

2016-01-01

Docker has become a very popular container-based virtualization platform for software distribution that has revolutionized the way in which scientific software and software dependencies (software stacks) can be packaged, distributed, and deployed. Docker makes the complex and time-consuming installation procedures needed for scientific software a one-time process. Because it enables platform-independent installation, versioning of software environments, and easy redeployment and reproducibility, Docker is an ideal candidate for the deployment of identical software stacks on different compute environments such as XSEDE and Amazon AWS. CyVerse's Discovery Environment also uses Docker for integrating its powerful, community-recommended software tools into CyVerse's production environment for public use. This paper will help users bring their tools into CyVerse Discovery Environment (DE) which will not only allows users to integrate their tools with relative ease compared to the earlier method of tool deployment in DE but will also help users to share their apps with collaborators and release them for public use.

VOLTTRON™: An Agent Platform for Integrating Electric Vehicles and Smart Grid

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

Haack, Jereme N.; Akyol, Bora A.; Tenney, Nathan D.

2013-12-06

The VOLTTRON™ platform provides a secure environment for the deployment of intelligent applications in the smart grid. VOLTTRON design is based on the needs of control applications running on small form factor devices, namely security and resource guarantees. Services such as resource discovery, secure agent mobility, and interacting with smart and legacy devices are provided by the platform to ease the development of control applications and accelerate their deployment. VOLTTRON platform has been demonstrated in several different domains that influenced and enhanced its capabilities. This paper will discuss the features of VOLTTRON and highlight its usage to coordinate electric vehiclemore » charging with home energy usage« less

Discovery of Regulators of Receptor Internalization with High-Throughput Flow Cytometry

PubMed Central

Tapia, Phillip H.; Fisher, Gregory W.; Simons, Peter C.; Strouse, J. Jacob; Foutz, Terry; Waggoner, Alan S.; Jarvik, Jonathan; Sklar, Larry A.

2012-01-01

We developed a platform combining fluorogen-activating protein (FAP) technology with high-throughput flow cytometry to detect real-time protein trafficking to and from the plasma membrane in living cells. The hybrid platform facilitates drug discovery for trafficking receptors such as G protein-coupled receptors and was validated with the β2-adrenergic receptor (β2AR) system. When a chemical library containing ∼1200 off-patent drugs was screened against cells expressing FAP-tagged β2ARs, all 33 known β2AR-active ligands in the library were successfully identified, together with a number of compounds that might regulate receptor internalization in a nontraditional manner. Results indicated that the platform identified ligands of target proteins regardless of the associated signaling pathway; therefore, this approach presents opportunities to search for biased receptor modulators and is suitable for screening of multiplexed targets for improved efficiency. The results revealed that ligands may be biased with respect to the rate or duration of receptor internalization and that receptor internalization may be independent of activation of the mitogen-activated protein kinase pathway. PMID:22767611

A novel in silico approach to drug discovery via computational intelligence.

PubMed

Hecht, David; Fogel, Gary B

2009-04-01

A computational intelligence drug discovery platform is introduced as an innovative technology designed to accelerate high-throughput drug screening for generalized protein-targeted drug discovery. This technology results in collections of novel small molecule compounds that bind to protein targets as well as details on predicted binding modes and molecular interactions. The approach was tested on dihydrofolate reductase (DHFR) for novel antimalarial drug discovery; however, the methods developed can be applied broadly in early stage drug discovery and development. For this purpose, an initial fragment library was defined, and an automated fragment assembly algorithm was generated. These were combined with a computational intelligence screening tool for prescreening of compounds relative to DHFR inhibition. The entire method was assayed relative to spaces of known DHFR inhibitors and with chemical feasibility in mind, leading to experimental validation in future studies.

Discovery of extra-terrestrial life: assessment by scales of its importance and associated risks.

PubMed

Almár, Iván; Race, Margaret S

2011-02-13

The Rio Scale accepted by the SETI Committee of the International Academy of Astronautics in 2002 is intended for use in evaluating the impact on society of any announcement regarding the discovery of evidence of extra-terrestrial (ET) intelligence. The Rio Scale is mathematically defined using three parameters (class of phenomenon, type of discovery and distance) and a δ factor, the assumed credibility of a claim. This paper proposes a new scale applicable to announcements alleging evidence of ET life within or outside our Solar System. The London Scale for astrobiology has mathematical structure and logic similar to the Rio Scale, and uses four parameters (life form, nature of phenomenon, type of discovery and distance) as well as a credibility factor δ to calculate a London Scale index (LSI) with values ranging from 0 to 10. The level of risk or biohazard associated with a purported discovery is evaluated independently of the LSI value and may be ranked in four categories. The combined information is intended to provide a scalar assessment of the scientific importance, validity and potential risks associated with putative evidence of ET life discovered on Earth, on nearby bodies in the Solar System or in our Galaxy.

High-Throughput Nano-Biofilm Microarray for Antifungal Drug Discovery

DTIC Science & Technology

2013-06-25

High-Throughput Nano-Biofilm Microarray for Antifungal Drug Discovery Anand Srinivasan,a, c Kai P. Leung,d Jose L. Lopez-Ribot,b, c Anand K...Ramasubramaniana, c Departments of Biomedical Engineeringa and Biologyb and South Texas Center for Emerging Infectious Diseases, c The University of Texas at San...of the opportunistic fungal pathogen Candida albicans on a microarray platform. The mi- croarray consists of 1,200 individual cultures of 30 nl of C

Detail view of the forward section, port side, of the ...

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

Detail view of the forward section, port side, of the Orbiter Discovery from an elevated platform in the Vehicle Assembly Building at NASA's Kennedy Space Center. Note the removal of the Forward Reaction Control System Module from the nose section, the ground-support window covers and the strongback attached to the payload bay door. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Closeup view of a Space Shuttle Main Engine (SSME) installed ...

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

Close-up view of a Space Shuttle Main Engine (SSME) installed in position number one on the Orbiter Discovery. A ground-support mobile platform is in place below the engine to assist in technicians with the installation of the engine. This Photograph was taken in the Orbiter Processing Facility at the Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

WHAM!: a web-based visualization suite for user-defined analysis of metagenomic shotgun sequencing data.

PubMed

Devlin, Joseph C; Battaglia, Thomas; Blaser, Martin J; Ruggles, Kelly V

2018-06-25

Exploration of large data sets, such as shotgun metagenomic sequence or expression data, by biomedical experts and medical professionals remains as a major bottleneck in the scientific discovery process. Although tools for this purpose exist for 16S ribosomal RNA sequencing analysis, there is a growing but still insufficient number of user-friendly interactive visualization workflows for easy data exploration and figure generation. The development of such platforms for this purpose is necessary to accelerate and streamline microbiome laboratory research. We developed the Workflow Hub for Automated Metagenomic Exploration (WHAM!) as a web-based interactive tool capable of user-directed data visualization and statistical analysis of annotated shotgun metagenomic and metatranscriptomic data sets. WHAM! includes exploratory and hypothesis-based gene and taxa search modules for visualizing differences in microbial taxa and gene family expression across experimental groups, and for creating publication quality figures without the need for command line interface or in-house bioinformatics. WHAM! is an interactive and customizable tool for downstream metagenomic and metatranscriptomic analysis providing a user-friendly interface allowing for easy data exploration by microbiome and ecological experts to facilitate discovery in multi-dimensional and large-scale data sets.

Genetically programmed chiral organoborane synthesis

NASA Astrophysics Data System (ADS)

Kan, S. B. Jennifer; Huang, Xiongyi; Gumulya, Yosephine; Chen, Kai; Arnold, Frances H.

2017-12-01

Recent advances in enzyme engineering and design have expanded nature’s catalytic repertoire to functions that are new to biology. However, only a subset of these engineered enzymes can function in living systems. Finding enzymatic pathways that form chemical bonds that are not found in biology is particularly difficult in the cellular environment, as this depends on the discovery not only of new enzyme activities, but also of reagents that are both sufficiently reactive for the desired transformation and stable in vivo. Here we report the discovery, evolution and generalization of a fully genetically encoded platform for producing chiral organoboranes in bacteria. Escherichia coli cells harbouring wild-type cytochrome c from Rhodothermus marinus (Rma cyt c) were found to form carbon-boron bonds in the presence of borane-Lewis base complexes, through carbene insertion into boron-hydrogen bonds. Directed evolution of Rma cyt c in the bacterial catalyst provided access to 16 novel chiral organoboranes. The catalyst is suitable for gram-scale biosynthesis, providing up to 15,300 turnovers, a turnover frequency of 6,100 h-1, a 99:1 enantiomeric ratio and 100% chemoselectivity. The enantiopreference of the biocatalyst could also be tuned to provide either enantiomer of the organoborane products. Evolved in the context of whole-cell catalysts, the proteins were more active in the whole-cell system than in purified forms. This study establishes a DNA-encoded and readily engineered bacterial platform for borylation; engineering can be accomplished at a pace that rivals the development of chemical synthetic methods, with the ability to achieve turnovers that are two orders of magnitude (over 400-fold) greater than those of known chiral catalysts for the same class of transformation. This tunable method for manipulating boron in cells could expand the scope of boron chemistry in living systems.

IMG-ABC. A knowledge base to fuel discovery of biosynthetic gene clusters and novel secondary metabolites

DOE PAGES

Hadjithomas, Michalis; Chen, I-Min Amy; Chu, Ken; ...

2015-07-14

In the discovery of secondary metabolites, analysis of sequence data is a promising exploration path that remains largely underutilized due to the lack of computational platforms that enable such a systematic approach on a large scale. In this work, we present IMG-ABC (https://img.jgi.doe.gov/abc), an atlas of biosynthetic gene clusters within the Integrated Microbial Genomes (IMG) system, which is aimed at harnessing the power of “big” genomic data for discovering small molecules. IMG-ABC relies on IMG’s comprehensive integrated structural and functional genomic data for the analysis of biosynthetic gene clusters (BCs) and associated secondary metabolites (SMs). SMs and BCs serve asmore » the two main classes of objects in IMG-ABC, each with a rich collection of attributes. A unique feature of IMG-ABC is the incorporation of both experimentally validated and computationally predicted BCs in genomes as well as metagenomes, thus identifying BCs in uncultured populations and rare taxa. We demonstrate the strength of IMG-ABC’s focused integrated analysis tools in enabling the exploration of microbial secondary metabolism on a global scale, through the discovery of phenazine-producing clusters for the first time in lphaproteobacteria. IMG-ABC strives to fill the long-existent void of resources for computational exploration of the secondary metabolism universe; its underlying scalable framework enables traversal of uncovered phylogenetic and chemical structure space, serving as a doorway to a new era in the discovery of novel molecules. IMG-ABC is the largest publicly available database of predicted and experimental biosynthetic gene clusters and the secondary metabolites they produce. The system also includes powerful search and analysis tools that are integrated with IMG’s extensive genomic/metagenomic data and analysis tool kits. As new research on biosynthetic gene clusters and secondary metabolites is published and more genomes are sequenced, IMG-ABC will continue to expand, with the goal of becoming an essential component of any bioinformatic exploration of the secondary metabolism world.« less

Remembering Professor Benito Casu (1927-2016).

PubMed

Torri, Giangiacomo; Cassinelli, Giuseppe

2018-01-31

Heparin and related drugs have contributed in so many different ways to the drug discovery process, and have provided a platform to understand the pathophysiology of vascular and inflammatory diseases for nearly 100 years.

KENNEDY SPACE CENTER, FLA. - STS-114 Commander Eileen Collins and Mission Specialists Charles Camarda and Soichi Noguchi sit outside the crew hatch on the orbiter Discovery. Noguchi is with the Japanese Aerospace and Exploration Agency. They and other crew members are at KSC becoming familiar with Shuttle and mission equipment. The mission is Logistics Flight 1, which is scheduled to deliver supplies and equipment plus the external stowage platform to the International Space Station.

NASA Image and Video Library

2004-03-05

KENNEDY SPACE CENTER, FLA. - STS-114 Commander Eileen Collins and Mission Specialists Charles Camarda and Soichi Noguchi sit outside the crew hatch on the orbiter Discovery. Noguchi is with the Japanese Aerospace and Exploration Agency. They and other crew members are at KSC becoming familiar with Shuttle and mission equipment. The mission is Logistics Flight 1, which is scheduled to deliver supplies and equipment plus the external stowage platform to the International Space Station.

PCM-SABRE: a platform for benchmarking and comparing outcome prediction methods in precision cancer medicine.

PubMed

Eyal-Altman, Noah; Last, Mark; Rubin, Eitan

2017-01-17

Numerous publications attempt to predict cancer survival outcome from gene expression data using machine-learning methods. A direct comparison of these works is challenging for the following reasons: (1) inconsistent measures used to evaluate the performance of different models, and (2) incomplete specification of critical stages in the process of knowledge discovery. There is a need for a platform that would allow researchers to replicate previous works and to test the impact of changes in the knowledge discovery process on the accuracy of the induced models. We developed the PCM-SABRE platform, which supports the entire knowledge discovery process for cancer outcome analysis. PCM-SABRE was developed using KNIME. By using PCM-SABRE to reproduce the results of previously published works on breast cancer survival, we define a baseline for evaluating future attempts to predict cancer outcome with machine learning. We used PCM-SABRE to replicate previous work that describe predictive models of breast cancer recurrence, and tested the performance of all possible combinations of feature selection methods and data mining algorithms that was used in either of the works. We reconstructed the work of Chou et al. observing similar trends - superior performance of Probabilistic Neural Network (PNN) and logistic regression (LR) algorithms and inconclusive impact of feature pre-selection with the decision tree algorithm on subsequent analysis. PCM-SABRE is a software tool that provides an intuitive environment for rapid development of predictive models in cancer precision medicine.

Ocean Data Interoperability Platform (ODIP): Developing a Common Framework for Marine Data Management on a Global Scale

NASA Astrophysics Data System (ADS)

Glaves, H. M.; Schaap, D.

2014-12-01

As marine research becomes increasingly multidisciplinary in its approach there has been a corresponding rise in the demand for large quantities of high quality interoperable data. A number of regional initiatives are already addressing this requirement through the establishment of e-infrastructures to improve the discovery and access of marine data. Projects such as Geo-Seas and SeaDataNet in Europe, Rolling Deck to Repository (R2R) in the USA and IMOS in Australia have implemented local infrastructures to facilitate the exchange of standardised marine datasets. However, each of these regional initiatives has been developed to address their own requirements and independently of other regions. To establish a common framework for marine data management on a global scale these is a need to develop interoperability solutions that can be implemented across these initiatives.Through a series of workshops attended by the relevant domain specialists, the Ocean Data Interoperability Platform (ODIP) project has identified areas of commonality between the regional infrastructures and used these as the foundation for the development of three prototype interoperability solutions addressing: the use of brokering services for the purposes of providing access to the data available in the regional data discovery and access services including via the GEOSS portal the development of interoperability between cruise summary reporting systems in Europe, the USA and Australia for routine harvesting of cruise data for delivery via the Partnership for Observation of Global Oceans (POGO) portal the establishment of a Sensor Observation Service (SOS) for selected sensors installed on vessels and in real-time monitoring systems using sensor web enablement (SWE) These prototypes will be used to underpin the development of a common global approach to the management of marine data which can be promoted to the wider marine research community. ODIP is a community lead project that is currently focussed on regional initiatives in Europe, the USA and Australia but which is seeking to expand this framework to include other regional marine data infrastructures.

SSWAP: A Simple Semantic Web Architecture and Protocol for semantic web services.

PubMed

Gessler, Damian D G; Schiltz, Gary S; May, Greg D; Avraham, Shulamit; Town, Christopher D; Grant, David; Nelson, Rex T

2009-09-23

SSWAP (Simple Semantic Web Architecture and Protocol; pronounced "swap") is an architecture, protocol, and platform for using reasoning to semantically integrate heterogeneous disparate data and services on the web. SSWAP was developed as a hybrid semantic web services technology to overcome limitations found in both pure web service technologies and pure semantic web technologies. There are currently over 2400 resources published in SSWAP. Approximately two dozen are custom-written services for QTL (Quantitative Trait Loci) and mapping data for legumes and grasses (grains). The remaining are wrappers to Nucleic Acids Research Database and Web Server entries. As an architecture, SSWAP establishes how clients (users of data, services, and ontologies), providers (suppliers of data, services, and ontologies), and discovery servers (semantic search engines) interact to allow for the description, querying, discovery, invocation, and response of semantic web services. As a protocol, SSWAP provides the vocabulary and semantics to allow clients, providers, and discovery servers to engage in semantic web services. The protocol is based on the W3C-sanctioned first-order description logic language OWL DL. As an open source platform, a discovery server running at http://sswap.info (as in to "swap info") uses the description logic reasoner Pellet to integrate semantic resources. The platform hosts an interactive guide to the protocol at http://sswap.info/protocol.jsp, developer tools at http://sswap.info/developer.jsp, and a portal to third-party ontologies at http://sswapmeet.sswap.info (a "swap meet"). SSWAP addresses the three basic requirements of a semantic web services architecture (i.e., a common syntax, shared semantic, and semantic discovery) while addressing three technology limitations common in distributed service systems: i.e., i) the fatal mutability of traditional interfaces, ii) the rigidity and fragility of static subsumption hierarchies, and iii) the confounding of content, structure, and presentation. SSWAP is novel by establishing the concept of a canonical yet mutable OWL DL graph that allows data and service providers to describe their resources, to allow discovery servers to offer semantically rich search engines, to allow clients to discover and invoke those resources, and to allow providers to respond with semantically tagged data. SSWAP allows for a mix-and-match of terms from both new and legacy third-party ontologies in these graphs.

Gathering and Exploring Scientific Knowledge in Pharmacovigilance

PubMed Central

Lopes, Pedro; Nunes, Tiago; Campos, David; Furlong, Laura Ines; Bauer-Mehren, Anna; Sanz, Ferran; Carrascosa, Maria Carmen; Mestres, Jordi; Kors, Jan; Singh, Bharat; van Mulligen, Erik; Van der Lei, Johan; Diallo, Gayo; Avillach, Paul; Ahlberg, Ernst; Boyer, Scott; Diaz, Carlos; Oliveira, José Luís

2013-01-01

Pharmacovigilance plays a key role in the healthcare domain through the assessment, monitoring and discovery of interactions amongst drugs and their effects in the human organism. However, technological advances in this field have been slowing down over the last decade due to miscellaneous legal, ethical and methodological constraints. Pharmaceutical companies started to realize that collaborative and integrative approaches boost current drug research and development processes. Hence, new strategies are required to connect researchers, datasets, biomedical knowledge and analysis algorithms, allowing them to fully exploit the true value behind state-of-the-art pharmacovigilance efforts. This manuscript introduces a new platform directed towards pharmacovigilance knowledge providers. This system, based on a service-oriented architecture, adopts a plugin-based approach to solve fundamental pharmacovigilance software challenges. With the wealth of collected clinical and pharmaceutical data, it is now possible to connect knowledge providers’ analysis and exploration algorithms with real data. As a result, new strategies allow a faster identification of high-risk interactions between marketed drugs and adverse events, and enable the automated uncovering of scientific evidence behind them. With this architecture, the pharmacovigilance field has a new platform to coordinate large-scale drug evaluation efforts in a unique ecosystem, publicly available at http://bioinformatics.ua.pt/euadr/. PMID:24349421

Geospatial Data as a Service: Towards planetary scale real-time analytics

NASA Astrophysics Data System (ADS)

Evans, B. J. K.; Larraondo, P. R.; Antony, J.; Richards, C. J.

2017-12-01

The rapid growth of earth systems, environmental and geophysical datasets poses a challenge to both end-users and infrastructure providers. For infrastructure and data providers, tasks like managing, indexing and storing large collections of geospatial data needs to take into consideration the various use cases by which consumers will want to access and use the data. Considerable investment has been made by the Earth Science community to produce suitable real-time analytics platforms for geospatial data. There are currently different interfaces that have been defined to provide data services. Unfortunately, there is considerable difference on the standards, protocols or data models which have been designed to target specific communities or working groups. The Australian National University's National Computational Infrastructure (NCI) is used for a wide range of activities in the geospatial community. Earth observations, climate and weather forecasting are examples of these communities which generate large amounts of geospatial data. The NCI has been carrying out significant effort to develop a data and services model that enables the cross-disciplinary use of data. Recent developments in cloud and distributed computing provide a publicly accessible platform where new infrastructures can be built. One of the key components these technologies offer is the possibility of having "limitless" compute power next to where the data is stored. This model is rapidly transforming data delivery from centralised monolithic services towards ubiquitous distributed services that scale up and down adapting to fluctuations in the demand. NCI has developed GSKY, a scalable, distributed server which presents a new approach for geospatial data discovery and delivery based on OGC standards. We will present the architecture and motivating use-cases that drove GSKY's collaborative design, development and production deployment. We show our approach offers the community valuable exploratory analysis capabilities, for dealing with petabyte-scale geospatial data collections.

KSC01padig075

NASA Image and Video Library

2001-02-12

KENNEDY SPACE CENTER, Fla. -- As Space Shuttle Discovery, on its Mobile Launcher Platform, nears Launch Pad 39B, fog rolls over the top of the external tank and solid rocket boosters. Discovery will be flying on mission STS-102 to the International Space Station. Its payload is the Multi-Purpose Logistics Module Leonardo, a “moving van,” to carry laboratory racks filled with equipment, experiments and supplies to and from the Space Station aboard the Space Shuttle. The flight will also carry the Expedition Two crew up to the Space Station, replacing Expedition One, who will return to Earth on Discovery. Launch is scheduled for March 8 at 6:45 a.m. EST

KSC-05PD-1077

NASA Technical Reports Server (NTRS)

2005-01-01

KENNEDY SPACE CENTER, FLA. At Launch Complex 39B, technicians construct a platform in Space Shuttle Discovery's payload bay to support an upcoming borescope inspection of the retract link assembly on the orbiter's main landing gear door. The inspection is a precautionary measure after a small crack was found in a retract link assembly on the right-hand main landing gear on orbiter Atlantis. An initial review of the closeout photos of the link assembly on Discovery did not reveal any cracks. Discovery is scheduled to return the Space Shuttle fleet to operational status on mission STS-114. This additional work does not impact the launch planning window of July 13-31.

Accelerating target discovery using pre-competitive open science-patients need faster innovation more than anyone else.

PubMed

Low, Eric; Bountra, Chas; Lee, Wen Hwa

2016-01-01

We are experiencing a new era enabled by unencumbered access to high quality data through the emergence of open science initiatives in the historically challenging area of early stage drug discovery. At the same time, many patient-centric organisations are taking matters into their own hands by participating in, enabling and funding research. Here we present the rationale behind the innovative partnership between the Structural Genomics Consortium (SGC)-an open, pre-competitive pre-clinical research consortium and the research-focused patient organisation Myeloma UK to create a new, comprehensive platform to accelerate the discovery and development of new treatments for multiple myeloma.

KSC-05PD-1080

NASA Technical Reports Server (NTRS)

2005-01-01

KENNEDY SPACE CENTER, FLA. At Launch Complex 39B, technicians construct a platform in Space Shuttle Discovery's payload bay to support an upcoming borescope inspection of the retract link assembly on the orbiter's main landing gear door. The inspection is a precautionary measure after a small crack was found in a retract link assembly on the right-hand main landing gear on orbiter Atlantis. An initial review of the closeout photos of the link assembly on Discovery did not reveal any cracks. Discovery is scheduled to return the Space Shuttle fleet to operational status on mission STS-114. This additional work does not impact the launch planning window of July 13-31.

KSC-05PD-1079

NASA Technical Reports Server (NTRS)

2005-01-01

KENNEDY SPACE CENTER, FLA. At Launch Complex 39B, technicians construct a platform in Space Shuttle Discovery's payload bay to support an upcoming borescope inspection of the retract link assembly on the orbiter's main landing gear door. The inspection is a precautionary measure after a small crack was found in a retract link assembly on the right-hand main landing gear on orbiter Atlantis. An initial review of the closeout photos of the link assembly on Discovery did not reveal any cracks. Discovery is scheduled to return the Space Shuttle fleet to operational status on mission STS-114. This additional work does not impact the launch planning window of July 13-31.

Closeup view of the reflective insulation protecting the Crew Compartment ...

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

Close-up view of the reflective insulation protecting the Crew Compartment bulkhead, orbiter structure and landing gear housing in the void created by the removal of the Forward Reaction Control System Module from the forward section of the Orbiter Discovery. This image was taken from the service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Patient-derived tumour xenografts for breast cancer drug discovery.

PubMed

Cassidy, John W; Batra, Ankita S; Greenwood, Wendy; Bruna, Alejandra

2016-12-01

Despite remarkable advances in our understanding of the drivers of human malignancies, new targeted therapies often fail to show sufficient efficacy in clinical trials. Indeed, the cost of bringing a new agent to market has risen substantially in the last several decades, in part fuelled by extensive reliance on preclinical models that fail to accurately reflect tumour heterogeneity. To halt unsustainable rates of attrition in the drug discovery process, we must develop a new generation of preclinical models capable of reflecting the heterogeneity of varying degrees of complexity found in human cancers. Patient-derived tumour xenograft (PDTX) models prevail as arguably the most powerful in this regard because they capture cancer's heterogeneous nature. Herein, we review current breast cancer models and their use in the drug discovery process, before discussing best practices for developing a highly annotated cohort of PDTX models. We describe the importance of extensive multidimensional molecular and functional characterisation of models and combination drug-drug screens to identify complex biomarkers of drug resistance and response. We reflect on our own experiences and propose the use of a cost-effective intermediate pharmacogenomic platform (the PDTX-PDTC platform) for breast cancer drug and biomarker discovery. We discuss the limitations and unanswered questions of PDTX models; yet, still strongly envision that their use in basic and translational research will dramatically change our understanding of breast cancer biology and how to more effectively treat it. © 2016 The authors.

Sea Level Rise Data Discovery

NASA Astrophysics Data System (ADS)

Quach, N.; Huang, T.; Boening, C.; Gill, K. M.

2016-12-01

Research related to sea level rise crosses multiple disciplines from sea ice to land hydrology. The NASA Sea Level Change Portal (SLCP) is a one-stop source for current sea level change information and data, including interactive tools for accessing and viewing regional data, a virtual dashboard of sea level indicators, and ongoing updates through a suite of editorial products that include content articles, graphics, videos, and animations. The architecture behind the SLCP makes it possible to integrate web content and data relevant to sea level change that are archived across various data centers as well as new data generated by sea level change principal investigators. The Extensible Data Gateway Environment (EDGE) is incorporated into the SLCP architecture to provide a unified platform for web content and science data discovery. EDGE is a data integration platform designed to facilitate high-performance geospatial data discovery and access with the ability to support multi-metadata standard specifications. EDGE has the capability to retrieve data from one or more sources and package the resulting sets into a single response to the requestor. With this unified endpoint, the Data Analysis Tool that is available on the SLCP can retrieve dataset and granule level metadata as well as perform geospatial search on the data. This talk focuses on the architecture that makes it possible to seamlessly integrate and enable discovery of disparate data relevant to sea level rise.

Towards microfluidic technology-based MALDI-MS platforms for drug discovery: a review.

PubMed

Winkle, Richard F; Nagy, Judit M; Cass, Anthony Eg; Sharma, Sanjiv

2008-11-01

Microfluidic methods have found applications in various disciplines. It has been predicted that the microfluidic technology would be useful in performing routine steps in drug discovery ranging from target identification to lead optimisation in which the number of compounds evaluated in this regard determines the success of combinatorial screening. The sheer size of the parameter space that can be explored often poses an enormous challenge. We set out to find how close we are towards the use of integrated matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS) microfluidic systems for drug discovery. In this article we review the latest applications of microfluidic technology in the area of MALDI-MS and drug discovery. Our literature survey revealed microfluidic technologies-based approaches for various stages of drug discovery; however, they are in still in developmental stages. Furthermore, we speculate on how these technologies could be used in the future.

KSC-00pp1296

NASA Image and Video Library

2000-09-12

KENNEDY SPACE CENTER, Fla. -- The morning sun spotlights Launch Pad 39A and Space Shuttle Discovery atop the Mobile Launcher Platform. To its left is the Rotating Service Structure in its open position, at the top of the ramp that the Shuttle must negotiate on the crawler-transporter. Above Discovery looms the 80-foot fiberglass lightning mast. At the far left is the Vehicle Assembly Building, where a Space Shuttle begins its voyage to the pad. Discovery is scheduled to launch on mission STS-92 Oct. 5 at 9:30 p.m. EDT. Making the 100th Space Shuttle mission launched from Kennedy Space Center, Discovery will carry two pieces of hardware for the International Space Station, the Z1 truss, which is the cornerstone truss of the Station, and the third Pressurized Mating Adapter. Discovery also will be making its 28th flight into space, more than any of the other orbiters to date

KSC00pp1296

NASA Image and Video Library

2000-09-12

KENNEDY SPACE CENTER, Fla. -- The morning sun spotlights Launch Pad 39A and Space Shuttle Discovery atop the Mobile Launcher Platform. To its left is the Rotating Service Structure in its open position, at the top of the ramp that the Shuttle must negotiate on the crawler-transporter. Above Discovery looms the 80-foot fiberglass lightning mast. At the far left is the Vehicle Assembly Building, where a Space Shuttle begins its voyage to the pad. Discovery is scheduled to launch on mission STS-92 Oct. 5 at 9:30 p.m. EDT. Making the 100th Space Shuttle mission launched from Kennedy Space Center, Discovery will carry two pieces of hardware for the International Space Station, the Z1 truss, which is the cornerstone truss of the Station, and the third Pressurized Mating Adapter. Discovery also will be making its 28th flight into space, more than any of the other orbiters to date

KSC-05PD-1148

NASA Technical Reports Server (NTRS)

2005-01-01

KENNEDY SPACE CENTER, FLA. Dwarfing the accompanying vehicles, Space Shuttle Discovery, resting on the Mobile Launcher Platform atop the Crawler/Transporter, heads along the crawlerway to the Vehicle Assembly Building (VAB). Discovery is rolling back from Launch Pad 39B (in the background). Once inside the VAB, Discovery will be demated from its External Tank and lifted into the transfer aisle. On or about June 7, Discovery will be lifted and attached to its new tank and Solid Rocket Boosters, which are already in the VAB. Only the 15th rollback in Space Shuttle Program history, the 4.2-mile journey allows additional modifications to be made to the External Tank prior to a safe Return to Flight. Discovery is expected to be rolled back to the launch pad in mid-June for Return to Flight mission STS-114. The launch window extends from July 13 to July 31.

Ocean Data Interoperability Platform (ODIP): developing a common framework for marine data management on a global scale

NASA Astrophysics Data System (ADS)

Schaap, D.

2015-12-01

Europe, the USA, and Australia are making significant progress in facilitating the discovery, access and long term stewardship of ocean and marine data through the development, implementation, population and operation of national, regional or international distributed ocean and marine observing and data management infrastructures such as SeaDataNet, EMODnet, IOOS, R2R, and IMOS. All of these developments are resulting in the development of standards and services implemented and used by their regional communities. The Ocean Data Interoperability Platform (ODIP) project is supported by the EU FP7 Research Infrastructures programme, National Science Foundation (USA) and Australian government and has been initiated 1st October 2012. Recently the project has been continued as ODIP 2 for another 3 years with EU HORIZON 2020 funding. ODIP includes all the major organisations engaged in ocean data management in EU, US, and Australia. ODIP is also supported by the IOC-IODE, closely linking this activity with its Ocean Data Portal (ODP) and Ocean Data Standards Best Practices (ODSBP) projects. The ODIP platform aims to ease interoperability between the regional marine data management infrastructures. Therefore it facilitates an organised dialogue between the key infrastructure representatives by means of publishing best practice, organising a series of international workshops and fostering the development of common standards and interoperability solutions. These are evaluated and tested by means of prototype projects. The presentation will give further background on the ODIP projects and the latest information on the progress of three prototype projects addressing: establishing interoperability between the regional EU, USA and Australia data discovery and access services (SeaDataNet CDI, US NODC, and IMOS MCP) and contributing to the global GEOSS and IODE-ODP portals; establishing interoperability between cruise summary reporting systems in Europe, the USA and Australia for routine harvesting of cruise data for delivery via the Partnership for Observation of Global Oceans (POGO) global portal; establishing common standards for a Sensor Observation Service (SOS) for selected sensors installed on vessels and in real-time monitoring systems using sensor web enablement (SWE)

Ocean Data Interoperability Platform (ODIP): developing a common framework for marine data management on a global scale

NASA Astrophysics Data System (ADS)

Schaap, Dick M. A.; Glaves, Helen

2016-04-01

Europe, the USA, and Australia are making significant progress in facilitating the discovery, access and long term stewardship of ocean and marine data through the development, implementation, population and operation of national, regional or international distributed ocean and marine observing and data management infrastructures such as SeaDataNet, EMODnet, IOOS, R2R, and IMOS. All of these developments are resulting in the development of standards and services implemented and used by their regional communities. The Ocean Data Interoperability Platform (ODIP) project is supported by the EU FP7 Research Infrastructures programme, National Science Foundation (USA) and Australian government and has been initiated 1st October 2012. Recently the project has been continued as ODIP II for another 3 years with EU HORIZON 2020 funding. ODIP includes all the major organisations engaged in ocean data management in EU, US, and Australia. ODIP is also supported by the IOC-IODE, closely linking this activity with its Ocean Data Portal (ODP) and Ocean Data Standards Best Practices (ODSBP) projects. The ODIP platform aims to ease interoperability between the regional marine data management infrastructures. Therefore it facilitates an organised dialogue between the key infrastructure representatives by means of publishing best practice, organising a series of international workshops and fostering the development of common standards and interoperability solutions. These are evaluated and tested by means of prototype projects. The presentation will give further background on the ODIP projects and the latest information on the progress of three prototype projects addressing: 1. establishing interoperability between the regional EU, USA and Australia data discovery and access services (SeaDataNet CDI, US NODC, and IMOS MCP) and contributing to the global GEOSS and IODE-ODP portals; 2. establishing interoperability between cruise summary reporting systems in Europe, the USA and Australia for routine harvesting of cruise data for delivery via the Partnership for Observation of Global Oceans (POGO) global portal; 3. the establishment of common standards for a Sensor Observation Service (SOS) for selected sensors installed on vessels and in real-time monitoring systems using sensor web enablement (SWE)

Collaborative drug discovery for More Medicines for Tuberculosis (MM4TB)

PubMed Central

Ekins, Sean; Spektor, Anna Coulon; Clark, Alex M.; Dole, Krishna; Bunin, Barry A.

2016-01-01

Neglected disease drug discovery is generally poorly funded compared with major diseases and hence there is an increasing focus on collaboration and precompetitive efforts such as public–private partnerships (PPPs). The More Medicines for Tuberculosis (MM4TB) project is one such collaboration funded by the EU with the goal of discovering new drugs for tuberculosis. Collaborative Drug Discovery has provided a commercial web-based platform called CDD Vault which is a hosted collaborative solution for securely sharing diverse chemistry and biology data. Using CDD Vault alongside other commercial and free cheminformatics tools has enabled support of this and other large collaborative projects, aiding drug discovery efforts and fostering collaboration. We will describe CDD's efforts in assisting with the MM4TB project. PMID:27884746

istar: a web platform for large-scale protein-ligand docking.

PubMed

Li, Hongjian; Leung, Kwong-Sak; Ballester, Pedro J; Wong, Man-Hon

2014-01-01

Protein-ligand docking is a key computational method in the design of starting points for the drug discovery process. We are motivated by the desire to automate large-scale docking using our popular docking engine idock and thus have developed a publicly-accessible web platform called istar. Without tedious software installation, users can submit jobs using our website. Our istar website supports 1) filtering ligands by desired molecular properties and previewing the number of ligands to dock, 2) monitoring job progress in real time, and 3) visualizing ligand conformations and outputting free energy and ligand efficiency predicted by idock, binding affinity predicted by RF-Score, putative hydrogen bonds, and supplier information for easy purchase, three useful features commonly lacked on other online docking platforms like DOCK Blaster or iScreen. We have collected 17,224,424 ligands from the All Clean subset of the ZINC database, and revamped our docking engine idock to version 2.0, further improving docking speed and accuracy, and integrating RF-Score as an alternative rescoring function. To compare idock 2.0 with the state-of-the-art AutoDock Vina 1.1.2, we have carried out a rescoring benchmark and a redocking benchmark on the 2,897 and 343 protein-ligand complexes of PDBbind v2012 refined set and CSAR NRC HiQ Set 24Sept2010 respectively, and an execution time benchmark on 12 diverse proteins and 3,000 ligands of different molecular weight. Results show that, under various scenarios, idock achieves comparable success rates while outperforming AutoDock Vina in terms of docking speed by at least 8.69 times and at most 37.51 times. When evaluated on the PDBbind v2012 core set, our istar platform combining with RF-Score manages to reproduce Pearson's correlation coefficient and Spearman's correlation coefficient of as high as 0.855 and 0.859 respectively between the experimental binding affinity and the predicted binding affinity of the docked conformation. istar is freely available at http://istar.cse.cuhk.edu.hk/idock.

Revelations from the Literature: How Web-Scale Discovery Has Already Changed Us

ERIC Educational Resources Information Center

Richardson, Hillary A. H.

2013-01-01

For nearly a decade now, librarians have discussed and deliberated ways, for the sake of convenience, to integrate internet-like searching into their own catalogs to mimic what academic library patrons have been using outside the library. Discovery tools and web-scale discovery services (WSDS) attempt to provide users with a similar one-stop shop…

Localized Surface Plasmon Resonance as a Biosensing Platform for Developing Countries

PubMed Central

Hammond, Jules L.; Bhalla, Nikhil; Rafiee, Sarah D.; Estrela, Pedro

2014-01-01

The discovery of the phenomena known as localized surface plasmon resonance (LSPR) has provided the basis for many research areas, ranging from materials science to biosensing. LSPR has since been viewed as a transduction platform that could yield affordable, portable devices for a multitude of applications. This review aims to outline the potential applications within developing countries and the challenges that are likely to be faced before the technology can be effectively employed. PMID:25587417

Taking Open Innovation to the Molecular Level - Strengths and Limitations.

PubMed

Zdrazil, Barbara; Blomberg, Niklas; Ecker, Gerhard F

2012-08-01

The ever-growing availability of large-scale open data and its maturation is having a significant impact on industrial drug-discovery, as well as on academic and non-profit research. As industry is changing to an 'open innovation' business concept, precompetitive initiatives and strong public-private partnerships including academic research cooperation partners are gaining more and more importance. Now, the bioinformatics and cheminformatics communities are seeking for web tools which allow the integration of this large volume of life science datasets available in the public domain. Such a data exploitation tool would ideally be able to answer complex biological questions by formulating only one search query. In this short review/perspective, we outline the use of semantic web approaches for data and knowledge integration. Further, we discuss strengths and current limitations of public available data retrieval tools and integrated platforms.

A Wireless Monitoring System for Cracks on the Surface of Reactor Containment Buildings.

PubMed

Zhou, Jianguo; Xu, Yaming; Zhang, Tao

2016-06-14

Structural health monitoring with wireless sensor networks has been increasingly popular in recent years because of the convenience. In this paper, a real-time monitoring system for cracks on the surface of reactor containment buildings is presented. Customized wireless sensor networks platforms are designed and implemented with sensors especially for crack monitoring, which include crackmeters and temperature detectors. Software protocols like route discovery, time synchronization and data transfer are developed to satisfy the requirements of the monitoring system and stay simple at the same time. Simulation tests have been made to evaluate the performance of the system before full scale deployment. The real-life deployment of the crack monitoring system is carried out on the surface of reactor containment building in Daya Bay Nuclear Power Station during the in-service pressure test with 30 wireless sensor nodes.

Yeast as a tool to identify anti-aging compounds

PubMed Central

Zimmermann, Andreas; Hofer, Sebastian; Pendl, Tobias; Kainz, Katharina; Madeo, Frank; Carmona-Gutierrez, Didac

2018-01-01

Abstract In the search for interventions against aging and age-related diseases, biological screening platforms are indispensable tools to identify anti-aging compounds among large substance libraries. The budding yeast, Saccharomyces cerevisiae, has emerged as a powerful chemical and genetic screening platform, as it combines a rapid workflow with experimental amenability and the availability of a wide range of genetic mutant libraries. Given the amount of conserved genes and aging mechanisms between yeast and human, testing candidate anti-aging substances in yeast gene-deletion or overexpression collections, or de novo derived mutants, has proven highly successful in finding potential molecular targets. Yeast-based studies, for example, have led to the discovery of the polyphenol resveratrol and the natural polyamine spermidine as potential anti-aging agents. Here, we present strategies for pharmacological anti-aging screens in yeast, discuss common pitfalls and summarize studies that have used yeast for drug discovery and target identification. PMID:29905792

Microfluidics for cell-based high throughput screening platforms - A review.

PubMed

Du, Guansheng; Fang, Qun; den Toonder, Jaap M J

2016-01-15

In the last decades, the basic techniques of microfluidics for the study of cells such as cell culture, cell separation, and cell lysis, have been well developed. Based on cell handling techniques, microfluidics has been widely applied in the field of PCR (Polymerase Chain Reaction), immunoassays, organ-on-chip, stem cell research, and analysis and identification of circulating tumor cells. As a major step in drug discovery, high-throughput screening allows rapid analysis of thousands of chemical, biochemical, genetic or pharmacological tests in parallel. In this review, we summarize the application of microfluidics in cell-based high throughput screening. The screening methods mentioned in this paper include approaches using the perfusion flow mode, the droplet mode, and the microarray mode. We also discuss the future development of microfluidic based high throughput screening platform for drug discovery. Copyright © 2015 Elsevier B.V. All rights reserved.

Synthetic biology approaches: Towards sustainable exploitation of marine bioactive molecules.

PubMed

Seghal Kiran, G; Ramasamy, Pasiyappazham; Sekar, Sivasankari; Ramu, Meenatchi; Hassan, Saqib; Ninawe, A S; Selvin, Joseph

2018-06-01

The discovery of genes responsible for the production of bioactive metabolites via metabolic pathways combined with the advances in synthetic biology tools, has allowed the establishment of numerous microbial cell factories, for instance the yeast cell factories, for the manufacture of highly useful metabolites from renewable biomass. Genome mining and metagenomics are two platforms provide base-line data for reconstruction of genomes and metabolomes which is based in the development of synthetic/semi-synthetic genomes for marine natural products discovery. Engineered biofilms are being innovated on synthetic biology platform using genetic circuits and cell signalling systems as represillators controlling biofilm formation. Recombineering is a process of homologous recombination mediated genetic engineering, includes insertion, deletion or modification of any sequence specifically. Although this discipline considered new to the scientific domain, this field has now developed as promising endeavor on the accomplishment of sustainable exploitation of marine natural products. Copyright © 2018 Elsevier B.V. All rights reserved.

RNA-Targeted Therapeutics.

PubMed

Crooke, Stanley T; Witztum, Joseph L; Bennett, C Frank; Baker, Brenda F

2018-04-03

RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding motif, Watson-Crick base pairing. Numerous hurdles considered by many to be impassable have been overcome. Today, four RNA-targeted therapies are approved for commercial use for indications as diverse as Spinal Muscular Atrophy (SMA) and reduction of low-density lipoprotein cholesterol (LDL-C) and by routes of administration including subcutaneous, intravitreal, and intrathecal delivery. The technology is efficient and supports approaching "undruggable" targets. Three additional agents are progressing through registration, and more are in clinical development, representing several chemical and structural classes. Moreover, progress in understanding the molecular mechanisms by which these drugs work has led to steadily better clinical performance and a wide range of mechanisms that may be exploited for therapeutic purposes. Here we summarize the progress, future challenges, and opportunities for this drug discovery platform. Copyright © 2018 Elsevier Inc. All rights reserved.

Discovery of a new type of topological Weyl fermion semimetal state in Mo xW 1-xTe 2

DOE PAGES

Belopolski, Ilya; Sanchez, Daniel S.; Ishida, Yukiaki; ...

2016-12-05

Here, the recent discovery of a Weyl semimetal in TaAs offers the first Weyl fermion observed in nature and dramatically broadens the classification of topological phases. However, in TaAs it has proven challenging to study the rich transport phenomena arising from emergent Weyl fermions. The series Mo xW 1-xTe 2 are inversion-breaking, layered, tunable semimetals already under study as a promising platform for new electronics and recently proposed to host Type II, or strongly Lorentz-violating, Weyl fermions. Here we report the discovery of a Weyl semimetal in Mo xW 1-xTe 2 at x=25%. We use pump-probe angle-resolved photoemission spectroscopy (pump-probemore » ARPES) to directly observe a topological Fermi arc above the Fermi level, demonstrating a Weyl semimetal. The excellent agreement with calculation suggests that Mo xW 1-xTe 2 is a Type II Weyl semimetal. We also find that certain Weyl points are at the Fermi level, making Mo xW 1-xTe 2 a promising platform for transport and optics experiments on Weyl semimetals.« less

Discovery of a new type of topological Weyl fermion semimetal state in Mo xW 1-xTe 2

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

Belopolski, Ilya; Sanchez, Daniel S.; Ishida, Yukiaki

Here, the recent discovery of a Weyl semimetal in TaAs offers the first Weyl fermion observed in nature and dramatically broadens the classification of topological phases. However, in TaAs it has proven challenging to study the rich transport phenomena arising from emergent Weyl fermions. The series Mo xW 1-xTe 2 are inversion-breaking, layered, tunable semimetals already under study as a promising platform for new electronics and recently proposed to host Type II, or strongly Lorentz-violating, Weyl fermions. Here we report the discovery of a Weyl semimetal in Mo xW 1-xTe 2 at x=25%. We use pump-probe angle-resolved photoemission spectroscopy (pump-probemore » ARPES) to directly observe a topological Fermi arc above the Fermi level, demonstrating a Weyl semimetal. The excellent agreement with calculation suggests that Mo xW 1-xTe 2 is a Type II Weyl semimetal. We also find that certain Weyl points are at the Fermi level, making Mo xW 1-xTe 2 a promising platform for transport and optics experiments on Weyl semimetals.« less

Novel drug discovery approaches for treating arenavirus infections.

PubMed

Pasquato, Antonella; Kunz, Stefan

2016-01-01

Arenaviruses are enveloped negative stranded viruses endemic in Africa, Europe and the Americas. Several arenaviruses cause severe viral hemorrhagic fever with high mortality in humans and pose serious public health threats. So far, there are no FDA-approved vaccines and therapeutic options are restricted to the off-label use of ribavirin. The major human pathogenic arenaviruses are classified as Category A agents and require biosafety level (BSL)-4 containment. Herein, the authors cover the recent progress in the development of BSL2 surrogate systems that recapitulate the entire or specific steps of the arenavirus life cycle and are serving as powerful platforms for drug discovery. Furthermore, they highlight the identification of selected novel drugs that target individual steps of arenavirus multiplication describing their discovery, their targets, and mode of action. The lack of effective drugs against arenaviruses is an unmatched challenge in current medical virology. Novel technologies have provided important insights into the basic biology of arenaviruses and the mechanisms underlying virus-host cell interaction. Significant progress of our understanding of how the virus invades the host cell paved the way to develop powerful novel screening platforms. Recent efforts have provided a range of promising drug candidates currently under evaluation for therapeutic intervention in vivo.

Large-scale cross-species chemogenomic platform proposes a new drug discovery strategy of veterinary drug from herbal medicines.

PubMed

Huang, Chao; Yang, Yang; Chen, Xuetong; Wang, Chao; Li, Yan; Zheng, Chunli; Wang, Yonghua

2017-01-01

Veterinary Herbal Medicine (VHM) is a comprehensive, current, and informative discipline on the utilization of herbs in veterinary practice. Driven by chemistry but progressively directed by pharmacology and the clinical sciences, drug research has contributed more to address the needs for innovative veterinary medicine for curing animal diseases. However, research into veterinary medicine of vegetal origin in the pharmaceutical industry has reduced, owing to questions such as the short of compatibility of traditional natural-product extract libraries with high-throughput screening. Here, we present a cross-species chemogenomic screening platform to dissect the genetic basis of multifactorial diseases and to determine the most suitable points of attack for future veterinary medicines, thereby increasing the number of treatment options. First, based on critically examined pharmacology and text mining, we build a cross-species drug-likeness evaluation approach to screen the lead compounds in veterinary medicines. Second, a specific cross-species target prediction model is developed to infer drug-target connections, with the purpose of understanding how drugs work on the specific targets. Third, we focus on exploring the multiple targets interference effects of veterinary medicines by heterogeneous network convergence and modularization analysis. Finally, we manually integrate a disease pathway to test whether the cross-species chemogenomic platform could uncover the active mechanism of veterinary medicine, which is exemplified by a specific network module. We believe the proposed cross-species chemogenomic platform allows for the systematization of current and traditional knowledge of veterinary medicine and, importantly, for the application of this emerging body of knowledge to the development of new drugs for animal diseases.

Large-scale cross-species chemogenomic platform proposes a new drug discovery strategy of veterinary drug from herbal medicines

PubMed Central

Huang, Chao; Yang, Yang; Chen, Xuetong; Wang, Chao; Li, Yan; Zheng, Chunli

2017-01-01

Veterinary Herbal Medicine (VHM) is a comprehensive, current, and informative discipline on the utilization of herbs in veterinary practice. Driven by chemistry but progressively directed by pharmacology and the clinical sciences, drug research has contributed more to address the needs for innovative veterinary medicine for curing animal diseases. However, research into veterinary medicine of vegetal origin in the pharmaceutical industry has reduced, owing to questions such as the short of compatibility of traditional natural-product extract libraries with high-throughput screening. Here, we present a cross-species chemogenomic screening platform to dissect the genetic basis of multifactorial diseases and to determine the most suitable points of attack for future veterinary medicines, thereby increasing the number of treatment options. First, based on critically examined pharmacology and text mining, we build a cross-species drug-likeness evaluation approach to screen the lead compounds in veterinary medicines. Second, a specific cross-species target prediction model is developed to infer drug-target connections, with the purpose of understanding how drugs work on the specific targets. Third, we focus on exploring the multiple targets interference effects of veterinary medicines by heterogeneous network convergence and modularization analysis. Finally, we manually integrate a disease pathway to test whether the cross-species chemogenomic platform could uncover the active mechanism of veterinary medicine, which is exemplified by a specific network module. We believe the proposed cross-species chemogenomic platform allows for the systematization of current and traditional knowledge of veterinary medicine and, importantly, for the application of this emerging body of knowledge to the development of new drugs for animal diseases. PMID:28915268

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.

A base-modified PNA-graphene oxide platform as a turn-on fluorescence sensor for the detection of human telomeric repeats

NASA Astrophysics Data System (ADS)

Sabale, Pramod M.; George, Jerrin Thomas; Srivatsan, Seergazhi G.

2014-08-01

Given the biological and therapeutic significance of telomeres and other G-quadruplex forming sequences in human genome, it is highly desirable to develop simple methods to study these structures, which can also be implemented in screening formats for the discovery of G-quadruplex binders. The majority of telomere detection methods developed so far are laborious and use elaborate assay and instrumental setups, and hence, are not amenable to discovery platforms. Here, we describe the development of a simple homogeneous fluorescence turn-on method, which uses a unique combination of an environment-sensitive fluorescent nucleobase analogue, the superior base pairing property of PNA, and DNA-binding and fluorescence quenching properties of graphene oxide, to detect human telomeric DNA repeats of varying lengths. Our results demonstrate that this method, which does not involve a rigorous assay setup, would provide new opportunities to study G-quadruplex structures.Given the biological and therapeutic significance of telomeres and other G-quadruplex forming sequences in human genome, it is highly desirable to develop simple methods to study these structures, which can also be implemented in screening formats for the discovery of G-quadruplex binders. The majority of telomere detection methods developed so far are laborious and use elaborate assay and instrumental setups, and hence, are not amenable to discovery platforms. Here, we describe the development of a simple homogeneous fluorescence turn-on method, which uses a unique combination of an environment-sensitive fluorescent nucleobase analogue, the superior base pairing property of PNA, and DNA-binding and fluorescence quenching properties of graphene oxide, to detect human telomeric DNA repeats of varying lengths. Our results demonstrate that this method, which does not involve a rigorous assay setup, would provide new opportunities to study G-quadruplex structures. Electronic supplementary information (ESI) available. Figures, tables, experimental procedures and NMR spectra. See DOI: 10.1039/c4nr00878b

KSC-07pd2397

NASA Image and Video Library

2007-09-05

KENNEDY SPACE CENTER, FLA. -- In the Vehicle Assembly Building at NASA's Kennedy Space Center, the top of external tank No. 120 is seen as the tank is lowered between the solid rocket boosters for mating on the mobile launcher platform. The external tank-SRB stack is being prepared for the orbiter Discovery, which will be mated to the stack in the VAB in two weeks. Space Shuttle Discovery is targeted to launch Oct. 23 on mission STS-120 to the International Space Station. Photo credit: NASA/George Shelton

Closeup view of the reinforced carboncarbon nose of the Orbiter ...

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

Close-up view of the reinforced carbon-carbon nose of the Orbiter Discovery from the service platform in the Orbiter Processing Facility at Kennedy Space Center. Note the clear protective shield around the nose cap, and the reflective insulation protecting the Crew Compartment bulkhead and orbiter structure in the void created by the removal of the Forward Reaction Control Module. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Innovations in Undergraduate Science Education: Going Viral.

PubMed

Hatfull, Graham F

2015-08-01

Bacteriophage discovery and genomics provides a powerful and effective platform for integrating missions in research and education. Implementation of the Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) program facilitates a broad impact by including a diverse array of schools, faculty, and students. The program generates new insights into the diversity and evolution of the bacteriophage population and presents a model for introducing first-year undergraduate students to discovery-based research experiences. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

View looking aft along the starboard side of the midfuselage ...

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

View looking aft along the starboard side of the mid-fuselage of the Orbiter Discovery. This view shows the wing profile as it intersects with the fuselage. Also note in the foreground the panels protecting the Reinforced Carbon-Carbon leading edge of the wing. This view was taken from the service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Live Cell in Vitro and in Vivo Imaging Applications: Accelerating Drug Discovery

PubMed Central

Isherwood, Beverley; Timpson, Paul; McGhee, Ewan J; Anderson, Kurt I; Canel, Marta; Serrels, Alan; Brunton, Valerie G; Carragher, Neil O

2011-01-01

Dynamic regulation of specific molecular processes and cellular phenotypes in live cell systems reveal unique insights into cell fate and drug pharmacology that are not gained from traditional fixed endpoint assays. Recent advances in microscopic imaging platform technology combined with the development of novel optical biosensors and sophisticated image analysis solutions have increased the scope of live cell imaging applications in drug discovery. We highlight recent literature examples where live cell imaging has uncovered novel insight into biological mechanism or drug mode-of-action. We survey distinct types of optical biosensors and associated analytical methods for monitoring molecular dynamics, in vitro and in vivo. We describe the recent expansion of live cell imaging into automated target validation and drug screening activities through the development of dedicated brightfield and fluorescence kinetic imaging platforms. We provide specific examples of how temporal profiling of phenotypic response signatures using such kinetic imaging platforms can increase the value of in vitro high-content screening. Finally, we offer a prospective view of how further application and development of live cell imaging technology and reagents can accelerate preclinical lead optimization cycles and enhance the in vitro to in vivo translation of drug candidates. PMID:24310493

Remote visualization and scale analysis of large turbulence datatsets

NASA Astrophysics Data System (ADS)

Livescu, D.; Pulido, J.; Burns, R.; Canada, C.; Ahrens, J.; Hamann, B.

2015-12-01

Accurate simulations of turbulent flows require solving all the dynamically relevant scales of motions. This technique, called Direct Numerical Simulation, has been successfully applied to a variety of simple flows; however, the large-scale flows encountered in Geophysical Fluid Dynamics (GFD) would require meshes outside the range of the most powerful supercomputers for the foreseeable future. Nevertheless, the current generation of petascale computers has enabled unprecedented simulations of many types of turbulent flows which focus on various GFD aspects, from the idealized configurations extensively studied in the past to more complex flows closer to the practical applications. The pace at which such simulations are performed only continues to increase; however, the simulations themselves are restricted to a small number of groups with access to large computational platforms. Yet the petabytes of turbulence data offer almost limitless information on many different aspects of the flow, from the hierarchy of turbulence moments, spectra and correlations, to structure-functions, geometrical properties, etc. The ability to share such datasets with other groups can significantly reduce the time to analyze the data, help the creative process and increase the pace of discovery. Using the largest DOE supercomputing platforms, we have performed some of the biggest turbulence simulations to date, in various configurations, addressing specific aspects of turbulence production and mixing mechanisms. Until recently, the visualization and analysis of such datasets was restricted by access to large supercomputers. The public Johns Hopkins Turbulence database simplifies the access to multi-Terabyte turbulence datasets and facilitates turbulence analysis through the use of commodity hardware. First, one of our datasets, which is part of the database, will be described and then a framework that adds high-speed visualization and wavelet support for multi-resolution analysis of turbulence will be highlighted. The addition of wavelet support reduces the latency and bandwidth requirements for visualization, allowing for many concurrent users, and enables new types of analyses, including scale decomposition and coherent feature extraction.

Rembrandt: Helping Personalized Medicine Become a Reality Through Integrative Translational Research

PubMed Central

Madhavan, Subha; Zenklusen, Jean-Claude; Kotliarov, Yuri; Sahni, Himanso; Fine, Howard A.; Buetow, Kenneth

2009-01-01

Finding better therapies for the treatment of brain tumors is hampered by the lack of consistently obtained molecular data in a large sample set, and ability to integrate biomedical data from disparate sources enabling translation of therapies from bench to bedside. Hence, a critical factor in the advancement of biomedical research and clinical translation is the ease with which data can be integrated, redistributed and analyzed both within and across functional domains. Novel biomedical informatics infrastructure and tools are essential for developing individualized patient treatment based on the specific genomic signatures in each patient’s tumor. Here we present Rembrandt, Repository of Molecular BRAin Neoplasia DaTa, a cancer clinical genomics database and a web-based data mining and analysis platform aimed at facilitating discovery by connecting the dots between clinical information and genomic characterization data. To date, Rembrandt contains data generated through the Glioma Molecular Diagnostic Initiative from 874 glioma specimens comprising nearly 566 gene expression arrays, 834 copy number arrays and 13,472 clinical phenotype data points. Data can be queried and visualized for a selected gene across all data platforms or for multiple genes in a selected platform. Additionally, gene sets can be limited to clinically important annotations including secreted, kinase, membrane, and known gene-anomaly pairs to facilitate the discovery of novel biomarkers and therapeutic targets. We believe that REMBRANDT represents a prototype of how high throughput genomic and clinical data can be integrated in a way that will allow expeditious and efficient translation of laboratory discoveries to the clinic. PMID:19208739

NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds

PubMed Central

Yu, Jun-lan; Chen, Tian-tian; Zhou, Chen; Lian, Fu-lin; Tang, Xu-long; Wen, Yi; Shen, Jing-kang; Xu, Ye-chun; Xiong, Bing; Zhang, Nai-xia

2016-01-01

Aim: Fragment-based lead discovery (FBLD) is a complementary approach in drug research and development. In this study, we established an NMR-based FBLD platform that was used to screen novel scaffolds targeting human bromodomain of BRD4, and investigated the binding interactions between hit compounds and the target protein. Methods: 1D NMR techniques were primarily used to generate the fragment library and to screen compounds. The inhibitory activity of hits on the first bromodomain of BRD4 [BRD4(I)] was examined using fluorescence anisotropy binding assay. 2D NMR and X-ray crystallography were applied to characterize the binding interactions between hit compounds and the target protein. Results: An NMR-based fragment library containing 539 compounds was established, which were clustered into 56 groups (8–10 compounds in each group). Eight hits with new scaffolds were found to inhibit BRD4(I). Four out of the 8 hits (compounds 1, 2, 8 and 9) had IC50 values of 100–260 μmol/L, demonstrating their potential for further BRD4-targeted hit-to-lead optimization. Analysis of the binding interactions revealed that compounds 1 and 2 shared a common quinazolin core structure and bound to BRD4(I) in a non-acetylated lysine mimetic mode. Conclusion: An NMR-based platform for FBLD was established and used in discovery of BRD4-targeted compounds. Four potential hit-to-lead optimization candidates have been found, two of them bound to BRD4(I) in a non-acetylated lysine mimetic mode, being selective BRD4(I) inhibitors. PMID:27238211

Microfluidic Bead Suspension Hopper

PubMed Central

2014-01-01

Many high-throughput analytical platforms, from next-generation DNA sequencing to drug discovery, rely on beads as carriers of molecular diversity. Microfluidic systems are ideally suited to handle and analyze such bead libraries with high precision and at minute volume scales; however, the challenge of introducing bead suspensions into devices before they sediment usually confounds microfluidic handling and analysis. We developed a bead suspension hopper that exploits sedimentation to load beads into a microfluidic droplet generator. A suspension hopper continuously delivered synthesis resin beads (17 μm diameter, 112,000 over 2.67 h) functionalized with a photolabile linker and pepstatin A into picoliter-scale droplets of an HIV-1 protease activity assay to model ultraminiaturized compound screening. Likewise, trypsinogen template DNA-coated magnetic beads (2.8 μm diameter, 176,000 over 5.5 h) were loaded into droplets of an in vitro transcription/translation system to model a protein evolution experiment. The suspension hopper should effectively remove any barriers to using suspensions as sample inputs, paving the way for microfluidic automation to replace robotic library distribution. PMID:24761972

IDEAL: Images Across Domains, Experiments, Algorithms and Learning

NASA Astrophysics Data System (ADS)

Ushizima, Daniela M.; Bale, Hrishikesh A.; Bethel, E. Wes; Ercius, Peter; Helms, Brett A.; Krishnan, Harinarayan; Grinberg, Lea T.; Haranczyk, Maciej; Macdowell, Alastair A.; Odziomek, Katarzyna; Parkinson, Dilworth Y.; Perciano, Talita; Ritchie, Robert O.; Yang, Chao

2016-11-01

Research across science domains is increasingly reliant on image-centric data. Software tools are in high demand to uncover relevant, but hidden, information in digital images, such as those coming from faster next generation high-throughput imaging platforms. The challenge is to analyze the data torrent generated by the advanced instruments efficiently, and provide insights such as measurements for decision-making. In this paper, we overview work performed by an interdisciplinary team of computational and materials scientists, aimed at designing software applications and coordinating research efforts connecting (1) emerging algorithms for dealing with large and complex datasets; (2) data analysis methods with emphasis in pattern recognition and machine learning; and (3) advances in evolving computer architectures. Engineering tools around these efforts accelerate the analyses of image-based recordings, improve reusability and reproducibility, scale scientific procedures by reducing time between experiments, increase efficiency, and open opportunities for more users of the imaging facilities. This paper describes our algorithms and software tools, showing results across image scales, demonstrating how our framework plays a role in improving image understanding for quality control of existent materials and discovery of new compounds.

Hybrid MPI/OpenMP Implementation of the ORAC Molecular Dynamics Program for Generalized Ensemble and Fast Switching Alchemical Simulations.

PubMed

Procacci, Piero

2016-06-27

We present a new release (6.0β) of the ORAC program [Marsili et al. J. Comput. Chem. 2010, 31, 1106-1116] with a hybrid OpenMP/MPI (open multiprocessing message passing interface) multilevel parallelism tailored for generalized ensemble (GE) and fast switching double annihilation (FS-DAM) nonequilibrium technology aimed at evaluating the binding free energy in drug-receptor system on high performance computing platforms. The production of the GE or FS-DAM trajectories is handled using a weak scaling parallel approach on the MPI level only, while a strong scaling force decomposition scheme is implemented for intranode computations with shared memory access at the OpenMP level. The efficiency, simplicity, and inherent parallel nature of the ORAC implementation of the FS-DAM algorithm, project the code as a possible effective tool for a second generation high throughput virtual screening in drug discovery and design. The code, along with documentation, testing, and ancillary tools, is distributed under the provisions of the General Public License and can be freely downloaded at www.chim.unifi.it/orac .

Intermittent photocatalytic activity of single CdS nanoparticles

PubMed Central

Li, Zhimin; Jiang, Yingyan; Wang, Xian; Chen, Hong-Yuan; Tao, Nongjian; Wang, Wei

2017-01-01

Semiconductor photocatalysis holds promising keys to address various energy and environmental challenges. Most studies to date are based on ensemble analysis, which may mask critical photocatalytic kinetics in single nanocatalysts. Here we report a study of imaging photocatalytic hydrogen production of single CdS nanoparticles with a plasmonic microscopy in an in operando manner. Surprisingly, we find that the photocatalytic reaction switches on and off stochastically despite the fact that the illumination is kept constant. The on and off states follow truncated and full-scale power-law distributions in broad time scales spanning 3–4 orders of magnitude, respectively, which can be described with a statistical model involving stochastic reactions rates at multiple active sites. This phenomenon is analogous to fluorescence photoblinking, but the underlying mechanism is different. As individual nanocatalyst represents the elementary photocatalytic platform, the discovery of the intermittent nature of the photocatalysis provides insights into the fundamental photochemistry and photophysics of semiconductor nanomaterials, which is anticipated to substantially benefit broad application fields such as clean energy, pollution treatment, and chemical synthesis. PMID:28923941

The mid-IR silicon photonics sensor platform (Conference Presentation)

NASA Astrophysics Data System (ADS)

Kimerling, Lionel; Hu, Juejun; Agarwal, Anuradha M.

2017-02-01

Advances in integrated silicon photonics are enabling highly connected sensor networks that offer sensitivity, selectivity and pattern recognition. Cost, performance and the evolution path of the so-called `Internet of Things' will gate the proliferation of these networks. The wavelength spectral range of 3-8um, commonly known as the mid-IR, is critical to specificity for sensors that identify materials by detection of local vibrational modes, reflectivity and thermal emission. For ubiquitous sensing applications in this regime, the sensors must move from premium to commodity level manufacturing volumes and cost. Scaling performance/cost is critically dependent on establishing a minimum set of platform attributes for point, wearable, and physical sensing. Optical sensors are ideal for non-invasive applications. Optical sensor device physics involves evanescent or intra-cavity structures for applied to concentration, interrogation and photo-catalysis functions. The ultimate utility of a platform is dependent on sample delivery/presentation modalities; system reset, recalibration and maintenance capabilities; and sensitivity and selectivity performance. The attributes and performance of a unified Glass-on-Silicon platform has shown good prospects for heterogeneous integration on materials and devices using a low cost process flow. Integrated, single mode, silicon photonic platforms offer significant performance and cost advantages, but they require discovery and qualification of new materials and process integration schemes for the mid-IR. Waveguide integrated light sources based on rare earth dopants and Ge-pumped frequency combs have promise. Optical resonators and waveguide spirals can enhance sensitivity. PbTe materials are among the best choices for a standard, waveguide integrated photodetector. Chalcogenide glasses are capable of transmitting mid-IR signals with high transparency. Integrated sensor case studies of i) high sensitivity analyte detection in solution; ii) gas sensing in air and iii) on-chip spectrometry provide good insight into the tradeoffs being made en route to ubiquitous sensor deployment in an Internet of Things.

KSC-05PD-0620

NASA Technical Reports Server (NTRS)

2005-01-01

KENNEDY SPACE CENTER, FLA. In the waning twilight, the service structures on Launch Pad 39B (left) and the Mobile Launcher Platform carrying Space Shuttle Discovery glow with lights. The Shuttle began rollout to the pad at 2:04 p.m. EDT from the Vehicle Assembly Building at NASAs Kennedy Space Center, marking a major milestone in the Space Shuttle Programs Return to Flight. Launch of Discovery on its Return to Flight mission, STS-114, is targeted for May 15 with a launch window that extends to June 3. During its 12-day mission, Discoverys seven-person crew will test new hardware and techniques to improve Shuttle safety, as well as deliver supplies to the International Space Station.

Three-Component Reaction Discovery Enabled by Mass Spectrometry of Self-Assembled Monolayers

PubMed Central

Montavon, Timothy J.; Li, Jing; Cabrera-Pardo, Jaime R.; Mrksich, Milan; Kozmin, Sergey A.

2011-01-01

Multi-component reactions have been extensively employed in many areas of organic chemistry. Despite significant progress, the discovery of such enabling transformations remains challenging. Here, we present the development of a parallel, label-free reaction-discovery platform, which can be used for identification of new multi-component transformations. Our approach is based on the parallel mass spectrometric screening of interfacial chemical reactions on arrays of self-assembled monolayers. This strategy enabled the identification of a simple organic phosphine that can catalyze a previously unknown condensation of siloxy alkynes, aldehydes and amines to produce 3-hydroxy amides with high efficiency and diastereoselectivity. The reaction was further optimized using solution phase methods. PMID:22169871

The Z1 truss is transported to Launch Pad 39A

NASA Technical Reports Server (NTRS)

2000-01-01

At Launch Pad 39A, the payload canister at left draws closer to the Rotating Service Structure where it will be lifted to the Payload Changeout Room. There its cargo, the Integrated Truss Structure Z1, will be removed and later transferred to Space Shuttle Discovery's payload bay. Discovery is at right, sitting atop the Mobile Launcher Platform. The Z1 truss is the first of 10 that will become the backbone of the International Space Station, eventually stretching the length of a football field. Along with its companion payload, the third Pressurized Mating Adapter, the Z1 is scheduled to be launched aboard Discovery Oct. 5 at 9:38 p.m. EDT.

ADMS Evaluation Platform

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

2018-01-23

Deploying an ADMS or looking to optimize its value? NREL offers a low-cost, low-risk evaluation platform for assessing ADMS performance. The National Renewable Energy Laboratory (NREL) has developed a vendor-neutral advanced distribution management system (ADMS) evaluation platform and is expanding its capabilities. The platform uses actual grid-scale hardware, large-scale distribution system models, and advanced visualization to simulate realworld conditions for the most accurate ADMS evaluation and experimentation.

A perspective on sustained marine observations for climate modelling and prediction

PubMed Central

Dunstone, Nick J.

2014-01-01

Here, I examine some of the many varied ways in which sustained global ocean observations are used in numerical modelling activities. In particular, I focus on the use of ocean observations to initialize predictions in ocean and climate models. Examples are also shown of how models can be used to assess the impact of both current ocean observations and to simulate that of potential new ocean observing platforms. The ocean has never been better observed than it is today and similarly ocean models have never been as capable at representing the real ocean as they are now. However, there remain important unanswered questions that can likely only be addressed via future improvements in ocean observations. In particular, ocean observing systems need to respond to the needs of the burgeoning field of near-term climate predictions. Although new ocean observing platforms promise exciting new discoveries, there is a delicate balance to be made between their funding and that of the current ocean observing system. Here, I identify the need to secure long-term funding for ocean observing platforms as they mature, from a mainly research exercise to an operational system for sustained observation over climate change time scales. At the same time, considerable progress continues to be made via ship-based observing campaigns and I highlight some that are dedicated to addressing uncertainties in key ocean model parametrizations. The use of ocean observations to understand the prominent long time scale changes observed in the North Atlantic is another focus of this paper. The exciting first decade of monitoring of the Atlantic meridional overturning circulation by the RAPID-MOCHA array is highlighted. The use of ocean and climate models as tools to further probe the drivers of variability seen in such time series is another exciting development. I also discuss the need for a concerted combined effort from climate models and ocean observations in order to understand the current slow-down in surface global warming. PMID:25157195

Mass spectrometry-driven drug discovery for development of herbal medicine.

PubMed

Zhang, Aihua; Sun, Hui; Wang, Xijun

2018-05-01

Herbal medicine (HM) has made a major contribution to the drug discovery process with regard to identifying products compounds. Currently, more attention has been focused on drug discovery from natural compounds of HM. Despite the rapid advancement of modern analytical techniques, drug discovery is still a difficult and lengthy process. Fortunately, mass spectrometry (MS) can provide us with useful structural information for drug discovery, has been recognized as a sensitive, rapid, and high-throughput technology for advancing drug discovery from HM in the post-genomic era. It is essential to develop an efficient, high-quality, high-throughput screening method integrated with an MS platform for early screening of candidate drug molecules from natural products. We have developed a new chinmedomics strategy reliant on MS that is capable of capturing the candidate molecules, facilitating their identification of novel chemical structures in the early phase; chinmedomics-guided natural product discovery based on MS may provide an effective tool that addresses challenges in early screening of effective constituents of herbs against disease. This critical review covers the use of MS with related techniques and methodologies for natural product discovery, biomarker identification, and determination of mechanisms of action. It also highlights high-throughput chinmedomics screening methods suitable for lead compound discovery illustrated by recent successes. © 2016 Wiley Periodicals, Inc.

The Application of the Open Pharmacological Concepts Triple Store (Open PHACTS) to Support Drug Discovery Research

PubMed Central

Ratnam, Joseline; Zdrazil, Barbara; Digles, Daniela; Cuadrado-Rodriguez, Emiliano; Neefs, Jean-Marc; Tipney, Hannah; Siebes, Ronald; Waagmeester, Andra; Bradley, Glyn; Chau, Chau Han; Richter, Lars; Brea, Jose; Evelo, Chris T.; Jacoby, Edgar; Senger, Stefan; Loza, Maria Isabel; Ecker, Gerhard F.; Chichester, Christine

2014-01-01

Integration of open access, curated, high-quality information from multiple disciplines in the Life and Biomedical Sciences provides a holistic understanding of the domain. Additionally, the effective linking of diverse data sources can unearth hidden relationships and guide potential research strategies. However, given the lack of consistency between descriptors and identifiers used in different resources and the absence of a simple mechanism to link them, gathering and combining relevant, comprehensive information from diverse databases remains a challenge. The Open Pharmacological Concepts Triple Store (Open PHACTS) is an Innovative Medicines Initiative project that uses semantic web technology approaches to enable scientists to easily access and process data from multiple sources to solve real-world drug discovery problems. The project draws together sources of publicly-available pharmacological, physicochemical and biomolecular data, represents it in a stable infrastructure and provides well-defined information exploration and retrieval methods. Here, we highlight the utility of this platform in conjunction with workflow tools to solve pharmacological research questions that require interoperability between target, compound, and pathway data. Use cases presented herein cover 1) the comprehensive identification of chemical matter for a dopamine receptor drug discovery program 2) the identification of compounds active against all targets in the Epidermal growth factor receptor (ErbB) signaling pathway that have a relevance to disease and 3) the evaluation of established targets in the Vitamin D metabolism pathway to aid novel Vitamin D analogue design. The example workflows presented illustrate how the Open PHACTS Discovery Platform can be used to exploit existing knowledge and generate new hypotheses in the process of drug discovery. PMID:25522365

An ion channel library for drug discovery and safety screening on automated platforms.

PubMed

Wible, Barbara A; Kuryshev, Yuri A; Smith, Stephen S; Liu, Zhiqi; Brown, Arthur M

2008-12-01

Ion channels represent the third largest class of targets in drug discovery after G-protein coupled receptors and kinases. In spite of this ranking, ion channels continue to be under exploited as drug targets compared with the other two groups for several reasons. First, with 400 ion channel genes and an even greater number of functional channels due to mixing and matching of individual subunits, a systematic collection of ion channel-expressing cell lines for drug discovery and safety screening has not been available. Second, the lack of high-throughput functional assays for ion channels has limited their use as drug targets. Now that automated electrophysiology has come of age and provided the technology to assay ion channels at medium to high throughput, we have addressed the need for a library of ion channel cell lines by constructing the Ion Channel Panel (ChanTest Corp., Cleveland, OH). From 400 ion channel genes, a collection of 82 of the most relevant human ion channels for drug discovery, safety, and human disease has been assembled.Each channel has been stably overexpressed in human embryonic kidney 293 or Chinese hamster ovary cells. Cell lines have been selected and validated on automated electrophysiology systems to facilitate cost-effective screening for safe and selective compounds at earlier stages in the drug development process. The screening and validation processes as well as the relative advantages of different screening platforms are discussed.

The Benefits and Complexities of Operating Geographic Information Systems (GIS) in a High Performance Computing (HPC) Environment

NASA Astrophysics Data System (ADS)

Shute, J.; Carriere, L.; Duffy, D.; Hoy, E.; Peters, J.; Shen, Y.; Kirschbaum, D.

2017-12-01

The NASA Center for Climate Simulation (NCCS) at the Goddard Space Flight Center is building and maintaining an Enterprise GIS capability for its stakeholders, to include NASA scientists, industry partners, and the public. This platform is powered by three GIS subsystems operating in a highly-available, virtualized environment: 1) the Spatial Analytics Platform is the primary NCCS GIS and provides users discoverability of the vast DigitalGlobe/NGA raster assets within the NCCS environment; 2) the Disaster Mapping Platform provides mapping and analytics services to NASA's Disaster Response Group; and 3) the internal (Advanced Data Analytics Platform/ADAPT) enterprise GIS provides users with the full suite of Esri and open source GIS software applications and services. All systems benefit from NCCS's cutting edge infrastructure, to include an InfiniBand network for high speed data transfers; a mixed/heterogeneous environment featuring seamless sharing of information between Linux and Windows subsystems; and in-depth system monitoring and warning systems. Due to its co-location with the NCCS Discover High Performance Computing (HPC) environment and the Advanced Data Analytics Platform (ADAPT), the GIS platform has direct access to several large NCCS datasets including DigitalGlobe/NGA, Landsat, MERRA, and MERRA2. Additionally, the NCCS ArcGIS Desktop Windows virtual machines utilize existing NetCDF and OPeNDAP assets for visualization, modelling, and analysis - thus eliminating the need for data duplication. With the advent of this platform, Earth scientists have full access to vast data repositories and the industry-leading tools required for successful management and analysis of these multi-petabyte, global datasets. The full system architecture and integration with scientific datasets will be presented. Additionally, key applications and scientific analyses will be explained, to include the NASA Global Landslide Catalog (GLC) Reporter crowdsourcing application, the NASA GLC Viewer discovery and analysis tool, the DigitalGlobe/NGA Data Discovery Tool, the NASA Disaster Response Group Mapping Platform (https://maps.disasters.nasa.gov), and support for NASA's Arctic - Boreal Vulnerability Experiment (ABoVE).

Interspecies chimeras.

PubMed

Suchy, Fabian; Nakauchi, Hiromitsu

2018-05-30

By probing early embryogenesis and regeneration, interspecies chimeras provide a unique platform for discovery and clinical use. Although efficient generation of human:animal chimeric embryos remains elusive, recent advancements attempt to overcome incompatibilities in xenogeneic development and transplantation. Copyright © 2018 Elsevier Ltd. All rights reserved.

A Combinatorial Platform for the Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists

NASA Astrophysics Data System (ADS)

Barnash, Kimberly D.

Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.

Development and Validation of a High Throughput System for Discovery of Antigens for Autoantibody Detection

PubMed Central

Macdonald, Isabel K.; Allen, Jared; Murray, Andrea; Parsy-Kowalska, Celine B.; Healey, Graham F.; Chapman, Caroline J.; Sewell, Herbert F.; Robertson, John F. R.

2012-01-01

An assay employing a panel of tumor-associated antigens has been validated and is available commercially (EarlyCDT®-Lung) to aid the early detection of lung cancer by measurement of serum autoantibodies. The high throughput (HTP) strategy described herein was pursued to identify new antigens to add to the EarlyCDT-Lung panel and to assist in the development of new panels for other cancers. Two ligation-independent cloning vectors were designed and synthesized, producing fusion proteins suitable for the autoantibody ELISA. We developed an abridged HTP version of the validated autoantibody ELISA, determining that results reflected the performance of the EarlyCDT assay, by comparing results on both formats. Once validated this HTP ELISA was utilized to screen multiple fusion proteins prepared on small-scale, by a HTP expression screen. We determined whether the assay performance for these HTP protein batches was an accurate reflection of the performance of R&D or commercial batches. A HTP discovery platform for the identification and optimal production of tumor- associated antigens which detects autoantibodies has been developed and validated. The most favorable conditions for the exposure of immunogenic epitopes were assessed to produce discriminatory proteins for use in a commercial ELISA. This process is rapid and cost-effective compared to standard cloning and screening technologies and enables rapid advancement in the field of autoantibody assay discovery. This approach will significantly reduce timescale and costs for developing similar panels of autoantibody assays for the detection of other cancer types with the ultimate aim of improved overall survival due to early diagnosis and treatment. PMID:22815807

The Classes of Authoring Programs.

ERIC Educational Resources Information Center

Kozel, Kathy

1997-01-01

Provides an overview of developments in authoring tools and describes ways to categorize products by platform, type of end-product, sophistication of end-product, and authoring metaphor. Discusses products from AimTech, Allegiant, Allen Communication, Asymetrix, Corel, Discovery Systems International, Enigma, Harrow Media, Horizons, Innovus,…

Multiplex amplification of large sets of human exons.

PubMed

Porreca, Gregory J; Zhang, Kun; Li, Jin Billy; Xie, Bin; Austin, Derek; Vassallo, Sara L; LeProust, Emily M; Peck, Bill J; Emig, Christopher J; Dahl, Fredrik; Gao, Yuan; Church, George M; Shendure, Jay

2007-11-01

A new generation of technologies is poised to reduce DNA sequencing costs by several orders of magnitude. But our ability to fully leverage the power of these technologies is crippled by the absence of suitable 'front-end' methods for isolating complex subsets of a mammalian genome at a scale that matches the throughput at which these platforms will routinely operate. We show that targeting oligonucleotides released from programmable microarrays can be used to capture and amplify approximately 10,000 human exons in a single multiplex reaction. Additionally, we show integration of this protocol with ultra-high-throughput sequencing for targeted variation discovery. Although the multiplex capture reaction is highly specific, we found that nonuniform capture is a key issue that will need to be resolved by additional optimization. We anticipate that highly multiplexed methods for targeted amplification will enable the comprehensive resequencing of human exons at a fraction of the cost of whole-genome resequencing.

Danio rerio: Small Fish Making a Big Splash in Leukemia.

PubMed

Squiban, Barbara; Frazer, J Kimble

2014-06-01

Zebrafish ( Danio rerio ) are widely used for developmental biology studies. In the past decade, D. rerio have become an important oncology model as well. Leukemia is one type of cancer where zebrafish are particularly valuable. As vertebrates, fish have great anatomic and biologic similarity to humans, including their hematopoietic and immune systems. As an experimental platform, D. rerio offer many advantages that mammalian models lack. These include their ease of genetic manipulation, capacity for imaging, and suitability for large-scale phenotypic and drug screens. In this review, we present examples of these strategies and others to illustrate how zebrafish have been and can be used to study leukemia. Besides appraising the techniques researchers apply and introducing the leukemia models they have created, we also highlight recent and exciting discoveries made using D. rerio with an eye to where the field is likely headed.

A Wireless Monitoring System for Cracks on the Surface of Reactor Containment Buildings

PubMed Central

Zhou, Jianguo; Xu, Yaming; Zhang, Tao

2016-01-01

Structural health monitoring with wireless sensor networks has been increasingly popular in recent years because of the convenience. In this paper, a real-time monitoring system for cracks on the surface of reactor containment buildings is presented. Customized wireless sensor networks platforms are designed and implemented with sensors especially for crack monitoring, which include crackmeters and temperature detectors. Software protocols like route discovery, time synchronization and data transfer are developed to satisfy the requirements of the monitoring system and stay simple at the same time. Simulation tests have been made to evaluate the performance of the system before full scale deployment. The real-life deployment of the crack monitoring system is carried out on the surface of reactor containment building in Daya Bay Nuclear Power Station during the in-service pressure test with 30 wireless sensor nodes. PMID:27314357

Next-Generation Sequencing Platforms

NASA Astrophysics Data System (ADS)

Mardis, Elaine R.

2013-06-01

Automated DNA sequencing instruments embody an elegant interplay among chemistry, engineering, software, and molecular biology and have built upon Sanger's founding discovery of dideoxynucleotide sequencing to perform once-unfathomable tasks. Combined with innovative physical mapping approaches that helped to establish long-range relationships between cloned stretches of genomic DNA, fluorescent DNA sequencers produced reference genome sequences for model organisms and for the reference human genome. New types of sequencing instruments that permit amazing acceleration of data-collection rates for DNA sequencing have been developed. The ability to generate genome-scale data sets is now transforming the nature of biological inquiry. Here, I provide an historical perspective of the field, focusing on the fundamental developments that predated the advent of next-generation sequencing instruments and providing information about how these instruments work, their application to biological research, and the newest types of sequencers that can extract data from single DNA molecules.

The Science DMZ: A Network Design Pattern for Data-Intensive Science

DOE PAGES

Dart, Eli; Rotman, Lauren; Tierney, Brian; ...

2014-01-01

The ever-increasing scale of scientific data has become a significant challenge for researchers that rely on networks to interact with remote computing systems and transfer results to collaborators worldwide. Despite the availability of high-capacity connections, scientists struggle with inadequate cyberinfrastructure that cripples data transfer performance, and impedes scientific progress. The Science DMZ paradigm comprises a proven set of network design patterns that collectively address these problems for scientists. We explain the Science DMZ model, including network architecture, system configuration, cybersecurity, and performance tools, that creates an optimized network environment for science. We describe use cases from universities, supercomputing centers andmore » research laboratories, highlighting the effectiveness of the Science DMZ model in diverse operational settings. In all, the Science DMZ model is a solid platform that supports any science workflow, and flexibly accommodates emerging network technologies. As a result, the Science DMZ vastly improves collaboration, accelerating scientific discovery.« less

An interview with James Wilbur, Ph.D. General Manager, Life Sciences, Meso Scale Discovery.

PubMed

Wilbur, James

2004-06-01

James L. Wilbur, Ph.D. received a Bachelor's degree from the University of California, San Diego and a Ph.D. in Chemistry from Stanford University. After completing an NIH Postdoctoral Fellowship with Professor George M. Whitesides in the Department of Chemistry at Harvard University, he joined IGEN International, Inc., where he held a variety of positions in Research and Development. During that time, he was part of the team that developed the core technology and products for Meso Scale Discovery. He assumed his current position in 2001 when Meso Scale Discovery launched the products discussed here.

Mems: Platform for Large-Scale Integrated Vacuum Electronic Circuits

DTIC Science & Technology

2017-03-20

SECURITY CLASSIFICATION OF: The objective of the LIVEC advanced study project was to develop a platform for large-scale integrated vacuum electronic ...Distribution Unlimited UU UU UU UU 20-03-2017 1-Jul-2014 30-Jun-2015 Final Report: MEMS Platform for Large-Scale Integrated Vacuum Electronic ... Electronic Circuits (LIVEC) Contract No: W911NF-14-C-0093 COR Dr. James Harvey U.S. ARO RTP, NC 27709-2211 Phone: 702-696-2533 e-mail

Detail view of the aft section, port side, of the ...

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

Detail view of the aft section, port side, of the Orbiter Discovery from an elevated platform in the Vehicle Assembly Building at NASA's Kennedy Space Center. Note the removed Orbiter Maneuvering System/Reaction Control System pod from the base of the vertical stabilizer the strongback ground-support equipment attached to the payload bay door. This view is also a good view of the leading edge and top surface of the Orbiter wing. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Closeup detail of the jackstand head and the attach mechanism ...

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

Close-up detail of the jack-stand head and the attach mechanism connection to the hoist attach point on the starboard forward fuselage of the Orbiter Discovery. Note the profile of the wing intersection with the fuselage and the payload bay door in an open position with the strongback support structure attached. This view was taken from a service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

STS-56 Discovery, OV-103, lifts off from KSC LC Pad 39B into darkness

NASA Technical Reports Server (NTRS)

1993-01-01

STS-56 Discovery, Orbiter Vehicle (OV) 103, lifts off from Kennedy Space Center (KSC) Launch Complex (LC) Pad 39B into the early morning darkness at 1:29 am (Eastern Daylight Time (EDT)). OV-103, atop its external tank (ET) and flanked by solid rocket boosters (SRBs), rises above the mobile launcher platform. Exhaust plumes trail from the SRBs. The glow of the SRB / space shuttle main engine (SSME) firings illuminate the fixed service structure (FSS) tower. Trees are silhouetted against the launch fireworks in the foreground.

DOVIS: an implementation for high-throughput virtual screening using AutoDock.

PubMed

Zhang, Shuxing; Kumar, Kamal; Jiang, Xiaohui; Wallqvist, Anders; Reifman, Jaques

2008-02-27

Molecular-docking-based virtual screening is an important tool in drug discovery that is used to significantly reduce the number of possible chemical compounds to be investigated. In addition to the selection of a sound docking strategy with appropriate scoring functions, another technical challenge is to in silico screen millions of compounds in a reasonable time. To meet this challenge, it is necessary to use high performance computing (HPC) platforms and techniques. However, the development of an integrated HPC system that makes efficient use of its elements is not trivial. We have developed an application termed DOVIS that uses AutoDock (version 3) as the docking engine and runs in parallel on a Linux cluster. DOVIS can efficiently dock large numbers (millions) of small molecules (ligands) to a receptor, screening 500 to 1,000 compounds per processor per day. Furthermore, in DOVIS, the docking session is fully integrated and automated in that the inputs are specified via a graphical user interface, the calculations are fully integrated with a Linux cluster queuing system for parallel processing, and the results can be visualized and queried. DOVIS removes most of the complexities and organizational problems associated with large-scale high-throughput virtual screening, and provides a convenient and efficient solution for AutoDock users to use this software in a Linux cluster platform.

Novel nanoplasmonic biosensor integrated in a microfluidic channel

NASA Astrophysics Data System (ADS)

Solis-Tinoco, V.; Sepulveda, B.; Lechuga, L. M.

2015-06-01

An important motivation of the actual biosensor research is to develop a multiplexed sensing platform of high sensitivity fabricated with large-scale and low-cost technologies for applications such as diagnosis and monitoring of diseases, drug discovery and environmental control. Biosensors based on localized plasmon resonance (LSPR) have demonstrated to be a novel and effective platform for quantitative detection of biological and chemical analytes. Here, we describe a novel label-free nanobiosensor consisting of an array of closely spaced, vertical, elastomeric nanopillars capped with plasmonic gold nanodisks in a SU-8 channel. The principle is based on the refractive index sensing using the LSPR of gold nanodisks. The fabrication of the nanobiosensor is based on replica molding technique and gold nanodisks are incorporated on the polymer structures by e-beam evaporation. In this work, we provide the strategies for controlling the silicon nanostructure replication using thermal polymers and photopolymers with different Young's modulus, in order to minimize the common distortions in the process and to obtain a reliable replica of the Si master. The master mold of the biosensor consists of a hexagonal array of silicon nanopillars, whose diameter is ~200 nm, and whose height can range from 250 nm to 1.300 μm, separated 400 nm from the center to center, integrated in a SU-8 microfluidic channel.

Efficient ethanol production from brown macroalgae sugars by a synthetic yeast platform.

PubMed

Enquist-Newman, Maria; Faust, Ann Marie E; Bravo, Daniel D; Santos, Christine Nicole S; Raisner, Ryan M; Hanel, Arthur; Sarvabhowman, Preethi; Le, Chi; Regitsky, Drew D; Cooper, Susan R; Peereboom, Lars; Clark, Alana; Martinez, Yessica; Goldsmith, Joshua; Cho, Min Y; Donohoue, Paul D; Luo, Lily; Lamberson, Brigit; Tamrakar, Pramila; Kim, Edward J; Villari, Jeffrey L; Gill, Avinash; Tripathi, Shital A; Karamchedu, Padma; Paredes, Carlos J; Rajgarhia, Vineet; Kotlar, Hans Kristian; Bailey, Richard B; Miller, Dennis J; Ohler, Nicholas L; Swimmer, Candace; Yoshikuni, Yasuo

2014-01-09

The increasing demands placed on natural resources for fuel and food production require that we explore the use of efficient, sustainable feedstocks such as brown macroalgae. The full potential of brown macroalgae as feedstocks for commercial-scale fuel ethanol production, however, requires extensive re-engineering of the alginate and mannitol catabolic pathways in the standard industrial microbe Saccharomyces cerevisiae. Here we present the discovery of an alginate monomer (4-deoxy-L-erythro-5-hexoseulose uronate, or DEHU) transporter from the alginolytic eukaryote Asteromyces cruciatus. The genomic integration and overexpression of the gene encoding this transporter, together with the necessary bacterial alginate and deregulated native mannitol catabolism genes, conferred the ability of an S. cerevisiae strain to efficiently metabolize DEHU and mannitol. When this platform was further adapted to grow on mannitol and DEHU under anaerobic conditions, it was capable of ethanol fermentation from mannitol and DEHU, achieving titres of 4.6% (v/v) (36.2 g l(-1)) and yields up to 83% of the maximum theoretical yield from consumed sugars. These results show that all major sugars in brown macroalgae can be used as feedstocks for biofuels and value-added renewable chemicals in a manner that is comparable to traditional arable-land-based feedstocks.

A Tale of Two Discoveries: Comparing the Usability of Summon and EBSCO Discovery Service

ERIC Educational Resources Information Center

Foster, Anita K.; MacDonald, Jean B.

2013-01-01

Web-scale discovery systems are gaining momentum among academic libraries as libraries seek a means to provide their users with a one-stop searching experience. Illinois State University's Milner Library found itself in the unique position of having access to two distinct discovery products, EBSCO Discovery Service and Serials Solutions' Summon.…

Computer-aided drug design at Boehringer Ingelheim

NASA Astrophysics Data System (ADS)

Muegge, Ingo; Bergner, Andreas; Kriegl, Jan M.

2017-03-01

Computer-Aided Drug Design (CADD) is an integral part of the drug discovery endeavor at Boehringer Ingelheim (BI). CADD contributes to the evaluation of new therapeutic concepts, identifies small molecule starting points for drug discovery, and develops strategies for optimizing hit and lead compounds. The CADD scientists at BI benefit from the global use and development of both software platforms and computational services. A number of computational techniques developed in-house have significantly changed the way early drug discovery is carried out at BI. In particular, virtual screening in vast chemical spaces, which can be accessed by combinatorial chemistry, has added a new option for the identification of hits in many projects. Recently, a new framework has been implemented allowing fast, interactive predictions of relevant on and off target endpoints and other optimization parameters. In addition to the introduction of this new framework at BI, CADD has been focusing on the enablement of medicinal chemists to independently perform an increasing amount of molecular modeling and design work. This is made possible through the deployment of MOE as a global modeling platform, allowing computational and medicinal chemists to freely share ideas and modeling results. Furthermore, a central communication layer called the computational chemistry framework provides broad access to predictive models and other computational services.

Accessing Nature’s diversity through metabolic engineering and synthetic biology

PubMed Central

King, Jason R.; Edgar, Steven; Qiao, Kangjian; Stephanopoulos, Gregory

2016-01-01

In this perspective, we highlight recent examples and trends in metabolic engineering and synthetic biology that demonstrate the synthetic potential of enzyme and pathway engineering for natural product discovery. In doing so, we introduce natural paradigms of secondary metabolism whereby simple carbon substrates are combined into complex molecules through “scaffold diversification”, and subsequent “derivatization” of these scaffolds is used to synthesize distinct complex natural products. We provide examples in which modern pathway engineering efforts including combinatorial biosynthesis and biological retrosynthesis can be coupled to directed enzyme evolution and rational enzyme engineering to allow access to the “privileged” chemical space of natural products in industry-proven microbes. Finally, we forecast the potential to produce natural product-like discovery platforms in biological systems that are amenable to single-step discovery, validation, and synthesis for streamlined discovery and production of biologically active agents. PMID:27081481

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

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

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

Microbial Efflux Pump Inhibition: Tactics and Strategies

PubMed Central

Tegos, George P.; Haynes, Mark; Strouse, J. Jacob; Khan, Mohiuddin Md. T.; Bologa, Cristian G.; Oprea, Tudor I.; Sklar, Larry A.

2013-01-01

Traditional antimicrobials are increasingly suffering from the emergence of multidrug resistance among pathogenic microorganisms. To overcome these deficiencies, a range of novel approaches to control microbial infections are under investigation as potential alternative treatments. Multidrug efflux is a key target of these efforts. Efflux mechanisms are broadly recognized as major components of resistance to many classes of chemotherapeutic agents as well as antimicrobials. Efflux occurs due to the activity of membrane transporter proteins widely known as Multidrug Efflux Systems (MES). They are implicated in a variety of physiological roles other than efflux and identifying natural substrates and inhibitors is an active and expanding research discipline. One plausible alternative is the combination of conventional antimicrobial agents/antibiotics with small molecules that block MES known as multidrug efflux pump inhibitors (EPIs). An array of approaches in academic and industrial research settings, varying from high-throughput screening (HTS) ventures to bioassay guided purification and determination, have yielded a number of promising EPIs in a series of pathogenic systems. This synergistic discovery platform has been exploited in translational directions beyond the potentiation of conventional antimicrobial treatments. This venture attempts to highlight different tactical elements of this platform, identifying the need for highly informative and comprehensive EPI-discovery strategies. Advances in assay development genomics, proteomics as well as the accumulation of bioactivity and structural information regarding MES facilitates the basis for a new discovery era. This platform is expanding drastically. A combination of chemogenomics and chemoinformatics approaches will integrate data mining with virtual and physical HTS ventures and populate the chemical-biological interface with a plethora of novel chemotypes. This comprehensive step will expedite the preclinical development of lead EPIs. PMID:21470111

Data Mining and Knowledge Discovery tools for exploiting big Earth-Observation data

NASA Astrophysics Data System (ADS)

Espinoza Molina, D.; Datcu, M.

2015-04-01

The continuous increase in the size of the archives and in the variety and complexity of Earth-Observation (EO) sensors require new methodologies and tools that allow the end-user to access a large image repository, to extract and to infer knowledge about the patterns hidden in the images, to retrieve dynamically a collection of relevant images, and to support the creation of emerging applications (e.g.: change detection, global monitoring, disaster and risk management, image time series, etc.). In this context, we are concerned with providing a platform for data mining and knowledge discovery content from EO archives. The platform's goal is to implement a communication channel between Payload Ground Segments and the end-user who receives the content of the data coded in an understandable format associated with semantics that is ready for immediate exploitation. It will provide the user with automated tools to explore and understand the content of highly complex images archives. The challenge lies in the extraction of meaningful information and understanding observations of large extended areas, over long periods of time, with a broad variety of EO imaging sensors in synergy with other related measurements and data. The platform is composed of several components such as 1.) ingestion of EO images and related data providing basic features for image analysis, 2.) query engine based on metadata, semantics and image content, 3.) data mining and knowledge discovery tools for supporting the interpretation and understanding of image content, 4.) semantic definition of the image content via machine learning methods. All these components are integrated and supported by a relational database management system, ensuring the integrity and consistency of Terabytes of Earth Observation data.

Case study: impact of technology investment on lead discovery at Bristol-Myers Squibb, 1998-2006.

PubMed

Houston, John G; Banks, Martyn N; Binnie, Alastair; Brenner, Stephen; O'Connell, Jonathan; Petrillo, Edward W

2008-01-01

We review strategic approaches taken over an eight-year period at BMS to implement new high-throughput approaches to lead discovery. Investments in compound management infrastructure and chemistry library production capability allowed significant growth in the size, diversity and quality of the BMS compound collection. Screening platforms were upgraded with robust automated technology to support miniaturized assay formats, while workflows and information handling technologies were streamlined for improved performance. These technology changes drove the need for a supporting organization in which critical engineering, informatics and scientific skills were more strongly represented. Taken together, these investments led to significant improvements in speed and productivity as well a greater impact of screening campaigns on the initiation of new drug discovery programs.

KSC-05PD-0633

NASA Technical Reports Server (NTRS)

2005-01-01

KENNEDY SPACE CENTER, FLA. Space Shuttle Discovery lingers at the foot of Launch Pad 39B in the evening twilight. First motion from the Vehicle Assembly Building was at 2:04 p.m. EDT April 6, and the Shuttle was hard down on the pad at 1:16 a.m. EDT April 7. The Shuttle sits atop a Mobile Launcher Platform transported by a Crawler-Transporter underneath. Launch of Discovery on its Return to Flight mission, STS-114, is targeted for May 15 with a launch window that extends to June 3. During its 12-day mission, Discoverys seven-member crew will test new hardware and techniques to improve Shuttle safety, as well as deliver supplies to the International Space Station. Photo courtesy of Scott Andrews.

Detail view of the lower portion of the vertical stabilizer ...

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

Detail view of the lower portion of the vertical stabilizer of the Orbiter Discovery. The section below the rudder, often referred to as the "stinger", is used to house the orbiter drag chute assembly. The system consisted of a mortar deployed pilot chute, the main drag chute, a controller assembly and an attach/jettison mechanism. This system was a modification to the original design of the Orbiter Discovery to safely reduce the roll to stop distance without adversely affecting the vehicle handling qualities. This view was taken from a service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

The Z1 truss is transported to Launch Pad 39A

NASA Technical Reports Server (NTRS)

2000-01-01

At Launch Pad 39A, the payload canister with the Integrated Truss Structure Z1 inside arrives at the spot under the Rotating Service Structure where the canister can be lifted to the Payload Changeout Room. There the Z1 truss will be removed and later transferred to Space Shuttle Discovery's payload bay. Discovery is at right, sitting atop the Mobile Launcher Platform. The Z1 truss is the first of 10 that will become the backbone of the International Space Station, eventually stretching the length of a football field. Along with its companion payload, the third Pressurized Mating Adapter, the Z1 is scheduled to be launched aboard Discovery Oct. 5 at 9:38 p.m. EDT.

KSC-2010-4716

NASA Image and Video Library

2010-09-20

CAPE CANAVERAL, Fla. -- Bathed in bright xenon lights, space shuttle Discovery makes its nighttime trek, known as "rollout," from the Vehicle Assembly Building to Launch Pad 39A at NASA's Kennedy Space Center in Florida. It will take the shuttle, attached to its external fuel tank, twin solid rocket boosters and mobile launcher platform, about six hours to complete the move atop a crawler-transporter. Rollout sets the stage for Discovery's STS-133 crew to practice countdown and launch procedures during the Terminal Countdown Demonstration Test in mid-October. Targeted to liftoff Nov. 1, Discovery will take the Permanent Multipurpose Module (PMM) packed with supplies and critical spare parts, as well as Robonaut 2 (R2) to the International Space Station. Photo credit: NASA/Frankie Martin

KSC-2010-4707

NASA Image and Video Library

2010-09-20

CAPE CANAVERAL, Fla. -- Bathed in bright xenon lights, space shuttle Discovery makes its nighttime trek, known as "rollout," from the Vehicle Assembly Building to Launch Pad 39A at NASA's Kennedy Space Center in Florida. It will take the shuttle, attached to its external fuel tank, twin solid rocket boosters and mobile launcher platform, about six hours to complete the move atop a crawler-transporter. Rollout sets the stage for Discovery's STS-133 crew to practice countdown and launch procedures during the Terminal Countdown Demonstration Test in mid-October. Targeted to liftoff Nov. 1, Discovery will take the Permanent Multipurpose Module (PMM) packed with supplies and critical spare parts, as well as Robonaut 2 (R2) to the International Space Station. Photo credit: NASA/Jim Grossmann

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

PubMed Central

2014-01-01

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

Optimization of miRNA-seq data preprocessing.

PubMed

Tam, Shirley; Tsao, Ming-Sound; McPherson, John D

2015-11-01

The past two decades of microRNA (miRNA) research has solidified the role of these small non-coding RNAs as key regulators of many biological processes and promising biomarkers for disease. The concurrent development in high-throughput profiling technology has further advanced our understanding of the impact of their dysregulation on a global scale. Currently, next-generation sequencing is the platform of choice for the discovery and quantification of miRNAs. Despite this, there is no clear consensus on how the data should be preprocessed before conducting downstream analyses. Often overlooked, data preprocessing is an essential step in data analysis: the presence of unreliable features and noise can affect the conclusions drawn from downstream analyses. Using a spike-in dilution study, we evaluated the effects of several general-purpose aligners (BWA, Bowtie, Bowtie 2 and Novoalign), and normalization methods (counts-per-million, total count scaling, upper quartile scaling, Trimmed Mean of M, DESeq, linear regression, cyclic loess and quantile) with respect to the final miRNA count data distribution, variance, bias and accuracy of differential expression analysis. We make practical recommendations on the optimal preprocessing methods for the extraction and interpretation of miRNA count data from small RNA-sequencing experiments. © The Author 2015. Published by Oxford University Press.

New experimental models of the blood-brain barrier for CNS drug discovery

PubMed Central

Kaisar, Mohammad A.; Sajja, Ravi K.; Prasad, Shikha; Abhyankar, Vinay V.; Liles, Taylor; Cucullo, Luca

2017-01-01

Introduction The blood-brain barrier (BBB) is a dynamic biological interface which actively controls the passage of substances between the blood and the central nervous system (CNS). From a biological and functional standpoint, the BBB plays a crucial role in maintaining brain homeostasis inasmuch that deterioration of BBB functions are prodromal to many CNS disorders. Conversely, the BBB hinders the delivery of drugs targeting the brain to treat a variety of neurological diseases. Area covered This article reviews recent technological improvements and innovation in the field of BBB modeling including static and dynamic cell-based platforms, microfluidic systems and the use of stem cells and 3D printing technologies. Additionally, the authors laid out a roadmap for the integration of microfluidics and stem cell biology as a holistic approach for the development of novel in vitro BBB platforms. Expert opinion Development of effective CNS drugs has been hindered by the lack of reliable strategies to mimic the BBB and cerebrovascular impairments in vitro. Technological advancements in BBB modeling have fostered the development of highly integrative and quasi- physiological in vitro platforms to support the process of drug discovery. These advanced in vitro tools are likely to further current understanding of the cerebrovascular modulatory mechanisms. PMID:27782770

Orthogonal Chip Based Electronic Sensors for Chemical Agents

DTIC Science & Technology

2012-04-06

operation with ultralow power requirements. This work has been carried out with the aid of substrate wafers provided by Qualcomm . The initial...produced by Qualcomm as a less expensive OTFT platform for sensors. 8. New Discoveries Air-stable organic thin-film transistor (OTFT) sensors

GeneLab: NASA's Open Access, Collaborative Platform for Systems Biology and Space Medicine

NASA Technical Reports Server (NTRS)

Berrios, Daniel C.; Thompson, Terri G.; Fogle, Homer W.; Rask, Jon C.; Coughlan, Joseph C.

2015-01-01

NASA is investing in GeneLab1 (http:genelab.nasa.gov), a multi-year effort to maximize utilization of the limited resources to conduct biological and medical research in space, principally aboard the International Space Station (ISS). High-throughput genomic, transcriptomic, proteomic or other omics analyses from experiments conducted on the ISS will be stored in the GeneLab Data Systems (GLDS), an open-science information system that will also include a biocomputation platform with collaborative science capabilities, to enable the discovery and validation of molecular networks.

A Fluorescence Displacement Assay for Antidepressant Drug Discovery Based on Ligand-Conjugated Quantum Dots

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

Chang, Jerry; Tomlinson, Ian; Warnement, Michael

2011-01-01

The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) protein plays a central role in terminating 5-HT neurotransmission and is the most important therapeutic target for the treatment of major depression and anxiety disorders. We report an innovative, versatile, and target-selective quantum dot (QD) labeling approach for SERT in single Xenopus oocytes that can be adopted as a drug-screening platform. Our labeling approach employs a custom-made, QD-tagged indoleamine derivative ligand, IDT318, that is structurally similar to 5-HT and accesses the primary binding site with enhanced human SERT selectivity. Incubating QD-labeled oocytes with paroxetine (Paxil), a high-affinity SERT-specific inhibitor, showed a concentration- and time-dependentmore » decrease in QD fluorescence, demonstrating the utility of our approach for the identification of SERT modulators. Furthermore, with the development of ligands aimed at other pharmacologically relevant targets, our approach may potentially form the basis for a multitarget drug discovery platform.« less

A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank

PubMed Central

Toledo, Jon B.; Van Deerlin, Vivianna M.; Lee, Edward B.; Suh, EunRan; Baek, Young; Robinson, John L.; Xie, Sharon X.; McBride, Jennifer; Wood, Elisabeth M.; Schuck, Theresa; Irwin, David J.; Gross, Rachel G.; Hurtig, Howard; McCluskey, Leo; Elman, Lauren; Karlawish, Jason; Schellenberg, Gerard; Chen-Plotkin, Alice; Wolk, David; Grossman, Murray; Arnold, Steven E.; Shaw, Leslie M.; Lee, Virginia M.-Y.; Trojanowski, John Q.

2014-01-01

Neurodegenerative diseases (NDs) are defined by the accumulation of abnormal protein deposits in the central nervous system (CNS), and only neuropathological examination enables a definitive diagnosis. Brain banks and their associated scientific programs have shaped the actual knowledge of NDs, identifying and characterizing the CNS deposits that define new diseases, formulating staging schemes, and establishing correlations between neuropathological changes and clinical features. However, brain banks have evolved to accommodate the banking of biofluids as well as DNA and RNA samples. Moreover, the value of biobanks is greatly enhanced if they link all the multidimensional clinical and laboratory information of each case, which is accomplished, optimally, using systematic and standardized operating procedures, and in the framework of multidisciplinary teams with the support of a flexible and user-friendly database system that facilitates the sharing of information of all the teams in the network. We describe a biobanking system that is a platform for discovery research at the Center for Neurodegenerative Disease Research at the University of Pennsylvania. PMID:23978324

Knowledge Discovery for Smart Grid Operation, Control, and Situation Awareness -- A Big Data Visualization Platform

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

Gu, Yi; Jiang, Huaiguang; Zhang, Yingchen

In this paper, a big data visualization platform is designed to discover the hidden useful knowledge for smart grid (SG) operation, control and situation awareness. The spawn of smart sensors at both grid side and customer side can provide large volume of heterogeneous data that collect information in all time spectrums. Extracting useful knowledge from this big-data poll is still challenging. In this paper, the Apache Spark, an open source cluster computing framework, is used to process the big-data to effectively discover the hidden knowledge. A high-speed communication architecture utilizing the Open System Interconnection (OSI) model is designed to transmitmore » the data to a visualization platform. This visualization platform uses Google Earth, a global geographic information system (GIS) to link the geological information with the SG knowledge and visualize the information in user defined fashion. The University of Denver's campus grid is used as a SG test bench and several demonstrations are presented for the proposed platform.« less

Organ-On-A-Chip Platforms: A Convergence of Advanced Materials, Cells, and Microscale Technologies.

PubMed

Ahadian, Samad; Civitarese, Robert; Bannerman, Dawn; Mohammadi, Mohammad Hossein; Lu, Rick; Wang, Erika; Davenport-Huyer, Locke; Lai, Ben; Zhang, Boyang; Zhao, Yimu; Mandla, Serena; Korolj, Anastasia; Radisic, Milica

2018-01-01

Significant advances in biomaterials, stem cell biology, and microscale technologies have enabled the fabrication of biologically relevant tissues and organs. Such tissues and organs, referred to as organ-on-a-chip (OOC) platforms, have emerged as a powerful tool in tissue analysis and disease modeling for biological and pharmacological applications. A variety of biomaterials are used in tissue fabrication providing multiple biological, structural, and mechanical cues in the regulation of cell behavior and tissue morphogenesis. Cells derived from humans enable the fabrication of personalized OOC platforms. Microscale technologies are specifically helpful in providing physiological microenvironments for tissues and organs. In this review, biomaterials, cells, and microscale technologies are described as essential components to construct OOC platforms. The latest developments in OOC platforms (e.g., liver, skeletal muscle, cardiac, cancer, lung, skin, bone, and brain) are then discussed as functional tools in simulating human physiology and metabolism. Future perspectives and major challenges in the development of OOC platforms toward accelerating clinical studies of drug discovery are finally highlighted. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Simultaneous electrical recording of cardiac electrophysiology and contraction on chip

DOE PAGES

Qian, Fang; Huang, Chao; Lin, Yi-Dong; ...

2017-04-18

Prevailing commercialized cardiac platforms for in vitro drug development utilize planar microelectrode arrays to map action potentials, or impedance sensing to record contraction in real time, but cannot record both functions on the same chip with high spatial resolution. We report a novel cardiac platform that can record cardiac tissue adhesion, electrophysiology, and contractility on the same chip. The platform integrates two independent yet interpenetrating sensor arrays: a microelectrode array for field potential readouts and an interdigitated electrode array for impedance readouts. Together, these arrays provide real-time, non-invasive data acquisition of both cardiac electrophysiology and contractility under physiological conditions andmore » under drug stimuli. Furthermore, we cultured human induced pluripotent stem cell-derived cardiomyocytes as a model system, and used to validate the platform with an excitation–contraction decoupling chemical. Preliminary data using the platform to investigate the effect of the drug norepinephrine are combined with computational efforts. Finally, this platform provides a quantitative and predictive assay system that can potentially be used for comprehensive assessment of cardiac toxicity earlier in the drug discovery process.« less

Simultaneous electrical recording of cardiac electrophysiology and contraction on chip

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

Qian, Fang; Huang, Chao; Lin, Yi-Dong

Prevailing commercialized cardiac platforms for in vitro drug development utilize planar microelectrode arrays to map action potentials, or impedance sensing to record contraction in real time, but cannot record both functions on the same chip with high spatial resolution. We report a novel cardiac platform that can record cardiac tissue adhesion, electrophysiology, and contractility on the same chip. The platform integrates two independent yet interpenetrating sensor arrays: a microelectrode array for field potential readouts and an interdigitated electrode array for impedance readouts. Together, these arrays provide real-time, non-invasive data acquisition of both cardiac electrophysiology and contractility under physiological conditions andmore » under drug stimuli. Furthermore, we cultured human induced pluripotent stem cell-derived cardiomyocytes as a model system, and used to validate the platform with an excitation–contraction decoupling chemical. Preliminary data using the platform to investigate the effect of the drug norepinephrine are combined with computational efforts. Finally, this platform provides a quantitative and predictive assay system that can potentially be used for comprehensive assessment of cardiac toxicity earlier in the drug discovery process.« less

Can We Build an Open-Science Model to Fund Young, Risky, Blue-Sky Research? First Insights into Funding Geoscientists Via Thinkable.Org

NASA Astrophysics Data System (ADS)

McNeil, B.

2014-12-01

Some of the biggest discoveries and advances in geoscience research have come from purely curiosity-driven, blue-sky research. Marine biologist Osamu Shimomura's discovery of Green-Fluorecent Protein (GFP) in the 1960s during his postdoc is just one example, which came about through his interest and pursuit of how certain jellyfish bioluminescence. His discovery would eventually revolutionise medicine, culminating in a Nobel Prize in Chemistry in 2008. Despite the known importance of "blue-sky" research that doesn't have immediate commercial or social applications, it continues to struggle for funding from both government and industry. Success rates for young scientists also continue to decline within the government competitive granting models due to the importance of track records, yet history tells us that young scientists tend to come up with science's greatest discoveries. The digital age however, gives us a new opportunity to create an alternative and sustainable funding model for young, risky, blue-sky science that tends not to be supported by governments and industry anymore. Here I will discuss how new digital platforms empower researchers and organisations to showcase their research using video, allowing wider community engagment and funding that can be used to directly support young, risky, blue-sky research that is so important to the future of science. I will then talk about recent experience with this model from some ocean researchers who used a new platform called thinkable.org to showcase and raise funding via the public.

Constellation Pharmacology: A new paradigm for drug discovery

PubMed Central

Schmidt, Eric W.; Olivera, Baldomero M.

2015-01-01

Constellation Pharmacology is a cell-based high-content phenotypic-screening platform that utilizes subtype-selective pharmacological agents to elucidate the cell-specific combinations (“constellations”) of key signaling proteins that define specific cell types. Heterogeneous populations of native cells, in which the different individual cell types have been identified and characterized, are the foundation for this screening platform. Constellation Pharmacology is useful for screening small molecules or for deconvoluting complex mixtures of biologically-active natural products. This platform has been used to purify natural products and discover their molecular mechanisms. In the on-going development of Constellation Pharmacology, there is a positive-feedback loop between the pharmacological characterization of cell types and screening for new drug candidates. As Constellation Pharmacology is used to discover compounds with novel targeting-selectivity profiles, those new compounds then further help to elucidate the constellations of specific cell types, thereby increasing the content of this high-content platform. PMID:25562646

An integrated micromechanical large particle in flow sorter (MILPIS)

NASA Astrophysics Data System (ADS)

Fuad, Nurul M.; Skommer, Joanna; Friedrich, Timo; Kaslin, Jan; Wlodkowic, Donald

2015-06-01

At present, the major hurdle to widespread deployment of zebrafish embryo and larvae in large-scale drug development projects is lack of enabling high-throughput analytical platforms. In order to spearhead drug discovery with the use of zebrafish as a model, platforms need to integrate automated pre-test sorting of organisms (to ensure quality control and standardization) and their in-test positioning (suitable for high-content imaging) with modules for flexible drug delivery. The major obstacle hampering sorting of millimetre sized particles such as zebrafish embryos on chip-based devices is their substantial diameter (above one millimetre), mass (above one milligram), which both lead to rapid gravitational-induced sedimentation and high inertial forces. Manual procedures associated with sorting hundreds of embryos are very monotonous and as such prone to significant analytical errors due to operator's fatigue. In this work, we present an innovative design of a micromechanical large particle in-flow sorter (MILPIS) capable of analysing, sorting and dispensing living zebrafish embryos for drug discovery applications. The system consisted of a microfluidic network, revolving micromechanical receptacle actuated by robotic servomotor and opto-electronic sensing module. The prototypes were fabricated in poly(methyl methacrylate) (PMMA) transparent thermoplastic using infrared laser micromachining. Elements of MILPIS were also fabricated in an optically transparent VisiJet resin using 3D stereolithography (SLA) processes (ProJet 7000HD, 3D Systems). The device operation was based on a rapidly revolving miniaturized mechanical receptacle. The latter function was to hold and position individual fish embryos for (i) interrogation, (ii) sorting decision-making and (iii) physical sorting..The system was designed to separate between fertilized (LIVE) and non-fertilized (DEAD) eggs, based on optical transparency using infrared (IR) emitters and receivers embedded in the system. Digital oscilloscope were used to distinguish the diffraction signals from IR sensors when both LIVE and DEAD embryos were flow through in the chip. Image process analysis were also used as detection module to track DEAD embryos as it flowed in the channel.

The shock/shear platform for planar radiation-hydrodynamics experiments on the National Ignition Facility

DOE PAGES

Doss, F. W.; Kline, J. L.; Flippo, K. A.; ...

2015-04-17

An indirectly-driven shock tube experiment fielded on the National Ignition Facility (NIF) was used to create a high-energy-density hydrodynamics platform at unprecedented scale. Scaling up a shear-induced mixing experiment previously fielded at OMEGA, the NIF shear platform drives 130 μm/ns shocks into a CH foam-filled shock tube (~ 60 mg/cc) with interior dimensions of 1.5 mm diameter and 5 mm length. The pulse-shaping capabilities of the NIF are used to extend the drive for >10 ns, and the large interior tube volumes are used to isolate physics-altering edge effects from the region of interest. The scaling of the experiment tomore » the NIF allows for considerable improvement in maximum driving time of hydrodynamics, in fidelity of physics under examination, and in diagnostic clarity. Details of the experimental platform and post-shot simulations used in the analysis of the platform-qualifying data are presented. Hydrodynamic scaling is used to compare shear data from OMEGA with that from NIF, suggesting a possible change in the dimensionality of the instability at late times from one platform to the other.« less

TOXICOGENOMICS DRUG DISCOVERY AND THE PATHOLOGIST

EPA Science Inventory

Toxicogenomics, drug discovery, and pathologist.

The field of toxicogenomics, which currently focuses on the application of large-scale differential gene expression (DGE) data to toxicology, is starting to influence drug discovery and development in the pharmaceutical indu...

"Pretty Rad": Explorations in User Satisfaction with a Discovery Layer at Ryerson University

ERIC Educational Resources Information Center

Lundrigan, Courtney; Manuel, Kevin; Yan, May

2015-01-01

Web-scale discovery systems are becoming prevalent in research libraries. Although a number of studies have explored various impacts of discovery systems, few studies exist on user satisfaction. The investigators of this study evaluated user satisfaction with the discovery service Summon at Ryerson University, using online questionnaires and…

The Pilot Project 'Optical Image Correlation' of the ESA Geohazards Thematic Exploitation Platform (GTEP)

NASA Astrophysics Data System (ADS)

Stumpf, André; Malet, Jean-Philippe

2016-04-01

Since more than 20 years, "Earth Observation" (EO) satellites developed or operated by ESA have provided a wealth of data. In the coming years, the Sentinel missions, along with the Copernicus Contributing Missions as well as Earth Explorers and other, Third Party missions will provide routine monitoring of our environment at the global scale, thereby delivering an unprecedented amount of data. While the availability of the growing volume of environmental data from space represents a unique opportunity for science, general R&D, and applications, it also poses major challenges to fully exploit the potential of archived and daily incoming datasets. Those challenges do not only comprise the discovery, access, processing, and visualization of large data volumes but also an increasing diversity of data sources and end users from different fields (e.g. EO, in-situ monitoring, and modeling). In this context, the GTEP (Geohazards Thematic Exploitation Platform) initiative aims to build an operational distributed processing platform to maximize the exploitation of EO data from past and future satellite missions for the detection and monitoring of natural hazards. This presentation focuses on the "Optical Image Correlation" Pilot Project (funded by ESA within the GTEP platform) which objectives are to develop an easy-to-use, flexible and distributed processing chain for: 1) the automated reconstruction of surface Digital Elevation Models from stereo (and tristereo) pairs of Spot 6/7 and Pléiades satellite imagery, 2) the creation of ortho-images (panchromatic and multi-spectral) of Landsat 8, Sentinel-2, Spot 6/7 and Pléiades scenes, 3) the calculation of horizontal (E-N) displacement vectors based on sub-pixel image correlation. The processing chains is being implemented on the GEP cloud-based (Hadoop, MapReduce) environment and designed for analysis of surface displacements at local to regional scale (10-1000 km2) targeting in particular co-seismic displacement and slow-moving landslides. The processing targets both the analysis of time-series of archived data (Pléiades, Landsat 8) and current satellite missions Spot 6/7 and Sentinel-2. The possibility of rapid calculation in near-real time is an important aspect of the design of the processing chain. Archived datasets will be processed for some 'demonstrator' test sites in order to develop and test the implemented workflows.

Large-scale transcriptome characterization and mass discovery of SNPs in globe artichoke and its related taxa.

PubMed

Scaglione, Davide; Lanteri, Sergio; Acquadro, Alberto; Lai, Zhao; Knapp, Steven J; Rieseberg, Loren; Portis, Ezio

2012-10-01

Cynara cardunculus (2n = 2× = 34) is a member of the Asteraceae family that contributes significantly to the agricultural economy of the Mediterranean basin. The species includes two cultivated varieties, globe artichoke and cardoon, which are grown mainly for food. Cynara cardunculus is an orphan crop species whose genome/transcriptome has been relatively unexplored, especially in comparison to other Asteraceae crops. Hence, there is a significant need to improve its genomic resources through the identification of novel genes and sequence-based markers, to design new breeding schemes aimed at increasing quality and crop productivity. We report the outcome of cDNA sequencing and assembly for eleven accessions of C. cardunculus. Sequencing of three mapping parental genotypes using Roche 454-Titanium technology generated 1.7 × 10⁶ reads, which were assembled into 38,726 reference transcripts covering 32 Mbp. Putative enzyme-encoding genes were annotated using the KEGG-database. Transcription factors and candidate resistance genes were surveyed as well. Paired-end sequencing was done for cDNA libraries of eight other representative C. cardunculus accessions on an Illumina Genome Analyzer IIx, generating 46 × 10⁶ reads. Alignment of the IGA and 454 reads to reference transcripts led to the identification of 195,400 SNPs with a Bayesian probability exceeding 95%; a validation rate of 90% was obtained by Sanger-sequencing of a subset of contigs. These results demonstrate that the integration of data from different NGS platforms enables large-scale transcriptome characterization, along with massive SNP discovery. This information will contribute to the dissection of key agricultural traits in C. cardunculus and facilitate the implementation of marker-assisted selection programs. © 2012 The Authors. Plant Biotechnology Journal © 2012 Society for Experimental Biology, Association of Applied Biologists and Blackwell Publishing Ltd.

Implementation of a protein profiling platform developed as an academic-pharmaceutical industry collaborative effort.

PubMed

Végvári, Akos; Magnusson, Mattias; Wallman, Lars; Ekström, Simon; Bolmsjö, Gunnar; Nilsson, Johan; Miliotis, Tasso; Ostling, Jörgen; Kjellström, Sven; Ottervald, Jan; Franzén, Bo; Hultberg, Hans; Marko-Varga, György; Laurell, Thomas

2008-06-01

As much attention has devoted to the proteome research during the last few years, biomarker discovery has become an increasingly hot area, potentially enabling the development of new assays for diagnosis and prognosis of severe diseases. This is the field of research interest where efforts originating from both academic and industrial groups should jointly work on solutions. In this paper, we would like to demonstrate the fruitful combination of both research domains where the scientific crossroads sprout fresh ideas from the basic research domain and how these are refined and tethered to industrial standards. We will present an approach that is based on novel microfluidic devices, utilizing their benefits in processing small-volume samples. Our biomarker discovery strategy, built around this platform, involves optimized samples processing (based on SPE and sample enrichment) and fast MALDI-MS readout. The identification of novel biomarkers at low-abundance level has been achieved by the utilization of a miniaturized sample handling platform, which offers clean-up and enrichment of proteins in one step. Complete automation has been realized in the form of a unique robotic instrumentation that is able to extract and transfer 96 samples onto standard MALDI target plates with high throughput. The developed platform was operated with a 60 sample turnaround per hour allowing sensitivities in femtomol regions of medium- and low-abundant target proteins from clinical studies on samples of multiple sclerosis and gastroesophageal reflux disease. Several proteins have been identified as new biomarkers from cerebrospinal fluid and esophagus epithelial cells.

High-throughput electrophysiological assays for voltage gated ion channels using SyncroPatch 768PE.

PubMed

Li, Tianbo; Lu, Gang; Chiang, Eugene Y; Chernov-Rogan, Tania; Grogan, Jane L; Chen, Jun

2017-01-01

Ion channels regulate a variety of physiological processes and represent an important class of drug target. Among the many methods of studying ion channel function, patch clamp electrophysiology is considered the gold standard by providing the ultimate precision and flexibility. However, its utility in ion channel drug discovery is impeded by low throughput. Additionally, characterization of endogenous ion channels in primary cells remains technical challenging. In recent years, many automated patch clamp (APC) platforms have been developed to overcome these challenges, albeit with varying throughput, data quality and success rate. In this study, we utilized SyncroPatch 768PE, one of the latest generation APC platforms which conducts parallel recording from two-384 modules with giga-seal data quality, to push these 2 boundaries. By optimizing various cell patching parameters and a two-step voltage protocol, we developed a high throughput APC assay for the voltage-gated sodium channel Nav1.7. By testing a group of Nav1.7 reference compounds' IC50, this assay was proved to be highly consistent with manual patch clamp (R > 0.9). In a pilot screening of 10,000 compounds, the success rate, defined by > 500 MΩ seal resistance and >500 pA peak current, was 79%. The assay was robust with daily throughput ~ 6,000 data points and Z' factor 0.72. Using the same platform, we also successfully recorded endogenous voltage-gated potassium channel Kv1.3 in primary T cells. Together, our data suggest that SyncroPatch 768PE provides a powerful platform for ion channel research and drug discovery.

Potential biological targets for bioassay development in drug discovery of Sturge-Weber syndrome.

PubMed

Mohammadipanah, Fatemeh; Salimi, Fatemeh

2018-02-01

Sturge-Weber Syndrome (SWS) is a neurocutaneous disease with clinical manifestations including ocular (glaucoma), cutaneous (port-wine birthmark), neurologic (seizures), and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against its progression. Development of such platforms of bioassay can bring along the implementation of high-throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of molecular targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholinesterase, alkaline phosphatase, GABAergic receptors, Hypoxia-Inducible Factor (HIF)-1α and 2α are suggested. © 2017 John Wiley & Sons A/S.

Label-assisted mass spectrometry for the acceleration of reaction discovery and optimization

NASA Astrophysics Data System (ADS)

Cabrera-Pardo, Jaime R.; Chai, David I.; Liu, Song; Mrksich, Milan; Kozmin, Sergey A.

2013-05-01

The identification of new reactions expands our knowledge of chemical reactivity and enables new synthetic applications. Accelerating the pace of this discovery process remains challenging. We describe a highly effective and simple platform for screening a large number of potential chemical reactions in order to discover and optimize previously unknown catalytic transformations, thereby revealing new chemical reactivity. Our strategy is based on labelling one of the reactants with a polyaromatic chemical tag, which selectively undergoes a photoionization/desorption process upon laser irradiation, without the assistance of an external matrix, and enables rapid mass spectrometric detection of any products originating from such labelled reactants in complex reaction mixtures without any chromatographic separation. This method was successfully used for high-throughput discovery and subsequent optimization of two previously unknown benzannulation reactions.

The insulin secretory action of novel polycyclic guanidines: discovery through open innovation phenotypic screening, and exploration of structure-activity relationships.

PubMed

Shaghafi, Michael B; Barrett, David G; Willard, Francis S; Overman, Larry E

2014-02-15

We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3-arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

The clinical impact of recent advances in LC-MS for cancer biomarker discovery and verification.

PubMed

Wang, Hui; Shi, Tujin; Qian, Wei-Jun; Liu, Tao; Kagan, Jacob; Srivastava, Sudhir; Smith, Richard D; Rodland, Karin D; Camp, David G

2016-01-01

Mass spectrometry (MS) -based proteomics has become an indispensable tool with broad applications in systems biology and biomedical research. With recent advances in liquid chromatography (LC) and MS instrumentation, LC-MS is making increasingly significant contributions to clinical applications, especially in the area of cancer biomarker discovery and verification. To overcome challenges associated with analyses of clinical samples (for example, a wide dynamic range of protein concentrations in bodily fluids and the need to perform high throughput and accurate quantification of candidate biomarker proteins), significant efforts have been devoted to improve the overall performance of LC-MS-based clinical proteomics platforms. Reviewed here are the recent advances in LC-MS and its applications in cancer biomarker discovery and quantification, along with the potentials, limitations and future perspectives.

The AppScale Cloud Platform

PubMed Central

Krintz, Chandra

2013-01-01

AppScale is an open source distributed software system that implements a cloud platform as a service (PaaS). AppScale makes cloud applications easy to deploy and scale over disparate cloud fabrics, implementing a set of APIs and architecture that also makes apps portable across the services they employ. AppScale is API-compatible with Google App Engine (GAE) and thus executes GAE applications on-premise or over other cloud infrastructures, without modification. PMID:23828721

Moon-based Earth Observation for Large Scale Geoscience Phenomena

NASA Astrophysics Data System (ADS)

Guo, Huadong; Liu, Guang; Ding, Yixing

2016-07-01

The capability of Earth observation for large-global-scale natural phenomena needs to be improved and new observing platform are expected. We have studied the concept of Moon as an Earth observation in these years. Comparing with manmade satellite platform, Moon-based Earth observation can obtain multi-spherical, full-band, active and passive information,which is of following advantages: large observation range, variable view angle, long-term continuous observation, extra-long life cycle, with the characteristics of longevity ,consistency, integrity, stability and uniqueness. Moon-based Earth observation is suitable for monitoring the large scale geoscience phenomena including large scale atmosphere change, large scale ocean change,large scale land surface dynamic change,solid earth dynamic change,etc. For the purpose of establishing a Moon-based Earth observation platform, we already have a plan to study the five aspects as follows: mechanism and models of moon-based observing earth sciences macroscopic phenomena; sensors' parameters optimization and methods of moon-based Earth observation; site selection and environment of moon-based Earth observation; Moon-based Earth observation platform; and Moon-based Earth observation fundamental scientific framework.

CREDO: a structural interactomics database for drug discovery

PubMed Central

Schreyer, Adrian M.; Blundell, Tom L.

2013-01-01

CREDO is a unique relational database storing all pairwise atomic interactions of inter- as well as intra-molecular contacts between small molecules and macromolecules found in experimentally determined structures from the Protein Data Bank. These interactions are integrated with further chemical and biological data. The database implements useful data structures and algorithms such as cheminformatics routines to create a comprehensive analysis platform for drug discovery. The database can be accessed through a web-based interface, downloads of data sets and web services at http://www-cryst.bioc.cam.ac.uk/credo. Database URL: http://www-cryst.bioc.cam.ac.uk/credo PMID:23868908

KSC-07pd2026

NASA Image and Video Library

2007-07-19

KENNEDY SPACE CENTER, Fla. -- In the Orbiter Processing Facility bay 3, workers are ready to move a main bus switching unit into Discovery's payload bay. A main bus switching unit is used for power distribution, circuit protection and fault isolation on the space station's power system. The units route power to proper locations in the space station, such as from solar arrays through umbilicals into the U.S. Lab. The unit will be installed on the external stowage platform 2 attached to the Quest airlock for temporary storage. Discovery is targeted to launch mission STS-120 no earlier than Oct. 20. Photo credit: NASA/Jim Grossmann

KSC-07pd2028

NASA Image and Video Library

2007-07-19

KENNEDY SPACE CENTER, Fla. -- In the Orbiter Processing Facility bay 3, workers check the placement of a main bus switching unit in Discovery's payload bay. A main bus switching unit is used for power distribution, circuit protection and fault isolation on the space station's power system. The units route power to proper locations in the space station, such as from solar arrays through umbilicals into the U.S. Lab. The unit will be installed on the external stowage platform 2 attached to the Quest airlock for temporary storage. Discovery is targeted to launch mission STS-120 no earlier than Oct. 20. Photo credit: NASA/Jim Grossmann

KSC-04PD-1133

NASA Technical Reports Server (NTRS)

2004-01-01

KENNEDY SPACE CENTER, FLA. -- Technicians in the Orbiter Processing Facility attach a crane to Discoverys airlock before lifting it for installation. The airlock is located inside the orbiters payload bay and is sized to accommodate two fully suited flight crew members simultaneously. Support functions include airlock depressurization and repressurization, extravehicular activity equipment recharge, liquid-cooled garment water cooling, EVA equipment checkout, and communications. Discovery is designated as the Return to Flight vehicle for mission STS-114, no earlier than March 2005. STS-114 mission is Logistics Flight 1, which is scheduled to deliver supplies and equipment plus the external stowage platform to the International Space Station.

Closeup view of the nose and landing gear on the ...

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

Close-up view of the nose and landing gear on the forward section of the Orbiter Discovery in the Orbiter Processing Facility at Kennedy Space Center. The Orbiter is being supported by jack stands in the left and right portion of the view. The jack stands attach to the Orbiter at the four hoist attach points, two located on the forward fuselage and two on the aft fuselage. Note the access platforms that surround and nearly touch the orbiter. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Designing an intuitive web application for drug discovery scientists.

PubMed

Karamanis, Nikiforos; Pignatelli, Miguel; Carvalho-Silva, Denise; Rowland, Francis; Cham, Jennifer A; Dunham, Ian

2018-06-01

We discuss how we designed the Open Targets Platform (www.targetvalidation.org), an intuitive application for bench scientists working in early drug discovery. To meet the needs of our users, we applied lean user experience (UX) design methods: we started engaging with users very early and carried out research, design and evaluation activities within an iterative development process. We also emphasize the collaborative nature of applying lean UX design, which we believe is a foundation for success in this and many other scientific projects. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Detail view in engine bay three in the the aft ...

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

Detail view in engine bay three in the the aft fuselage of the Orbiter Discovery. This view shows the engine interface fittings and the hydraulic-actuator support structure. The propellant feed lines are the large plugged and capped orifices. Note the handwritten references on the thrust plate in proximity to the actuators that read E3 Pitch and E3 Yaw. This view was taken from a service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

KSC-2009-5141

NASA Image and Video Library

2009-09-15

EDWARDS AIR FORCE BASE, Calif. – (ED09-0253-73) The nose of Space Shuttle Discovery peers out from work platforms while undergoing servicing in the Mate-DeMate Device at NASA’s Dryden Flight Research Center in preparation for its ferry flight to NASA’s Kennedy Space Center in Florida. Discovery returned to Earth Sept. 11 on the STS-128 mission, landing at Edwards Air Force Base in California. The shuttle delivered more than 7 tons of supplies, science racks and equipment, as well as additional environmental hardware to sustain six crew members on the International Space Station. Photo credit: NASA/Tony Landis

Detail view of the leading and top edge of the ...

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

Detail view of the leading and top edge of the vertical stabilizer of the Orbiter Discovery showing the thermal protection system components with the white Advanced Flexible Reusable Surface Insulation (AFRSI) blanket and the black High-temperature Reusable Surface Insulation (HRSI) tiles along the outer edges. The marks seen on the HRSI tiles are injection point marks and holes for the application of waterproofing material. This view was taken from a service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Open chemistry registry and mapping platform based on open source cheminformatics toolkits (ACS Fall meeting)

EPA Science Inventory

TheOpen PHACTS project (openphacts.org) is a European initiative, constituting a public–private partnership to enable easier, cheaper and faster drug discovery [1]. The project is supported by the Open PHACTS Foundation (www.openphactsfoundation.org) and funded by contributions f...

Sequenced sorghum mutant library- an efficient platform for discovery of causal gene mutations

USDA-ARS?s Scientific Manuscript database

Ethyl methanesulfonate (EMS) efficiently generates high-density mutations in genomes. We applied whole-genome sequencing to 256 phenotyped mutant lines of sorghum (Sorghum bicolor L. Moench) to 16x coverage. Comparisons with the reference sequence revealed >1.8 million canonical EMS-induced G/C to A...

Genome-wide annotation of mutations in a phenotyped mutant library provides an efficient platform for discovery of casual gene mutations

USDA-ARS?s Scientific Manuscript database

Ethyl methanesulfonate (EMS) efficiently generates high-density mutations in genomes. Conventionally, these mutations are identified by techniques that can detect single-nucleotide mismatches in heteroduplexes of individual PCR amplicons. We applied whole-genome sequencing to 256-phenotyped mutant l...

Public-Private Consortium Aims to Cut Preclinical Cancer Drug Discovery from Six Years to Just One | Frederick National Laboratory for Cancer Research

Cancer.gov

Scientists from two U.S. national laboratories, industry, and academia today launched an unprecedented effort to transform the way cancer drugs are discovered by creating an open and sharable platform that integrates high-performance computing, share

Mining conifers’ mega-genome using rapid and efficient multiplexed high-throughput genotyping-by-sequencing (GBS) SNP discovery platform

USDA-ARS?s Scientific Manuscript database

Next-generation sequencing (NGS) technologies are revolutionizing both medical and biological research through generation of massive SNP data sets for identifying heritable genome variation underlying key traits, from rare human diseases to important agronomic phenotypes in crop species. We evaluate...

Genome editing: progress and challenges for medical applications.

PubMed

Carroll, Dana

2016-11-15

The development of the CRISPR-Cas platform for genome editing has greatly simplified the process of making targeted genetic modifications. Applications of genome editing are expected to have a substantial impact on human therapies through the development of better animal models, new target discovery, and direct therapeutic intervention.

CINT - Center for Integrated Nanotechnologies

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Multi-platform next-generation sequencing of the domestic turkey (Meleagris gallopavo) genome assembly and analysis

USDA-ARS?s Scientific Manuscript database

Next-generation sequencing technologies were used to rapidly and efficiently sequence the genome of the domestic turkey (Meleagris gallopavo). The current genome assembly (~1.1 Gb) includes 917 Mb of sequence assigned to chromosomes. Innate heterozygosity of the sequenced bird allowed discovery of...

Effect of intraarticular inoculation of mesenchymal stem cells in dogs with hip osteoarthritis by means of objective force platform gait analysis: concordance with numeric subjective scoring scales.

PubMed

Vilar, Jose M; Cuervo, Belen; Rubio, Monica; Sopena, Joaquín; Domínguez, Juan M; Santana, Angelo; Carrillo, Jose M

2016-10-07

Subjective pain assessment scales have been widely used for assessing lameness in response to pain, but the accuracy of these scales has been questioned. To assess scale accuracy, 10 lame, presa Canario dogs with osteoarthritis (OA) associated with bilateral hip dysplasia were first treated with mesenchymal stem cells. Then, potential lameness improvement was analyzed using two pain scales (Bioarth and visual analog scale). These data were compared with similar data collected using a force platform with the same animals during a period of 6 months after treatment. The F test for intraclass correlation showed that concordance in pain/lameness scores between the 2 measuring methodologies was not significant (P value ≥ 0.9213; 95 % confidence interval, -0.56, 0.11). Although subjective pain assessment showed improvement after 6 months, force platform data demonstrated those same animals had returned to the initial lameness state. Use of pain assessment scales to measure lameness associated with OA did not have great accuracy and concordance when compared with quantitative force platform gait analysis.

Material discovery by combining stochastic surface walking global optimization with a neural network.

PubMed

Huang, Si-Da; Shang, Cheng; Zhang, Xiao-Jie; Liu, Zhi-Pan

2017-09-01

While the underlying potential energy surface (PES) determines the structure and other properties of a material, it has been frustrating to predict new materials from theory even with the advent of supercomputing facilities. The accuracy of the PES and the efficiency of PES sampling are two major bottlenecks, not least because of the great complexity of the material PES. This work introduces a "Global-to-Global" approach for material discovery by combining for the first time a global optimization method with neural network (NN) techniques. The novel global optimization method, named the stochastic surface walking (SSW) method, is carried out massively in parallel for generating a global training data set, the fitting of which by the atom-centered NN produces a multi-dimensional global PES; the subsequent SSW exploration of large systems with the analytical NN PES can provide key information on the thermodynamics and kinetics stability of unknown phases identified from global PESs. We describe in detail the current implementation of the SSW-NN method with particular focuses on the size of the global data set and the simultaneous energy/force/stress NN training procedure. An important functional material, TiO 2 , is utilized as an example to demonstrate the automated global data set generation, the improved NN training procedure and the application in material discovery. Two new TiO 2 porous crystal structures are identified, which have similar thermodynamics stability to the common TiO 2 rutile phase and the kinetics stability for one of them is further proved from SSW pathway sampling. As a general tool for material simulation, the SSW-NN method provides an efficient and predictive platform for large-scale computational material screening.

WordSeeker: concurrent bioinformatics software for discovering genome-wide patterns and word-based genomic signatures

PubMed Central

2010-01-01

Background An important focus of genomic science is the discovery and characterization of all functional elements within genomes. In silico methods are used in genome studies to discover putative regulatory genomic elements (called words or motifs). Although a number of methods have been developed for motif discovery, most of them lack the scalability needed to analyze large genomic data sets. Methods This manuscript presents WordSeeker, an enumerative motif discovery toolkit that utilizes multi-core and distributed computational platforms to enable scalable analysis of genomic data. A controller task coordinates activities of worker nodes, each of which (1) enumerates a subset of the DNA word space and (2) scores words with a distributed Markov chain model. Results A comprehensive suite of performance tests was conducted to demonstrate the performance, speedup and efficiency of WordSeeker. The scalability of the toolkit enabled the analysis of the entire genome of Arabidopsis thaliana; the results of the analysis were integrated into The Arabidopsis Gene Regulatory Information Server (AGRIS). A public version of WordSeeker was deployed on the Glenn cluster at the Ohio Supercomputer Center. Conclusion WordSeeker effectively utilizes concurrent computing platforms to enable the identification of putative functional elements in genomic data sets. This capability facilitates the analysis of the large quantity of sequenced genomic data. PMID:21210985

Building the Petascale National Environmental Research Interoperability Data Platform (NERDIP): Minimizing the 'Trough of Disillusionment' and Accelerating Pathways to the 'Plateau of Productivity'

NASA Astrophysics Data System (ADS)

Wyborn, L. A.; Evans, B. J. K.

2015-12-01

The National Computational Infrastructure (NCI) at the Australian National University (ANU) has evolved to become Australia's peak computing centre for national computational and Data-intensive Earth system science. More recently NCI collocated 10 Petabytes of 34 major national and international environmental, climate, earth system, geophysics and astronomy data collections to create the National Environmental Research Interoperability Data Platform (NERDIP). Spatial scales of the collections range from global to local ultra-high resolution, whilst sizes range from 3PB down to a few GB. The data is highly connected to both NCI HPC and cloud resources via low latency internal networks with massive bandwidth. Now that the collections are collocated on a single data platform, the 'Hype' and expectations around potential use cases for the NERDIP are high. Not unexpected issues are emerging such as access, licensing issues, ownership, and incompatible data standards. Many communities are standardised within their domain, but achieving true interdisciplinary science will require all communities to move towards open interoperable data formats such as NetCDF4/HDF5. This transition will impact on software using proprietary or non-open standards. But before we reach the 'Plateau of Productivity', there needs to be greater 'Enlightenment' of users to encourage them to realise that this unprecedented Earth system science platform provides a rich mine of opportunities for discovery and innovation for a diverse range of both domain-specific and interdisciplinary investigations including climate and weather research, impact analysis, environment, remote sensing and geophysics and develop new and innovative interdisciplinary use cases that will guide those architecting the system and help minimise the amplitude of the 'Trough of Disillusionment' and ensure greater productivity and uptake of the collections that make NERDIP unique in the next generation of Data-intensive Science.

Crowd computing: using competitive dynamics to develop and refine highly predictive models.

PubMed

Bentzien, Jörg; Muegge, Ingo; Hamner, Ben; Thompson, David C

2013-05-01

A recent application of a crowd computing platform to develop highly predictive in silico models for use in the drug discovery process is described. The platform, Kaggle™, exploits a competitive dynamic that results in model optimization as the competition unfolds. Here, this dynamic is described in detail and compared with more-conventional modeling strategies. The complete and full structure of the underlying dataset is disclosed and some thoughts as to the broader utility of such 'gamification' approaches to the field of modeling are offered. Copyright © 2013 Elsevier Ltd. All rights reserved.

An engineered microbial platform for direct biofuel production from brown macroalgae.

PubMed

Wargacki, Adam J; Leonard, Effendi; Win, Maung Nyan; Regitsky, Drew D; Santos, Christine Nicole S; Kim, Peter B; Cooper, Susan R; Raisner, Ryan M; Herman, Asael; Sivitz, Alicia B; Lakshmanaswamy, Arun; Kashiyama, Yuki; Baker, David; Yoshikuni, Yasuo

2012-01-20

Prospecting macroalgae (seaweeds) as feedstocks for bioconversion into biofuels and commodity chemical compounds is limited primarily by the availability of tractable microorganisms that can metabolize alginate polysaccharides. Here, we present the discovery of a 36-kilo-base pair DNA fragment from Vibrio splendidus encoding enzymes for alginate transport and metabolism. The genomic integration of this ensemble, together with an engineered system for extracellular alginate depolymerization, generated a microbial platform that can simultaneously degrade, uptake, and metabolize alginate. When further engineered for ethanol synthesis, this platform enables bioethanol production directly from macroalgae via a consolidated process, achieving a titer of 4.7% volume/volume and a yield of 0.281 weight ethanol/weight dry macroalgae (equivalent to ~80% of the maximum theoretical yield from the sugar composition in macroalgae).

Geneious Basic: An integrated and extendable desktop software platform for the organization and analysis of sequence data

PubMed Central

Kearse, Matthew; Moir, Richard; Wilson, Amy; Stones-Havas, Steven; Cheung, Matthew; Sturrock, Shane; Buxton, Simon; Cooper, Alex; Markowitz, Sidney; Duran, Chris; Thierer, Tobias; Ashton, Bruce; Meintjes, Peter; Drummond, Alexei

2012-01-01

Summary: The two main functions of bioinformatics are the organization and analysis of biological data using computational resources. Geneious Basic has been designed to be an easy-to-use and flexible desktop software application framework for the organization and analysis of biological data, with a focus on molecular sequences and related data types. It integrates numerous industry-standard discovery analysis tools, with interactive visualizations to generate publication-ready images. One key contribution to researchers in the life sciences is the Geneious public application programming interface (API) that affords the ability to leverage the existing framework of the Geneious Basic software platform for virtually unlimited extension and customization. The result is an increase in the speed and quality of development of computation tools for the life sciences, due to the functionality and graphical user interface available to the developer through the public API. Geneious Basic represents an ideal platform for the bioinformatics community to leverage existing components and to integrate their own specific requirements for the discovery, analysis and visualization of biological data. Availability and implementation: Binaries and public API freely available for download at http://www.geneious.com/basic, implemented in Java and supported on Linux, Apple OSX and MS Windows. The software is also available from the Bio-Linux package repository at http://nebc.nerc.ac.uk/news/geneiousonbl. Contact: peter@biomatters.com PMID:22543367

Geneious Basic: an integrated and extendable desktop software platform for the organization and analysis of sequence data.

PubMed

Kearse, Matthew; Moir, Richard; Wilson, Amy; Stones-Havas, Steven; Cheung, Matthew; Sturrock, Shane; Buxton, Simon; Cooper, Alex; Markowitz, Sidney; Duran, Chris; Thierer, Tobias; Ashton, Bruce; Meintjes, Peter; Drummond, Alexei

2012-06-15

The two main functions of bioinformatics are the organization and analysis of biological data using computational resources. Geneious Basic has been designed to be an easy-to-use and flexible desktop software application framework for the organization and analysis of biological data, with a focus on molecular sequences and related data types. It integrates numerous industry-standard discovery analysis tools, with interactive visualizations to generate publication-ready images. One key contribution to researchers in the life sciences is the Geneious public application programming interface (API) that affords the ability to leverage the existing framework of the Geneious Basic software platform for virtually unlimited extension and customization. The result is an increase in the speed and quality of development of computation tools for the life sciences, due to the functionality and graphical user interface available to the developer through the public API. Geneious Basic represents an ideal platform for the bioinformatics community to leverage existing components and to integrate their own specific requirements for the discovery, analysis and visualization of biological data. Binaries and public API freely available for download at http://www.geneious.com/basic, implemented in Java and supported on Linux, Apple OSX and MS Windows. The software is also available from the Bio-Linux package repository at http://nebc.nerc.ac.uk/news/geneiousonbl.

DCO-VIVO: A Collaborative Data Platform for the Deep Carbon Science Communities

NASA Astrophysics Data System (ADS)

Wang, H.; Chen, Y.; West, P.; Erickson, J. S.; Ma, X.; Fox, P. A.

2014-12-01

Deep Carbon Observatory (DCO) is a decade-long scientific endeavor to understand carbon in the complex deep Earth system. Thousands of DCO scientists from institutions across the globe are organized into communities representing four domains of exploration: Extreme Physics and Chemistry, Reservoirs and Fluxes, Deep Energy, and Deep Life. Cross-community and cross-disciplinary collaboration is one of the most distinctive features in DCO's flexible research framework. VIVO is an open-source Semantic Web platform that facilitates cross-institutional researcher and research discovery. it includes a number of standard ontologies that interconnect people, organizations, publications, activities, locations, and other entities of research interest to enable browsing, searching, visualizing, and generating Linked Open (research) Data. The DCO-VIVO solution expedites research collaboration between DCO scientists and communities. Based on DCO's specific requirements, the DCO Data Science team developed a series of extensions to the VIVO platform including extending the VIVO information model, extended query over the semantic information within VIVO, integration with other open source collaborative environments and data management systems, using single sign-on, assigning of unique Handles to DCO objects, and publication and dataset ingesting extensions using existing publication systems. We present here the iterative development of these requirements that are now in daily use by the DCO community of scientists for research reporting, information sharing, and resource discovery in support of research activities and program management.

K2 Citizen Science Discovery of a Four-Planet System in a Chain of 3:2 Resonances

NASA Astrophysics Data System (ADS)

Barentsen, Geert; Christiansen, Jessie; Crossfield, Ian; Barclay, Thomas; Lintott, Chris; Cox, Brian; Zemiro, Julia; Simmons, Brooke; Miller, Grant; NASA K2, Zooniverse, BBC, ABC

2017-06-01

We report on the discovery of a compact system of four transiting super-Earth-sized planets around a moderately bright K-type star (V=12) using data from Campaign 12 of NASA's K2 mission. Uniquely, the periods of the planets are 3.6d, 5.4d, 8.3d, and 12.8d, forming an unbroken chain of near 3:2 resonances. It is the first discovery made by citizen scientists participating in the Exoplanet Explorers project on the Zooniverse platform, and was discovered with the help of 15,000 volunteers recruited via the "Stargazing Live" show on Australia's ABC TV channel. K2's open data policy, combined with the unique format of a BBC TV production that does not shy away from including advanced scientific content, enabled the process of a genuine scientific discovery to be executed and witnessed live on air by nearly a million viewers.

Host-Brucella interactions and the Brucella genome as tools for subunit antigen discovery and immunization against brucellosis

PubMed Central

Gomez, Gabriel; Adams, Leslie G.; Rice-Ficht, Allison; Ficht, Thomas A.

2013-01-01

Vaccination is the most important approach to counteract infectious diseases. Thus, the development of new and improved vaccines for existing, emerging, and re-emerging diseases is an area of great interest to the scientific community and general public. Traditional approaches to subunit antigen discovery and vaccine development lack consideration for the critical aspects of public safety and activation of relevant protective host immunity. The availability of genomic sequences for pathogenic Brucella spp. and their hosts have led to development of systems-wide analytical tools that have provided a better understanding of host and pathogen physiology while also beginning to unravel the intricacies at the host-pathogen interface. Advances in pathogen biology, host immunology, and host-agent interactions have the potential to serve as a platform for the design and implementation of better-targeted antigen discovery approaches. With emphasis on Brucella spp., we probe the biological aspects of host and pathogen that merit consideration in the targeted design of subunit antigen discovery and vaccine development. PMID:23720712

The contribution of fiscal/financial decentralization to the debt expansion of the local financing platform

NASA Astrophysics Data System (ADS)

Huayang, Yin; Di, Zhou; Bing, Cui

2018-02-01

Using soft budget theory to explore the formation mechanism and the deep institutional incentive of the local financing platform debt expansion from the perspective of fiscal / financial decentralization, construct theoretical framework which explain the expansion of local debt financing platform and conduct an empirical test, the results showed that the higher the degree of fiscal decentralization, fiscal autonomy as a soft constraint body of local government the stronger, local financing platform debt scale is greater; the higher the degree of financial decentralization, local government and financial institutions have the higher autonomy with respect to the central, local financing platform debt scale is bigger; financial synergy degree is stronger, local government financial mutual supervision prompted the local government debt more transparency, local debt financing platform size is smaller.

46. DETAILS OF PLATFORMS & STAIRS, Y&D No. 107724 Scales ...

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

46. DETAILS OF PLATFORMS & STAIRS, Y&D No. 107724 Scales 3/4' = 1' and as indicated; July 2, 1929 - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

Learning to Love Your Discovery Tool: Strategies for Integrating a Discovery Tool in Face-to-Face, Synchronous, and Asynchronous Instruction

ERIC Educational Resources Information Center

Fawley, Nancy; Krysak, Nikki

2014-01-01

Some librarians embrace discovery tools while others refuse to use them. This lack of consensus can have consequences for student learning when there is inconsistent use, especially in large-scale instruction programs. The authors surveyed academic librarians whose institutions have a discovery tool and who teach information literacy classes in…

Final Report Scalable Analysis Methods and In Situ Infrastructure for Extreme Scale Knowledge Discovery

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

O'Leary, Patrick

The primary challenge motivating this project is the widening gap between the ability to compute information and to store it for subsequent analysis. This gap adversely impacts science code teams, who can perform analysis only on a small fraction of the data they calculate, resulting in the substantial likelihood of lost or missed science, when results are computed but not analyzed. Our approach is to perform as much analysis or visualization processing on data while it is still resident in memory, which is known as in situ processing. The idea in situ processing was not new at the time ofmore » the start of this effort in 2014, but efforts in that space were largely ad hoc, and there was no concerted effort within the research community that aimed to foster production-quality software tools suitable for use by Department of Energy (DOE) science projects. Our objective was to produce and enable the use of production-quality in situ methods and infrastructure, at scale, on DOE high-performance computing (HPC) facilities, though we expected to have an impact beyond DOE due to the widespread nature of the challenges, which affect virtually all large-scale computational science efforts. To achieve this objective, we engaged in software technology research and development (R&D), in close partnerships with DOE science code teams, to produce software technologies that were shown to run efficiently at scale on DOE HPC platforms.« less

Development of an Unmanned Aerial System (UAS) for Scaling Terrestrial Ecosystem Traits

NASA Astrophysics Data System (ADS)

Meng, R.; McMahon, A. M.; Serbin, S.; Rogers, A.

2015-12-01

The next generation of Ecosystem and Earth System Models (EESMs) will require detailed information on ecosystem structure and function, including properties of vegetation related to carbon (C), water, and energy cycling, in order to project the future state of ecosystems. High spatial-temporal resolution measurements of terrestrial ecosystem are also important for EESMs, because they can provide critical inputs and benchmark datasets for evaluation of EESMs simulations across scales. The recent development of high-quality, low-altitude remote sensing platforms or small UAS (< 25 kg) enables measurements of terrestrial ecosystems at unprecedented temporal and spatial scales. Specifically, these new platforms can provide detailed information on patterns and processes of terrestrial ecosystems at a critical intermediate scale between point measurements and suborbital and satellite platforms. Given their potential for sub-decimeter spatial resolution, improved mission safety, high revisit frequency, and reduced operation cost, these platforms are of particular interest in the development of ecological scaling algorithms to parameterize and benchmark EESMs, particularly over complex and remote terrain. Our group is developing a small UAS platform and integrated sensor package focused on measurement needs for scaling and informing ecosystem modeling activities, as well as scaling and mapping plant functional traits. To do this we are developing an integrated software workflow and hardware package using off-the-shelf instrumentation including a high-resolution digital camera for Structure from Motion, spectroradiometer, and a thermal infrared camera. Our workflow includes platform design, measurement, image processing, data management, and information extraction. The fusion of 3D structure information, thermal-infrared imagery, and spectroscopic measurements, will provide a foundation for the development of ecological scaling and mapping algorithms. Our initial focus is in temperate forests but near-term research will expand into the high-arctic and eventually tropical systems. The results of this prototype study show that off-the-shelf technology can be used to develop a low-cost alternative for mapping plant traits and three-dimensional structure for ecological research.

A perspective on sustained marine observations for climate modelling and prediction.

PubMed

Dunstone, Nick J

2014-09-28

Here, I examine some of the many varied ways in which sustained global ocean observations are used in numerical modelling activities. In particular, I focus on the use of ocean observations to initialize predictions in ocean and climate models. Examples are also shown of how models can be used to assess the impact of both current ocean observations and to simulate that of potential new ocean observing platforms. The ocean has never been better observed than it is today and similarly ocean models have never been as capable at representing the real ocean as they are now. However, there remain important unanswered questions that can likely only be addressed via future improvements in ocean observations. In particular, ocean observing systems need to respond to the needs of the burgeoning field of near-term climate predictions. Although new ocean observing platforms promise exciting new discoveries, there is a delicate balance to be made between their funding and that of the current ocean observing system. Here, I identify the need to secure long-term funding for ocean observing platforms as they mature, from a mainly research exercise to an operational system for sustained observation over climate change time scales. At the same time, considerable progress continues to be made via ship-based observing campaigns and I highlight some that are dedicated to addressing uncertainties in key ocean model parametrizations. The use of ocean observations to understand the prominent long time scale changes observed in the North Atlantic is another focus of this paper. The exciting first decade of monitoring of the Atlantic meridional overturning circulation by the RAPID-MOCHA array is highlighted. The use of ocean and climate models as tools to further probe the drivers of variability seen in such time series is another exciting development. I also discuss the need for a concerted combined effort from climate models and ocean observations in order to understand the current slow-down in surface global warming. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Real-time bacterial microcolony counting using on-chip microscopy

NASA Astrophysics Data System (ADS)

Jung, Jae Hee; Lee, Jung Eun

2016-02-01

Observing microbial colonies is the standard method for determining the microbe titer and investigating the behaviors of microbes. Here, we report an automated, real-time bacterial microcolony-counting system implemented on a wide field-of-view (FOV), on-chip microscopy platform, termed ePetri. Using sub-pixel sweeping microscopy (SPSM) with a super-resolution algorithm, this system offers the ability to dynamically track individual bacterial microcolonies over a wide FOV of 5.7 mm × 4.3 mm without requiring a moving stage or lens. As a demonstration, we obtained high-resolution time-series images of S. epidermidis at 20-min intervals. We implemented an image-processing algorithm to analyze the spatiotemporal distribution of microcolonies, the development of which could be observed from a single bacterial cell. Test bacterial colonies with a minimum diameter of 20 μm could be enumerated within 6 h. We showed that our approach not only provides results that are comparable to conventional colony-counting assays but also can be used to monitor the dynamics of colony formation and growth. This microcolony-counting system using on-chip microscopy represents a new platform that substantially reduces the detection time for bacterial colony counting. It uses chip-scale image acquisition and is a simple and compact solution for the automation of colony-counting assays and microbe behavior analysis with applications in antibacterial drug discovery.

Real-time bacterial microcolony counting using on-chip microscopy

PubMed Central

Jung, Jae Hee; Lee, Jung Eun

2016-01-01

Observing microbial colonies is the standard method for determining the microbe titer and investigating the behaviors of microbes. Here, we report an automated, real-time bacterial microcolony-counting system implemented on a wide field-of-view (FOV), on-chip microscopy platform, termed ePetri. Using sub-pixel sweeping microscopy (SPSM) with a super-resolution algorithm, this system offers the ability to dynamically track individual bacterial microcolonies over a wide FOV of 5.7 mm × 4.3 mm without requiring a moving stage or lens. As a demonstration, we obtained high-resolution time-series images of S. epidermidis at 20-min intervals. We implemented an image-processing algorithm to analyze the spatiotemporal distribution of microcolonies, the development of which could be observed from a single bacterial cell. Test bacterial colonies with a minimum diameter of 20 μm could be enumerated within 6 h. We showed that our approach not only provides results that are comparable to conventional colony-counting assays but also can be used to monitor the dynamics of colony formation and growth. This microcolony-counting system using on-chip microscopy represents a new platform that substantially reduces the detection time for bacterial colony counting. It uses chip-scale image acquisition and is a simple and compact solution for the automation of colony-counting assays and microbe behavior analysis with applications in antibacterial drug discovery. PMID:26902822

[Recent advances in metabonomics].

PubMed

Xu, Guo-Wang; Lu, Xin; Yang, Sheng-Li

2007-12-01

Metabonomics (or metabolomics) aims at the comprehensive and quantitative analysis of the wide arrays of metabolites in biological samples. Metabonomics has been labeled as one of the new" -omics" joining genomics, transcriptomics, and proteomics as a science employed toward the understanding of global systems biology. It has been widely applied in many research areas including drug toxicology, biomarker discovery, functional genomics, and molecular pathology etc. The comprehensive analysis of the metabonome is particularly challenging due to the diverse chemical natures of metabolites. Metabonomics investigations require special approaches for sample preparation, data-rich analytical chemical measurements, and information mining. The outputs from a metabonomics study allow sample classification, biomarker discovery, and interpretation of the reasons for classification information. This review focuses on the currently new advances in various technical platforms of metabonomics and its applications in drug discovery and development, disease biomarker identification, plant and microbe related fields.

Harvest: a web-based biomedical data discovery and reporting application development platform.

PubMed

Italia, Michael J; Pennington, Jeffrey W; Ruth, Byron; Wrazien, Stacey; Loutrel, Jennifer G; Crenshaw, E Bryan; Miller, Jeffrey; White, Peter S

2013-01-01

Biomedical researchers share a common challenge of making complex data understandable and accessible. This need is increasingly acute as investigators seek opportunities for discovery amidst an exponential growth in the volume and complexity of laboratory and clinical data. To address this need, we developed Harvest, an open source framework that provides a set of modular components to aid the rapid development and deployment of custom data discovery software applications. Harvest incorporates visual representations of multidimensional data types in an intuitive, web-based interface that promotes a real-time, iterative approach to exploring complex clinical and experimental data. The Harvest architecture capitalizes on standards-based, open source technologies to address multiple functional needs critical to a research and development environment, including domain-specific data modeling, abstraction of complex data models, and a customizable web client.

FLIM FRET Technology for Drug Discovery: Automated Multiwell-Plate High-Content Analysis, Multiplexed Readouts and Application in Situ**

PubMed Central

Kumar, Sunil; Alibhai, Dominic; Margineanu, Anca; Laine, Romain; Kennedy, Gordon; McGinty, James; Warren, Sean; Kelly, Douglas; Alexandrov, Yuriy; Munro, Ian; Talbot, Clifford; Stuckey, Daniel W; Kimberly, Christopher; Viellerobe, Bertrand; Lacombe, Francois; Lam, Eric W-F; Taylor, Harriet; Dallman, Margaret J; Stamp, Gordon; Murray, Edward J; Stuhmeier, Frank; Sardini, Alessandro; Katan, Matilda; Elson, Daniel S; Neil, Mark A A; Dunsby, Chris; French, Paul M W

2011-01-01

A fluorescence lifetime imaging (FLIM) technology platform intended to read out changes in Förster resonance energy transfer (FRET) efficiency is presented for the study of protein interactions across the drug-discovery pipeline. FLIM provides a robust, inherently ratiometric imaging modality for drug discovery that could allow the same sensor constructs to be translated from automated cell-based assays through small transparent organisms such as zebrafish to mammals. To this end, an automated FLIM multiwell-plate reader is described for high content analysis of fixed and live cells, tomographic FLIM in zebrafish and FLIM FRET of live cells via confocal endomicroscopy. For cell-based assays, an exemplar application reading out protein aggregation using FLIM FRET is presented, and the potential for multiple simultaneous FLIM (FRET) readouts in microscopy is illustrated. PMID:21337485

KSC-05PD-1177

NASA Technical Reports Server (NTRS)

2005-01-01

KENNEDY SPACE CENTER, FLA. At NASAs Kennedy Space Center, Space Shuttle Discovery, resting on the Mobile Launcher Platform, rolls into high bay 1 of the Vehicle Assembly Building (VAB). The Shuttle is being rolled back from Launch Pad 39B. It will be demated from its External Tank and lifted into the transfer aisle. On or about June 7, Discovery will be attached to its new tank and Solid Rocket Boosters, which are already in the VAB. Only the 15th rollback in Space Shuttle Program history, the 4.2- mile journey allows additional modifications to be made to the External Tank prior to a safe Return to Flight. Discovery is expected to be rolled back to the launch pad in mid-June for Return to Flight mission STS-114. The launch window extends from July 13 to July 31. [Photo courtesy of Scott Andrews

Discovery touches down after successful mission STS-95

NASA Technical Reports Server (NTRS)

1998-01-01

After nine days and 3.6 million miles in space, orbiter Discovery prepares to land on runway 33 at the Shuttle Landing Facility. Discovery returns to Earth with its crew of seven after successfully completing mission STS-95. The STS-95 crew members are Mission Commander Curtis L. Brown Jr.; Pilot Steven W. Lindsey; Mission Specialist Scott E. Parazynski; Mission Specialist Stephen K. Robinson; Payload Specialist John H. Glenn Jr., a senator from Ohio; Mission Specialist Pedro Duque of Spain, with the European Space Agency (ESA); and Payload Specialist Chiaki Mukai, with the National Space Development Agency of Japan (NASDA). The mission included research payloads such as the Spartan solar-observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process.

Discovery touches down after successful mission STS-95

NASA Technical Reports Server (NTRS)

1998-01-01

Orbiter Discovery lowers its nose wheel after touching down on runway 33 at the Shuttle Landing Facility. Discovery returns to Earth with its crew of seven after successfully completing mission STS-95, lasting nearly nine days and 3.6 million miles. The STS-95 crew is composed of Mission Commander Curtis L. Brown Jr., Pilot Steven W. Lindsey, Mission Specialist Scott E. Parazynski, Mission Specialist Stephen K. Robinson, Payload Specialist John H. Glenn Jr., senator from Ohio, Mission Specialist Pedro Duque, with the European Space Agency (ESA), and Payload Specialist Chiaki Mukai, with the National Space Development Agency of Japan (NASDA). The mission included research payloads such as the Spartan solar-observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process.

Discovery prepares to land after successful mission STS-95

NASA Technical Reports Server (NTRS)

1998-01-01

Orbiter Discovery prepares to land on runway 33 at the Shuttle Landing Facility. Discovery returns to Earth with its crew of seven after successfully completing mission STS-95, lasting nearly nine days and 3.6 million miles. The crew members are Mission Commander Curtis L. Brown Jr., Pilot Steven W. Lindsey, Mission Specialist Scott E. Parazynski, Mission Specialist Stephen K. Robinson, Payload Specialist John H. Glenn Jr., senator from Ohio, Mission Specialist Pedro Duque, with the European Space Agency (ESA), and Payload Specialist Chiaki Mukai, with the National Space Development Agency of Japan (NASDA). The mission included research payloads such as the Spartan solar- observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process.

Discovery touches down after successful mission STS-95

NASA Technical Reports Server (NTRS)

1998-01-01

Orbiter Discovery touches down in a cloud of smoke on runway 33 at the Shuttle Landing Facility. Discovery returns to Earth with its crew of seven after successfully completing mission STS-95, lasting nearly nine days and 3.6 million miles. The crew members are Mission Commander Curtis L. Brown Jr., Pilot Steven W. Lindsey, Mission Specialist Scott E. Parazynski, Mission Specialist Stephen K. Robinson, Payload Specialist John H. Glenn Jr., senator from Ohio, Mission Specialist Pedro Duque, with the European Space Agency (ESA), and Payload Specialist Chiaki Mukai, with the National Space Development Agency of Japan (NASDA). The mission included research payloads such as the Spartan solar- observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process.

KSC-2009-4416

NASA Image and Video Library

2009-08-04

CAPE CANAVERAL, Fla. –Sitting on top of the mobile launcher platform, space shuttle Discovery arrives on Launch Pad 39A at NASA's Kennedy Space Center in Florida. Traveling from the Vehicle Assembly Building, the journey took nearly 12 hours as technicians stopped several times to clear mud from the crawler's treads and bearings caused by the waterlogged crawlerway. First motion out of the VAB was at 2:07 a.m. EDT Aug. 4. Rollout was delayed approximately 2 hours due to lightning in the area. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the International Space Station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for late August. Photo credit: NASA/Troy Cryder

KSC-2011-1265

NASA Image and Video Library

2011-01-31

CAPE CANAVERAL, Fla. -- Xenon lights illuminate space shuttle Discovery as it makes its nighttime trek, known as "rollout," from the Vehicle Assembly Building to Launch Pad 39A at NASA's Kennedy Space Center in Florida. It will take the shuttle, attached to its external fuel tank, twin solid rocket boosters and mobile launcher platform, about seven hours to complete the move atop a crawler-transporter. This is the second time Discovery has rolled out to the pad for the STS-133 mission, and comes after a thorough check and modifications to the shuttle's external tank. Targeted to liftoff Feb. 24, Discovery will take the Permanent Multipurpose Module (PMM) packed with supplies and critical spare parts, as well as Robonaut 2 (R2) to the International Space Station. For more information on STS-133, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Kim Shiflett

KSC-2011-1277

NASA Image and Video Library

2011-01-31

CAPE CANAVERAL, Fla. -- Xenon lights illuminate space shuttle Discovery as it makes its nighttime trek, known as "rollout," from the Vehicle Assembly Building to Launch Pad 39A at NASA's Kennedy Space Center in Florida. It will take the shuttle, attached to its external fuel tank, twin solid rocket boosters and mobile launcher platform, about seven hours to complete the move atop a crawler-transporter. This is the second time Discovery has rolled out to the pad for the STS-133 mission, and comes after a thorough check and modifications to the shuttle's external tank. Targeted to liftoff Feb. 24, Discovery will take the Permanent Multipurpose Module (PMM) packed with supplies and critical spare parts, as well as Robonaut 2 (R2) to the International Space Station. For more information on STS-133, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Jim Grossmann

Ground robotic measurement of aeolian processes

NASA Astrophysics Data System (ADS)

Qian, Feifei; Jerolmack, Douglas; Lancaster, Nicholas; Nikolich, George; Reverdy, Paul; Roberts, Sonia; Shipley, Thomas; Van Pelt, R. Scott; Zobeck, Ted M.; Koditschek, Daniel E.

2017-08-01

Models of aeolian processes rely on accurate measurements of the rates of sediment transport by wind, and careful evaluation of the environmental controls of these processes. Existing field approaches typically require intensive, event-based experiments involving dense arrays of instruments. These devices are often cumbersome and logistically difficult to set up and maintain, especially near steep or vegetated dune surfaces. Significant advances in instrumentation are needed to provide the datasets that are required to validate and improve mechanistic models of aeolian sediment transport. Recent advances in robotics show great promise for assisting and amplifying scientists' efforts to increase the spatial and temporal resolution of many environmental measurements governing sediment transport. The emergence of cheap, agile, human-scale robotic platforms endowed with increasingly sophisticated sensor and motor suites opens up the prospect of deploying programmable, reactive sensor payloads across complex terrain in the service of aeolian science. This paper surveys the need and assesses the opportunities and challenges for amassing novel, highly resolved spatiotemporal datasets for aeolian research using partially-automated ground mobility. We review the limitations of existing measurement approaches for aeolian processes, and discuss how they may be transformed by ground-based robotic platforms, using examples from our initial field experiments. We then review how the need to traverse challenging aeolian terrains and simultaneously make high-resolution measurements of critical variables requires enhanced robotic capability. Finally, we conclude with a look to the future, in which robotic platforms may operate with increasing autonomy in harsh conditions. Besides expanding the completeness of terrestrial datasets, bringing ground-based robots to the aeolian research community may lead to unexpected discoveries that generate new hypotheses to expand the science itself.

Essential Skills and Knowledge for Troubleshooting E-Resources Access Issues in a Web-Scale Discovery Environment

ERIC Educational Resources Information Center

Carter, Sunshine; Traill, Stacie

2017-01-01

Electronic resource access troubleshooting is familiar work in most libraries. The added complexity introduced when a library implements a web-scale discovery service, however, creates a strong need for well-organized, rigorous training to enable troubleshooting staff to provide the best service possible. This article outlines strategies, tools,…

Predicting Developmental Toxicity of ToxCast Phase I Chemicals Using Human Embryonic Stem Cells and Metabolomics

EPA Science Inventory

EPA’s ToxRefDB contains prenatal guideline study data from rats and rabbits for over 240 chemicals that overlap with the ToxCast in vitro high throughput screening project. A subset of these compounds were tested in Stemina Biomarker Discovery's developmental toxicity platform, a...

A Coordinated Approach to Peach SNP Discovery in RosBREED

USDA-ARS?s Scientific Manuscript database

In the USDA-funded multi-institutional and trans-disciplinary project, “RosBREED”, crop-specific SNP genome scan platforms are being developed for peach, apple, strawberry, and cherry at a resolution of at least one polymorphic SNP marker every 5 cM in any random cross, for use in Pedigree-Based Ana...

A population of deletion mutants and an integrated mapping and Exome-seq pipeline for gene discovery in maize

USDA-ARS?s Scientific Manuscript database

To better understand maize endosperm filling and maturation, we developed a novel functional genomics platform that combined Bulked Segregant RNA and Exome sequencing (BSREx-seq) to map causative mutations and identify candidate genes within mapping intervals. Using gamma-irradiation of B73 maize to...

Clinical proteomic biomarkers: relevant issues on study design & technical considerations in biomarker development

PubMed Central

2014-01-01

Biomarker research is continuously expanding in the field of clinical proteomics. A combination of different proteomic–based methodologies can be applied depending on the specific clinical context of use. Moreover, current advancements in proteomic analytical platforms are leading to an expansion of biomarker candidates that can be identified. Specifically, mass spectrometric techniques could provide highly valuable tools for biomarker research. Ideally, these advances could provide with biomarkers that are clinically applicable for disease diagnosis and/ or prognosis. Unfortunately, in general the biomarker candidates fail to be implemented in clinical decision making. To improve on this current situation, a well-defined study design has to be established driven by a clear clinical need, while several checkpoints between the different phases of discovery, verification and validation have to be passed in order to increase the probability of establishing valid biomarkers. In this review, we summarize the technical proteomic platforms that are available along the different stages in the biomarker discovery pipeline, exemplified by clinical applications in the field of bladder cancer biomarker research. PMID:24679154

Towards a Web-Enabled Geovisualization and Analytics Platform for the Energy and Water Nexus

NASA Astrophysics Data System (ADS)

Sanyal, J.; Chandola, V.; Sorokine, A.; Allen, M.; Berres, A.; Pang, H.; Karthik, R.; Nugent, P.; McManamay, R.; Stewart, R.; Bhaduri, B. L.

2017-12-01

Interactive data analytics are playing an increasingly vital role in the generation of new, critical insights regarding the complex dynamics of the energy/water nexus (EWN) and its interactions with climate variability and change. Integration of impacts, adaptation, and vulnerability (IAV) science with emerging, and increasingly critical, data science capabilities offers a promising potential to meet the needs of the EWN community. To enable the exploration of pertinent research questions, a web-based geospatial visualization platform is being built that integrates a data analysis toolbox with advanced data fusion and data visualization capabilities to create a knowledge discovery framework for the EWN. The system, when fully built out, will offer several geospatial visualization capabilities including statistical visual analytics, clustering, principal-component analysis, dynamic time warping, support uncertainty visualization and the exploration of data provenance, as well as support machine learning discoveries to render diverse types of geospatial data and facilitate interactive analysis. Key components in the system architecture includes NASA's WebWorldWind, the Globus toolkit, postgresql, as well as other custom built software modules.

KENNEDY SPACE CENTER, FLA. - The rising sun and some scattered clouds provide a picturesque backdrop for the Space Shuttle Discovery as it travels along the crawlerway toward Launch Pad 39A in preparation for the STS-82 mission. The Shuttle is on a Mobile Launcher Platform, and the entire assemblage is being carried by a large, tracked vehicle called the crawler transporter. A seven-member crew will perform the second servicing of the orbiting Hubble Space Telescope (HST) during the 10-day STS-82 flight, whcih is targeted for a Feb. 11 liftoff.

NASA Image and Video Library

1997-01-17

KENNEDY SPACE CENTER, FLA. - The rising sun and some scattered clouds provide a picturesque backdrop for the Space Shuttle Discovery as it travels along the crawlerway toward Launch Pad 39A in preparation for the STS-82 mission. The Shuttle is on a Mobile Launcher Platform, and the entire assemblage is being carried by a large, tracked vehicle called the crawler transporter. A seven-member crew will perform the second servicing of the orbiting Hubble Space Telescope (HST) during the 10-day STS-82 flight, whcih is targeted for a Feb. 11 liftoff.

Using the High-Level Based Program Interface to Facilitate the Large Scale Scientific Computing

PubMed Central

Shang, Yizi; Shang, Ling; Gao, Chuanchang; Lu, Guiming; Ye, Yuntao; Jia, Dongdong

2014-01-01

This paper is to make further research on facilitating the large-scale scientific computing on the grid and the desktop grid platform. The related issues include the programming method, the overhead of the high-level program interface based middleware, and the data anticipate migration. The block based Gauss Jordan algorithm as a real example of large-scale scientific computing is used to evaluate those issues presented above. The results show that the high-level based program interface makes the complex scientific applications on large-scale scientific platform easier, though a little overhead is unavoidable. Also, the data anticipation migration mechanism can improve the efficiency of the platform which needs to process big data based scientific applications. PMID:24574931

Potential biological targets for bioassay development in drug discovery of Sturge-Weber syndrome.

PubMed

Mohammadipanah, Fatemeh; Salimi, Fatemeh

2017-04-29

Sturge-Weber Syndrome (SWS) is among the neurocutaneous diseases, which has several clinical manifestations of ocular (glaucoma), cutaneous (port-wine stain), neurological (seizures) and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for the SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against this syndrome. Development of such platforms of bioassay can bring along the implementation of high throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of biological targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholine esterase, alkaline phosphatase, gamma-aminobutyricacidergic, Hypoxia-Inducible Factor (HIF) -1α and 2α are suggested. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Enlisting User Community Perspectives to Inform Development of a Semantic Web Application for Discovery of Cross-Institutional Research Information and Data

NASA Astrophysics Data System (ADS)

Johns, E. M.; Mayernik, M. S.; Boler, F. M.; Corson-Rikert, J.; Daniels, M. D.; Gross, M. B.; Khan, H.; Maull, K. E.; Rowan, L. R.; Stott, D.; Williams, S.; Krafft, D. B.

2015-12-01

Researchers seek information and data through a variety of avenues: published literature, search engines, repositories, colleagues, etc. In order to build a web application that leverages linked open data to enable multiple paths for information discovery, the EarthCollab project has surveyed two geoscience user communities to consider how researchers find and share scholarly output. EarthCollab, a cross-institutional, EarthCube funded project partnering UCAR, Cornell University, and UNAVCO, is employing the open-source semantic web software, VIVO, as the underlying technology to connect the people and resources of virtual research communities. This study will present an analysis of survey responses from members of the two case study communities: (1) the Bering Sea Project, an interdisciplinary field program whose data archive is hosted by NCAR's Earth Observing Laboratory (EOL), and (2) UNAVCO, a geodetic facility and consortium that supports diverse research projects informed by geodesy. The survey results illustrate the types of research products that respondents indicate should be discoverable within a digital platform and the current methods used to find publications, data, personnel, tools, and instrumentation. The responses showed that scientists rely heavily on general purpose search engines, such as Google, to find information, but that data center websites and the published literature were also critical sources for finding collaborators, data, and research tools.The survey participants also identify additional features of interest for an information platform such as search engine indexing, connection to institutional web pages, generation of bibliographies and CVs, and outward linking to social media. Through the survey, the user communities prioritized the type of information that is most important to display and describe their work within a research profile. The analysis of this survey will inform our further development of a platform that will facilitate different types of information discovery strategies, and help researchers to find and use the associated resources of a research project.

Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors

PubMed Central

Frett, Brendan; McConnell, Nick; Smith, Catherine C.; Wang, Yuanxiang; Shah, Neil P.; Li, Hong-yu

2015-01-01

The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates. PMID:25765758

Receptor-Mediated Uptake of Phosphorothioate Antisense Oligonucleotides in Different Cell Types of the Liver.

PubMed

Miller, Colton M; Tanowitz, Michael; Donner, Aaron J; Prakash, Thazha P; Swayze, Eric E; Harris, Edward N; Seth, Punit P

2018-06-01

Oligonucleotide therapeutics have emerged as a third distinct platform for drug discovery within the pharmaceutical industry. Five oligonucleotide-based drugs have been approved by the US FDA and over 100 oligonucleotides drugs are currently at different stages of human trials. Several of these oligonucleotide drugs are modified using the phosphorothioate (PS) backbone modification where one of the nonbridging oxygen atoms of the phosphodiester linkage is replaced with sulfur. In this review, we summarize our knowledge on receptor-mediated uptake of PS antisense oligonucleotides (ASOs) within different cell types of the liver-a privileged organ for the discovery of oligonucleotide-based therapeutics.

KSC-07pd2025

NASA Image and Video Library

2007-07-19

KENNEDY SPACE CENTER, Fla. -- In the Orbiter Processing Facility bay 3, a crane lowers the main bus switching unit into Discovery's payload bay. The unit is part of the payload on mission STS-120.A main bus switching unit is used for power distribution, circuit protection and fault isolation on the space station's power system. The units route power to proper locations in the space station, such as from solar arrays through umbilicals into the U.S. Lab. The unit will be installed on the external stowage platform 2 attached to the Quest airlock for temporary storage. Discovery is targeted to launch mission STS-120 no earlier than Oct. 20. Photo credit: NASA/Jim Grossmann

KSC-07pd2027

NASA Image and Video Library

2007-07-19

KENNEDY SPACE CENTER, Fla. -- In the Orbiter Processing Facility bay 3, with the help of a crane, workers check the placement of a main bus switching unit in Discovery's payload bay. A main bus switching unit is used for power distribution, circuit protection and fault isolation on the space station's power system. The units route power to proper locations in the space station, such as from solar arrays through umbilicals into the U.S. Lab. The unit will be installed on the external stowage platform 2 attached to the Quest airlock for temporary storage. Discovery is targeted to launch mission STS-120 no earlier than Oct. 20. Photo credit: NASA/Jim Grossmann

General view looking aft from the starboard side of the ...

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

General view looking aft from the starboard side of the Orbiter Discovery looking into the payload bay and the bulkhead of the aft fuselage. Note that the Orbiter Boom Sensor System is still attached while the Remote Manipulator System has been removed. Also note the suspended protective panels and walkways in place to protect the interior surfaces of the payload bay doors while in their open position. This view was taken from a service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Building a discovery partnership with Sarawak Biodiversity Centre: a gateway to access natural products from the rainforests.

PubMed

Yeo, Tiong Chia; Naming, Margarita; Manurung, Rita

2014-03-01

The Sarawak Biodiversity Centre (SBC) is a state government agency which regulates research and promotes the sustainable use of biodiversity. It has a program on documentation of traditional knowledge (TK) and is well-equipped with facilities for natural product research. SBC maintains a Natural Product Library (NPL) consisting of local plant and microbial extracts for bioprospecting. The NPL is a core discovery platform for screening of bioactive compounds by researchers through a formal agreement with clear benefit sharing obligations. SBC aims to develop partnerships with leading institutions and the industries to explore the benefits of biodiversity.

STS-114 Discovery Return to Flight: International Space Station Processing Overview

NASA Technical Reports Server (NTRS)

2005-01-01

Bruce Buckingham, NASA Public Affairs, introduces Scott Higgenbotham, STS-114 Payload Manager. Higgenbotham gives a power point presentation on the hardware that is going to fly in the Discovery Mission to the International Space Station. He presents a layout of the hardware which includes The Logistics Flight 1 (LF1) launch package configuration Multipurpose Logistics Module (MPLM), External Stowage Platform-2 (ESP-2) and the Lightweight Mission Peculiar Equipment Support Structure Carrier (LMC). He explains these payloads in detail. The LF-1 team is also shown in the International Space Station Processing Facility. This presentation ends with a brief question and answer period.

Promising Practices in Instruction of Discovery Tools

ERIC Educational Resources Information Center

Buck, Stefanie; Steffy, Christina

2013-01-01

Libraries are continually changing to meet the needs of users; this includes implementing discovery tools, also referred to as web-scale discovery tools, to make searching library resources easier. Because these tools are so new, it is difficult to establish definitive best practices for teaching these tools; however, promising practices are…

A new large-scale manufacturing platform for complex biopharmaceuticals.

PubMed

Vogel, Jens H; Nguyen, Huong; Giovannini, Roberto; Ignowski, Jolene; Garger, Steve; Salgotra, Anil; Tom, Jennifer

2012-12-01

Complex biopharmaceuticals, such as recombinant blood coagulation factors, are addressing critical medical needs and represent a growing multibillion-dollar market. For commercial manufacturing of such, sometimes inherently unstable, molecules it is important to minimize product residence time in non-ideal milieu in order to obtain acceptable yields and consistently high product quality. Continuous perfusion cell culture allows minimization of residence time in the bioreactor, but also brings unique challenges in product recovery, which requires innovative solutions. In order to maximize yield, process efficiency, facility and equipment utilization, we have developed, scaled-up and successfully implemented a new integrated manufacturing platform in commercial scale. This platform consists of a (semi-)continuous cell separation process based on a disposable flow path and integrated with the upstream perfusion operation, followed by membrane chromatography on large-scale adsorber capsules in rapid cycling mode. Implementation of the platform at commercial scale for a new product candidate led to a yield improvement of 40% compared to the conventional process technology, while product quality has been shown to be more consistently high. Over 1,000,000 L of cell culture harvest have been processed with 100% success rate to date, demonstrating the robustness of the new platform process in GMP manufacturing. While membrane chromatography is well established for polishing in flow-through mode, this is its first commercial-scale application for bind/elute chromatography in the biopharmaceutical industry and demonstrates its potential in particular for manufacturing of potent, low-dose biopharmaceuticals. Copyright © 2012 Wiley Periodicals, Inc.

Hyperspectral imaging to monitor simultaneously multiple protein subtypes and live track their spatial dynamics: a new platform to screen drugs for CNS diseases

NASA Astrophysics Data System (ADS)

Labrecque, S.; Sylvestre, J.-P.; Marcet, S.; Mangiarini, F.; Verhaegen, M.; De Koninck, P.; Blais-Ouellette, S.

2015-03-01

In the past decade, the efficacy of existing therapies and the discovery of innovative treatments for Central Nervous System (CNS) diseases have been limited by the lack of appropriate methods to investigate complex molecular processes at the synaptic level. In order to better understand the fundamental mechanisms that regulate diseases of the CNS, a fast fluorescence hyperspectral imaging platform was designed to track simultaneously various neurotransmitter receptors trafficking in and out of synapses. With this hyperspectral imaging platform, it was possible to image simultaneously five different synaptic proteins, including subtypes of glutamate receptors (mGluR, NMDAR, AMPAR), postsynaptic density proteins, and signaling proteins. This new imaging platform allows fast simultaneous acquisitions of at least five fluorescent markers in living neurons with a high spatial resolution. This technique provides an effective method to observe several synaptic proteins at the same time, thus study how drugs for CNS impact the spatial dynamics of these proteins.

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.

PubMed

Potter, Paul K; Bowl, Michael R; Jeyarajan, Prashanthini; Wisby, Laura; Blease, Andrew; Goldsworthy, Michelle E; Simon, Michelle M; Greenaway, Simon; Michel, Vincent; Barnard, Alun; Aguilar, Carlos; Agnew, Thomas; Banks, Gareth; Blake, Andrew; Chessum, Lauren; Dorning, Joanne; Falcone, Sara; Goosey, Laurence; Harris, Shelley; Haynes, Andy; Heise, Ines; Hillier, Rosie; Hough, Tertius; Hoslin, Angela; Hutchison, Marie; King, Ruairidh; Kumar, Saumya; Lad, Heena V; Law, Gemma; MacLaren, Robert E; Morse, Susan; Nicol, Thomas; Parker, Andrew; Pickford, Karen; Sethi, Siddharth; Starbuck, Becky; Stelma, Femke; Cheeseman, Michael; Cross, Sally H; Foster, Russell G; Jackson, Ian J; Peirson, Stuart N; Thakker, Rajesh V; Vincent, Tonia; Scudamore, Cheryl; Wells, Sara; El-Amraoui, Aziz; Petit, Christine; Acevedo-Arozena, Abraham; Nolan, Patrick M; Cox, Roger; Mallon, Anne-Marie; Brown, Steve D M

2016-08-18

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss.

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease

PubMed Central

Potter, Paul K.; Bowl, Michael R.; Jeyarajan, Prashanthini; Wisby, Laura; Blease, Andrew; Goldsworthy, Michelle E.; Simon, Michelle M.; Greenaway, Simon; Michel, Vincent; Barnard, Alun; Aguilar, Carlos; Agnew, Thomas; Banks, Gareth; Blake, Andrew; Chessum, Lauren; Dorning, Joanne; Falcone, Sara; Goosey, Laurence; Harris, Shelley; Haynes, Andy; Heise, Ines; Hillier, Rosie; Hough, Tertius; Hoslin, Angela; Hutchison, Marie; King, Ruairidh; Kumar, Saumya; Lad, Heena V.; Law, Gemma; MacLaren, Robert E.; Morse, Susan; Nicol, Thomas; Parker, Andrew; Pickford, Karen; Sethi, Siddharth; Starbuck, Becky; Stelma, Femke; Cheeseman, Michael; Cross, Sally H.; Foster, Russell G.; Jackson, Ian J.; Peirson, Stuart N.; Thakker, Rajesh V.; Vincent, Tonia; Scudamore, Cheryl; Wells, Sara; El-Amraoui, Aziz; Petit, Christine; Acevedo-Arozena, Abraham; Nolan, Patrick M.; Cox, Roger; Mallon, Anne-Marie; Brown, Steve D. M.

2016-01-01

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss. PMID:27534441

Three-dimensional patterning in biomedicine: Importance and applications in neuropharmacology.

PubMed

Vikram Singh, Ajay; Gharat, Tanmay; Batuwangala, Madu; Park, Byung-Wook; Endlein, Thomas; Sitti, Metin

2018-04-01

Nature manufactures biological systems in three dimensions with precisely controlled spatiotemporal profiles on hierarchical length and time scales. In this article, we review 3D patterning of biological systems on synthetic platforms for neuropharmacological applications. We briefly describe 3D versus 2D chemical and topographical patterning methods and their limitations. Subsequently, an overview of introducing a third dimension in neuropharmacological research with delineation of chemical and topographical roles is presented. Finally, toward the end of this article, an explanation of how 3D patterning has played a pivotal role in relevant fields of neuropharmacology to understand neurophysiology during development, normal health, and disease conditions is described. The future prospects of organs-on-a--like devices to mimic patterned blood-brain barrier in the context of neurotherapeutic discovery and development for the prioritization of lead candidates, membrane potential, and toxicity testing are also described. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1369-1382, 2018. © 2017 Wiley Periodicals, Inc.

Interactive Visualization of Large-Scale Hydrological Data using Emerging Technologies in Web Systems and Parallel Programming

NASA Astrophysics Data System (ADS)

Demir, I.; Krajewski, W. F.

2013-12-01

As geoscientists are confronted with increasingly massive datasets from environmental observations to simulations, one of the biggest challenges is having the right tools to gain scientific insight from the data and communicate the understanding to stakeholders. Recent developments in web technologies make it easy to manage, visualize and share large data sets with general public. Novel visualization techniques and dynamic user interfaces allow users to interact with data, and modify the parameters to create custom views of the data to gain insight from simulations and environmental observations. This requires developing new data models and intelligent knowledge discovery techniques to explore and extract information from complex computational simulations or large data repositories. Scientific visualization will be an increasingly important component to build comprehensive environmental information platforms. This presentation provides an overview of the trends and challenges in the field of scientific visualization, and demonstrates information visualization and communication tools developed within the light of these challenges.

Towards Precision Medicine in the Clinic: From Biomarker Discovery to Novel Therapeutics.

PubMed

Collins, Dearbhaile C; Sundar, Raghav; Lim, Joline S J; Yap, Timothy A

2017-01-01

Precision medicine continues to be the benchmark to which we strive in cancer research. Seeking out actionable aberrations that can be selectively targeted by drug compounds promises to optimize treatment efficacy and minimize toxicity. Utilizing these different targeted agents in combination or in sequence may further delay resistance to treatments and prolong antitumor responses. Remarkable progress in the field of immunotherapy adds another layer of complexity to the management of cancer patients. Corresponding advances in companion biomarker development, novel methods of serial tumor assessments, and innovative trial designs act synergistically to further precision medicine. Ongoing hurdles such as clonal evolution, intra- and intertumor heterogeneity, and varied mechanisms of drug resistance continue to be challenges to overcome. Large-scale data-sharing and collaborative networks using next-generation sequencing (NGS) platforms promise to take us further into the cancer 'ome' than ever before, with the goal of achieving successful precision medicine. Copyright © 2016 Elsevier Ltd. All rights reserved.

Low on the London Scale

NASA Astrophysics Data System (ADS)

Webb, S.

2013-09-01

Until relatively recently, many authors have assumed that if extraterrestrial life is discovered it will be via the discovery of extraterrestrial intelligence: we can best try to detect life by adopting the SETI approach of trying to detect beacons or artefacts. The Rio Scale, proposed by Almár and Tarter in 2000, is a tool for quantifying the potential significance for society of any such reported detection. However, improvements in technology and advances in astrobiology raise the possibility that the discovery of extraterrestrial life will instead be via the detection of atmospheric biosignatures. The London Scale, proposed by Almár in 2010, attempts to quantify the potential significance of the discovery of extraterrestrial life rather than extraterrestrial intelligence. What might be the consequences of the announcement of a discovery that ranks low on the London Scale? In other words, what might be society's reaction if 'first contact' is via the remote sensing of the byproducts of unicellular organisms rather than with the products of high intelligence? Here, I examine some possible reactions to that question; in particular, I discuss how such an announcement might affect our views of life here on Earth and of humanity's place in the universe.

An integrative data analysis platform for gene set analysis and knowledge discovery in a data warehouse framework.

PubMed

Chen, Yi-An; Tripathi, Lokesh P; Mizuguchi, Kenji

2016-01-01

Data analysis is one of the most critical and challenging steps in drug discovery and disease biology. A user-friendly resource to visualize and analyse high-throughput data provides a powerful medium for both experimental and computational biologists to understand vastly different biological data types and obtain a concise, simplified and meaningful output for better knowledge discovery. We have previously developed TargetMine, an integrated data warehouse optimized for target prioritization. Here we describe how upgraded and newly modelled data types in TargetMine can now survey the wider biological and chemical data space, relevant to drug discovery and development. To enhance the scope of TargetMine from target prioritization to broad-based knowledge discovery, we have also developed a new auxiliary toolkit to assist with data analysis and visualization in TargetMine. This toolkit features interactive data analysis tools to query and analyse the biological data compiled within the TargetMine data warehouse. The enhanced system enables users to discover new hypotheses interactively by performing complicated searches with no programming and obtaining the results in an easy to comprehend output format. Database URL: http://targetmine.mizuguchilab.org. © The Author(s) 2016. Published by Oxford University Press.

An integrative data analysis platform for gene set analysis and knowledge discovery in a data warehouse framework

PubMed Central

Chen, Yi-An; Tripathi, Lokesh P.; Mizuguchi, Kenji

2016-01-01

Data analysis is one of the most critical and challenging steps in drug discovery and disease biology. A user-friendly resource to visualize and analyse high-throughput data provides a powerful medium for both experimental and computational biologists to understand vastly different biological data types and obtain a concise, simplified and meaningful output for better knowledge discovery. We have previously developed TargetMine, an integrated data warehouse optimized for target prioritization. Here we describe how upgraded and newly modelled data types in TargetMine can now survey the wider biological and chemical data space, relevant to drug discovery and development. To enhance the scope of TargetMine from target prioritization to broad-based knowledge discovery, we have also developed a new auxiliary toolkit to assist with data analysis and visualization in TargetMine. This toolkit features interactive data analysis tools to query and analyse the biological data compiled within the TargetMine data warehouse. The enhanced system enables users to discover new hypotheses interactively by performing complicated searches with no programming and obtaining the results in an easy to comprehend output format. Database URL: http://targetmine.mizuguchilab.org PMID:26989145

Integration of Antibody Array Technology into Drug Discovery and Development.

PubMed

Huang, Wei; Whittaker, Kelly; Zhang, Huihua; Wu, Jian; Zhu, Si-Wei; Huang, Ruo-Pan

Antibody arrays represent a high-throughput technique that enables the parallel detection of multiple proteins with minimal sample volume requirements. In recent years, antibody arrays have been widely used to identify new biomarkers for disease diagnosis or prognosis. Moreover, many academic research laboratories and commercial biotechnology companies are starting to apply antibody arrays in the field of drug discovery. In this review, some technical aspects of antibody array development and the various platforms currently available will be addressed; however, the main focus will be on the discussion of antibody array technologies and their applications in drug discovery. Aspects of the drug discovery process, including target identification, mechanisms of drug resistance, molecular mechanisms of drug action, drug side effects, and the application in clinical trials and in managing patient care, which have been investigated using antibody arrays in recent literature will be examined and the relevance of this technology in progressing this process will be discussed. Protein profiling with antibody array technology, in addition to other applications, has emerged as a successful, novel approach for drug discovery because of the well-known importance of proteins in cell events and disease development.

21 CFR 890.3940 - Wheelchair platform scale.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Wheelchair platform scale. 890.3940 Section 890.3940 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Prosthetic Devices § 890.3940 Wheelchair...

21 CFR 890.3940 - Wheelchair platform scale.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Wheelchair platform scale. 890.3940 Section 890.3940 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Prosthetic Devices § 890.3940 Wheelchair...

21 CFR 890.3940 - Wheelchair platform scale.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Wheelchair platform scale. 890.3940 Section 890.3940 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Prosthetic Devices § 890.3940 Wheelchair...

21 CFR 890.3940 - Wheelchair platform scale.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Wheelchair platform scale. 890.3940 Section 890.3940 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Prosthetic Devices § 890.3940 Wheelchair...

21 CFR 890.3940 - Wheelchair platform scale.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Wheelchair platform scale. 890.3940 Section 890.3940 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Prosthetic Devices § 890.3940 Wheelchair...

Compound scale-up at the discovery-development interface.

PubMed

Nikitenko, Antonia A

2006-11-01

As a result of an economically challenging environment within the pharmaceutical industry, pharmaceutical companies and their departments must increase productivity and cut costs to stay in line with the market. Discovery-led departments such as the medicinal chemistry and lead optimization groups focus on synthesizing large varieties of compounds in minimal amounts, while the chemical development groups must then deliver a few chosen leads employing an optimized synthesis method and using multi-kilogram quantities of material. A research group at the discovery-development interface has the task of medium-scale synthesis which is important in the lead selection stage. The primary objective of this group is the initial scale-up of promising leads for extensive physicochemical and biological testing. The challenge of the interface group involves overcoming synthetic issues within the rigid, accelerated timelines.

High-Throughput Screening Platform for the Discovery of New Immunomodulator Molecules from Natural Product Extract Libraries.

PubMed

Pérez Del Palacio, José; Díaz, Caridad; de la Cruz, Mercedes; Annang, Frederick; Martín, Jesús; Pérez-Victoria, Ignacio; González-Menéndez, Víctor; de Pedro, Nuria; Tormo, José R; Algieri, Francesca; Rodriguez-Nogales, Alba; Rodríguez-Cabezas, M Elena; Reyes, Fernando; Genilloud, Olga; Vicente, Francisca; Gálvez, Julio

2016-07-01

It is widely accepted that central nervous system inflammation and systemic inflammation play a significant role in the progression of chronic neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, neurotropic viral infections, stroke, paraneoplastic disorders, traumatic brain injury, and multiple sclerosis. Therefore, it seems reasonable to propose that the use of anti-inflammatory drugs might diminish the cumulative effects of inflammation. Indeed, some epidemiological studies suggest that sustained use of anti-inflammatory drugs may prevent or slow down the progression of neurodegenerative diseases. However, the anti-inflammatory drugs and biologics used clinically have the disadvantage of causing side effects and a high cost of treatment. Alternatively, natural products offer great potential for the identification and development of bioactive lead compounds into drugs for treating inflammatory diseases with an improved safety profile. In this work, we present a validated high-throughput screening approach in 96-well plate format for the discovery of new molecules with anti-inflammatory/immunomodulatory activity. The in vitro models are based on the quantitation of nitrite levels in RAW264.7 murine macrophages and interleukin-8 in Caco-2 cells. We have used this platform in a pilot project to screen a subset of 5976 noncytotoxic crude microbial extracts from the MEDINA microbial natural product collection. To our knowledge, this is the first report on an high-throughput screening of microbial natural product extracts for the discovery of immunomodulators. © 2016 Society for Laboratory Automation and Screening.

Building a Citizen Pscientist: Advancing Patient-Centered Psoriasis Research by Empowering Patients as Contributors and Analysts.

PubMed

Sanchez, Isabelle M; Shankle, Lindsey; Wan, Marilyn T; Afifi, Ladan; Wu, Jashin J; Doris, Frank; Bridges, Alisha; Boas, Marc; Lafoy, Brian; Truman, Sarah; Orbai, Ana-Maria; Takeshita, Junko; Gelfand, Joel M; Armstrong, April W; Siegel, Michael P; Liao, Wilson

2018-06-06

To design and implement a novel cloud-based digital platform that allows psoriatic patients and researchers to engage in the research process. Citizen Pscientist (CP) was created by the National Psoriasis Foundation (NPF) to support and educate the global psoriatic disease community, where patients and researchers have the ability to analyze data. Psoriatic patients were invited to enroll in CP and contribute health data to a cloud database by responding to a 59-question online survey. They were then invited to perform their own analyses of the data using built-in visualization tools allowing for the creation of "discovery charts." These charts were posted on the CP website allowing for further discussion. As of May 2017, 3534 patients have enrolled in CP and have collectively contributed over 200,000 data points on their health status. Patients posted 70 discovery charts, generating 209 discussion comments. With the growing influence of the internet and technology in society, medical research can be enhanced by crowdsourcing and online patient portals. Patient discovery charts focused on the topics of psoriatic disease demographics, clinical features, environmental triggers, and quality of life. Patients noted that the CP platform adds to their well-being and allows them to express what research questions matter most to them in a direct and quantifiable way. The implementation of CP is a successful and novel method of allowing patients to engage in research. Thus, CP is an important tool to promote patient-centered psoriatic disease research.

Artificial intelligence exploration of unstable protocells leads to predictable properties and discovery of collective behavior.

PubMed

Points, Laurie J; Taylor, James Ward; Grizou, Jonathan; Donkers, Kevin; Cronin, Leroy

2018-01-30

Protocell models are used to investigate how cells might have first assembled on Earth. Some, like oil-in-water droplets, can be seemingly simple models, while able to exhibit complex and unpredictable behaviors. How such simple oil-in-water systems can come together to yield complex and life-like behaviors remains a key question. Herein, we illustrate how the combination of automated experimentation and image processing, physicochemical analysis, and machine learning allows significant advances to be made in understanding the driving forces behind oil-in-water droplet behaviors. Utilizing >7,000 experiments collected using an autonomous robotic platform, we illustrate how smart automation cannot only help with exploration, optimization, and discovery of new behaviors, but can also be core to developing fundamental understanding of such systems. Using this process, we were able to relate droplet formulation to behavior via predicted physical properties, and to identify and predict more occurrences of a rare collective droplet behavior, droplet swarming. Proton NMR spectroscopic and qualitative pH methods enabled us to better understand oil dissolution, chemical change, phase transitions, and droplet and aqueous phase flows, illustrating the utility of the combination of smart-automation and traditional analytical chemistry techniques. We further extended our study for the simultaneous exploration of both the oil and aqueous phases using a robotic platform. Overall, this work shows that the combination of chemistry, robotics, and artificial intelligence enables discovery, prediction, and mechanistic understanding in ways that no one approach could achieve alone.

Insect-Specific Virus Discovery: Significance for the Arbovirus Community

PubMed Central

Bolling, Bethany G.; Weaver, Scott C.; Tesh, Robert B.; Vasilakis, Nikos

2015-01-01

Arthropod-borne viruses (arboviruses), especially those transmitted by mosquitoes, are a significant cause of morbidity and mortality in humans and animals worldwide. Recent discoveries indicate that mosquitoes are naturally infected with a wide range of other viruses, many within taxa occupied by arboviruses that are considered insect-specific. Over the past ten years there has been a dramatic increase in the literature describing novel insect-specific virus detection in mosquitoes, which has provided new insights about viral diversity and evolution, including that of arboviruses. It has also raised questions about what effects the mosquito virome has on arbovirus transmission. Additionally, the discovery of these new viruses has generated interest in their potential use as biological control agents as well as novel vaccine platforms. The arbovirus community will benefit from the growing database of knowledge concerning these newly described viral endosymbionts, as their impacts will likely be far reaching. PMID:26378568

KSC-05PD-1175

NASA Technical Reports Server (NTRS)

2005-01-01

KENNEDY SPACE CENTER, FLA. Space Shuttle Discovery, resting on the Mobile Launcher Platform, turns the corner on the crawlerway as it rolls back from Launch Pad 39B to the Vehicle Assembly Building (VAB) at NASAs Kennedy Space Center. Once inside the VAB, it will be demated from its External Tank and lifted into the transfer aisle. On or about June 7, Discovery will be attached to its new tank and Solid Rocket Boosters, which are already in the VAB. Only the 15th rollback in Space Shuttle Program history, the 4.2-mile journey allows additional modifications to be made to the External Tank prior to a safe Return to Flight. Discovery is expected to be rolled back to the launch pad in mid-June for Return to Flight mission STS-114. The launch window extends from July 13 to July 31. [Photo courtesy of Scott Andrews

The RSS rolls back revealing STS-102 Discovery on Launch Pad 39B

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. - With the Rotating Service Structure rolled back, Space Shuttle Discovery is revealed, poised for launch on mission STS-102 at 6:42 a.m. EST March 8. It sits on the Mobile Launcher Platform, which straddles the flame trench below that helps deflect the intense heat of launch. Made of concrete and refractory brick, the trench is 490 feet long, 58 feet wide and 40 feet high. Situated above the external tank is the Gaseous Oxygen Vent Arm with the '''beanie cap,''' a vent hood. On this eighth construction flight to the International Space Station, Discovery carries the Multi-Purpose Logistics Module Leonardo, the primary delivery system used to resupply and return Station cargo requiring a pressurized environment. Leonardo will deliver up to 10 tons of laboratory racks filled with equipment, experiments and supplies for outfitting the newly installed U.S. Laboratory Destiny.

The University of Kansas High-Throughput Screening laboratory. Part I: meeting drug-discovery needs in the heartland of America with entrepreneurial flair.

PubMed

McDonald, Peter R; Roy, Anuradha; Chaguturu, Rathnam

2011-05-01

The University of Kansas High-Throughput Screening (KU HTS) core is a state-of-the-art drug-discovery facility with an entrepreneurial open-service policy, which provides centralized resources supporting public- and private-sector research initiatives. The KU HTS core applies pharmaceutical industry project-management principles in an academic setting by bringing together multidisciplinary teams to fill critical scientific and technology gaps, using an experienced team of industry-trained researchers and project managers. The KU HTS proactively engages in supporting grant applications for extramural funding, intellectual-property management and technology transfer. The KU HTS staff further provides educational opportunities for the KU faculty and students to learn cutting-edge technologies in drug-discovery platforms through seminars, workshops, internships and course teaching. This is the first instalment of a two-part contribution from the KU HTS laboratory.

Microwave and continuous flow technologies in drug discovery.

PubMed

Sadler, Sara; Moeller, Alexander R; Jones, Graham B

2012-12-01

Microwave and continuous flow microreactors have become mainstream heating sources in contemporary pharmaceutical company laboratories. Such technologies will continue to benefit from design and engineering improvements, and now play a key role in the drug discovery process. The authors review the applications of flow- and microwave-mediated heating in library, combinatorial, solid-phase, metal-assisted, and protein chemistries. Additionally, the authors provide a description of the combination of microwave and continuous flow platforms, with applications in the preparation of radiopharmaceuticals and in drug candidate development. Literature reviewed is chiefly 2000 - 2012, plus key citations from earlier reports. With the advent of microwave irradiation, reactions that normally took days to complete can now be performed in a matter of minutes. Coupled with the introduction of continuous flow microreactors, pharmaceutical companies have an easy way to improve the greenness and efficiency of many synthetic operations. The combined force of these technologies offers the potential to revolutionize discovery and manufacturing processes.

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.

Space Shuttle Discovery lifts off successfully

NASA Technical Reports Server (NTRS)

1998-01-01

Space Shuttle Discovery clears Launch Pad 39B at 2:19 p.m. EST Oct. 29 as it lifts off on mission STS-95. Making his second voyage into space after 36 years is Payload Specialist John H. Glenn Jr., senator from Ohio. Other crew members are Mission Commander Curtis L. Brown Jr., Pilot Steven W. Lindsey, Payload Specialist Chiaki Mukai, (M.D., Ph.D.), with the National Space Development Agency of Japan (NASDA), Mission Specialist Stephen K. Robinson, Mission Specialist Pedro Duque of Spain, representing the European Space Agency (ESA), and Mission Specialist Scott E. Parazynski. The STS-95 mission includes research payloads such as the Spartan solar-observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process. Discovery is expected to return to KSC at 11:49 a.m. EST on Nov. 7.

Space Shuttle Discovery lifts off successfully

NASA Technical Reports Server (NTRS)

1998-01-01

Tree branches on the Space Coast frame Space Shuttle Discovery's liftoff from Launch Pad 39B at 2:19 p.m. EST Oct. 29 on mission STS-95. Making his second voyage into space after 36 years is Payload Specialist John H. Glenn Jr., senator from Ohio. Other crew members are Mission Commander Curtis L. Brown Jr., Pilot Steven W. Lindsey, Payload Specialist Chiaki Mukai, (M.D., Ph.D.), with the National Space Development Agency of Japan (NASDA), Mission Specialist Stephen K. Robinson, Mission Specialist Pedro Duque of Spain, representing the European Space Agency (ESA), and Mission Specialist Scott E. Parazynski. The STS-95 mission includes research payloads such as the Spartan solar-observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process. Discovery is expected to return to KSC at 11:49 a.m. EST on Nov. 7.

STS-85 Mission Specialist Robinson prepares to enter Discovery

NASA Technical Reports Server (NTRS)

1997-01-01

STS-85 Mission Specialist Stephen K. Robinson prepares to enter the Space Shuttle orbiter Discovery at Launch Complex 39A just prior to launch, scheduled for 10:41 a.m. EDT. The primary payload on this mission is the Cryogenic Infrared Spectrometers and Telescopes for the Atmosphere-Shuttle Pallet Satellite-2 (CRISTA-SPAS-2) free-flyer. The CRISTA-SPAS-2 will be deployed on flight day 1 to study trace gases in the Earths atmosphere as a part of NASAs Mission to Planet Earth program. Also aboard the free-flying research platform will be the Middle Atmosphere High Resolution Spectrograph Instrument (MAHRSI). Other payloads on the 11-day mission include the Manipulator Flight Demonstration (MFD), a Japanese Space Agency-sponsored experiment. Also in Discoverys payload bay are the Technology Applications and Science-1 (TAS-1) and International Extreme Ultraviolet Hitchhiker-2 (IEH-2) experiments.

KSC-2009-4414

NASA Image and Video Library

2009-08-04

CAPE CANAVERAL, Fla. –Sitting on top of the mobile launcher platform and propelled by the crawler-transporter, space shuttle Discovery rolls up Launch Pad 39A at NASA's Kennedy Space Center in Florida after a nearly 12-hour journey from the Vehicle Assembly Building. First motion out of the VAB was at 2:07 a.m. EDT Aug. 4. Rollout was delayed approximately 2 hours due to lightning in the area. The rollout was slower than usual as technicians stopped several times to clear mud from the crawler's treads and bearings caused by the waterlogged crawlerway. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the International Space Station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for late August. Photo credit: NASA/Troy Cryder

KSC-2009-4417

NASA Image and Video Library

2009-08-04

CAPE CANAVERAL, Fla. – Sitting on top of the mobile launcher platform, space shuttle Discovery arrives on top of Launch Pad 39A at NASA's Kennedy Space Center in Florida. Traveling from the Vehicle Assembly Building, the shuttle took nearly 12 hours on the journey as technicians stopped several times to clear mud from the crawler's treads and bearings caused by the waterlogged crawlerway. First motion out of the VAB was at 2:07 a.m. EDT Aug. 4. Rollout was delayed approximately 2 hours due to lightning in the area. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the International Space Station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for late August. Photo credit: NASA/Troy Cryder

KSC-2009-4415

NASA Image and Video Library

2009-08-04

CAPE CANAVERAL, Fla. –Sitting on top of the mobile launcher platform and propelled by the crawler-transporter, space shuttle Discovery rolls up Launch Pad 39A at NASA's Kennedy Space Center in Florida after a nearly 12-hour journey from the Vehicle Assembly Building. First motion out of the VAB was at 2:07 a.m. EDT Aug. 4. Rollout was delayed approximately 2 hours due to lightning in the area. The rollout was slower than usual as technicians stopped several times to clear mud from the crawler's treads and bearings caused by the waterlogged crawlerway. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the International Space Station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for late August. Photo credit: NASA/Troy Cryder

KSC-2009-4420

NASA Image and Video Library

2009-08-04

CAPE CANAVERAL, Fla. –Sitting on top of the mobile launcher platform and propelled by the crawler-transporter, space shuttle Discovery rolls onto Launch Pad 39A at NASA's Kennedy Space Center in Florida after a nearly 12-hour journey from the Vehicle Assembly Building. First motion out of the VAB was at 2:07 a.m. EDT Aug. 4. Rollout was delayed approximately 2 hours due to lightning in the area. The rollout was slower than usual as technicians stopped several times to clear mud from the crawler's treads and bearings caused by the waterlogged crawlerway. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the International Space Station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for late August. Photo credit: NASA/Troy Cryder

Modern mass spectrometry for synthetic biology and structure-based discovery of natural products.

PubMed

Henke, Matthew T; Kelleher, Neil L

2016-08-27

Covering: up to 2016In this highlight, we describe the current landscape for dereplication and discovery of natural products based on the measurement of the intact mass by LC-MS. Often it is assumed that because better mass accuracy (provided by higher resolution mass spectrometers) is necessary for absolute chemical formula determination (≤1 part-per-million), that it is also necessary for dereplication of natural products. However, the average ability to dereplicate tapers off at ∼10 ppm, with modest improvement gained from better mass accuracy when querying focused databases of natural products. We also highlight some recent examples of how these platforms are applied to synthetic biology, and recent methods for dereplication and correlation of substructures using tandem MS data. We also offer this highlight to serve as a brief primer for those entering the field of mass spectrometry-based natural products discovery.

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

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

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

Concepts and Principles of Photodynamic Therapy as an Alternative Antifungal Discovery Platform

PubMed Central

Dai, Tianhong; Fuchs, Beth B.; Coleman, Jeffrey J.; Prates, Renato A.; Astrakas, Christos; St. Denis, Tyler G.; Ribeiro, Martha S.; Mylonakis, Eleftherios; Hamblin, Michael R.; Tegos, George P.

2012-01-01

Opportunistic fungal pathogens may cause superficial or serious invasive infections, especially in immunocompromised and debilitated patients. Invasive mycoses represent an exponentially growing threat for human health due to a combination of slow diagnosis and the existence of relatively few classes of available and effective antifungal drugs. Therefore systemic fungal infections result in high attributable mortality. There is an urgent need to pursue and deploy novel and effective alternative antifungal countermeasures. Photodynamic therapy (PDT) was established as a successful modality for malignancies and age-related macular degeneration but photodynamic inactivation has only recently been intensively investigated as an alternative antimicrobial discovery and development platform. The concept of photodynamic inactivation requires microbial exposure to either exogenous or endogenous photosensitizer molecules, followed by visible light energy, typically wavelengths in the red/near infrared region that cause the excitation of the photosensitizers resulting in the production of singlet oxygen and other reactive oxygen species that react with intracellular components, and consequently produce cell inactivation and death. Antifungal PDT is an area of increasing interest, as research is advancing (i) to identify the photochemical and photophysical mechanisms involved in photoinactivation; (ii) to develop potent and clinically compatible photosensitizers; (iii) to understand how photoinactivation is affected by key microbial phenotypic elements multidrug resistance and efflux, virulence and pathogenesis determinants, and formation of biofilms; (iv) to explore novel photosensitizer delivery platforms; and (v) to identify photoinactivation applications beyond the clinical setting such as environmental disinfectants. PMID:22514547

Multifunctional picoliter droplet manipulation platform and its application in single cell analysis.

PubMed

Gu, Shu-Qing; Zhang, Yun-Xia; Zhu, Ying; Du, Wen-Bin; Yao, Bo; Fang, Qun

2011-10-01

We developed an automated and multifunctional microfluidic platform based on DropLab to perform flexible generation and complex manipulations of picoliter-scale droplets. Multiple manipulations including precise droplet generation, sequential reagent merging, and multistep solid-phase extraction for picoliter-scale droplets could be achieved in the present platform. The system precision in generating picoliter-scale droplets was significantly improved by minimizing the thermo-induced fluctuation of flow rate. A novel droplet fusion technique based on the difference of droplet interfacial tensions was developed without the need of special microchannel networks or external devices. It enabled sequential addition of reagents to droplets on demand for multistep reactions. We also developed an effective picoliter-scale droplet splitting technique with magnetic actuation. The difficulty in phase separation of magnetic beads from picoliter-scale droplets due to the high interfacial tension was overcome using ferromagnetic particles to carry the magnetic beads to pass through the phase interface. With this technique, multistep solid-phase extraction was achieved among picoliter-scale droplets. The present platform had the ability to perform complex multistep manipulations to picoliter-scale droplets, which is particularly required for single cell analysis. Its utility and potentials in single cell analysis were preliminarily demonstrated in achieving high-efficiency single-cell encapsulation, enzyme activity assay at the single cell level, and especially, single cell DNA purification based on solid-phase extraction.

Harvest: an open platform for developing web-based biomedical data discovery and reporting applications.

PubMed

Pennington, Jeffrey W; Ruth, Byron; Italia, Michael J; Miller, Jeffrey; Wrazien, Stacey; Loutrel, Jennifer G; Crenshaw, E Bryan; White, Peter S

2014-01-01

Biomedical researchers share a common challenge of making complex data understandable and accessible as they seek inherent relationships between attributes in disparate data types. Data discovery in this context is limited by a lack of query systems that efficiently show relationships between individual variables, but without the need to navigate underlying data models. We have addressed this need by developing Harvest, an open-source framework of modular components, and using it for the rapid development and deployment of custom data discovery software applications. Harvest incorporates visualizations of highly dimensional data in a web-based interface that promotes rapid exploration and export of any type of biomedical information, without exposing researchers to underlying data models. We evaluated Harvest with two cases: clinical data from pediatric cardiology and demonstration data from the OpenMRS project. Harvest's architecture and public open-source code offer a set of rapid application development tools to build data discovery applications for domain-specific biomedical data repositories. All resources, including the OpenMRS demonstration, can be found at http://harvest.research.chop.edu.

KSC-05PD-1142

NASA Technical Reports Server (NTRS)

2005-01-01

KENNEDY SPACE CENTER, FLA. Under post-dawn cloudy skies, Space Shuttle Discovery, resting on the Mobile Launcher Platform, rolls away from Launch Pad 39B via the Crawler/Transporter underneath. At left are the Rotating and Fixed Service Structures (RSS and FSS). Atop the FSS is the 80-foot lightning mast. At right is the 290-foot-tall water tower that holds 300,000 gallons of water, part of the sound suppression system during a launch. Discovery is returning to the Vehicle Assembly Buildling where it will be demated from its External Tank and lifted into the transfer aisle. On or about June 7, Discovery will be lifted and attached to its new tank and Solid Rocket Boosters, which are already in the VAB. Only the 15th rollback in Space Shuttle Program history, the 4.2-mile journey allows additional modifications to be made to the External Tank prior to a safe Return to Flight. Discovery is expected to be rolled back to the launch pad in mid-June for Return to Flight mission STS-114. The launch window extends from July 13 to July 31.

Harvest: an open platform for developing web-based biomedical data discovery and reporting applications

PubMed Central

Pennington, Jeffrey W; Ruth, Byron; Italia, Michael J; Miller, Jeffrey; Wrazien, Stacey; Loutrel, Jennifer G; Crenshaw, E Bryan; White, Peter S

2014-01-01

Biomedical researchers share a common challenge of making complex data understandable and accessible as they seek inherent relationships between attributes in disparate data types. Data discovery in this context is limited by a lack of query systems that efficiently show relationships between individual variables, but without the need to navigate underlying data models. We have addressed this need by developing Harvest, an open-source framework of modular components, and using it for the rapid development and deployment of custom data discovery software applications. Harvest incorporates visualizations of highly dimensional data in a web-based interface that promotes rapid exploration and export of any type of biomedical information, without exposing researchers to underlying data models. We evaluated Harvest with two cases: clinical data from pediatric cardiology and demonstration data from the OpenMRS project. Harvest's architecture and public open-source code offer a set of rapid application development tools to build data discovery applications for domain-specific biomedical data repositories. All resources, including the OpenMRS demonstration, can be found at http://harvest.research.chop.edu PMID:24131510

Space Shuttle Discovery lifts off successfully

NASA Technical Reports Server (NTRS)

1998-01-01

As if sprung from the rolling exhaust clouds below, Space Shuttle Discovery shoots into the heavens over the blue Atlantic Ocean from Launch Pad 39B on mission STS-95. Lifting off at 2:19 p.m. EST, Discovery carries a crew of six, including Payload Specialist John H. Glenn Jr., senator from Ohio, who is making his second voyage into space after 36 years. Other crew members are Mission Commander Curtis L. Brown Jr., Pilot Steven W. Lindsey, Payload Specialist Chiaki Mukai, (M.D., Ph.D.), with the National Space Development Agency of Japan (NASDA), Mission Specialist Stephen K. Robinson, Mission Specialist Pedro Duque of Spain, representing the European Space Agency (ESA), and Mission Specialist Scott E. Parazynski. The STS-95 mission includes research payloads such as the Spartan solar-observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process. Discovery is expected to return to KSC at 11:49 a.m. EST on Nov. 7.

Authentic Astronomical Discovery in Planetariums: Bringing Data to Domes

NASA Astrophysics Data System (ADS)

Wyatt, Ryan Jason; Subbarao, Mark; Christensen, Lars; Emmons, Ben; Hurt, Robert

2018-01-01

Planetariums offer a unique opportunity to disseminate astronomical discoveries using data visualization at all levels of complexity: the technical infrastructure to display data and a sizeable cohort of enthusiastic educators to interpret results. “Data to Dome” is an initiative the International Planetarium Society to develop our community’s capacity to integrate data in fulldome planetarium systems—including via open source software platforms such as WorldWide Telescope and OpenSpace. We are cultivating a network of planetarium professionals who integrate data into their presentations and share their content with others. Furthermore, we propose to shorten the delay between discovery and dissemination in planetariums. Currently, the “latest science” is often presented days or weeks after discoveries are announced, and we can shorten this to hours or even minutes. The Data2Dome (D2D) initiative, led by the European Southern Observatory, proposes technical infrastructure and data standards that will streamline content flow from research institutions to planetariums, offering audiences a unique opportunity to access to the latest astronomical data in near real time.

KSC-2009-4424

NASA Image and Video Library

2009-08-04

CAPE CANAVERAL, Fla. – Sitting on top of the mobile launcher platform, space shuttle Discovery arrives on top of Launch Pad 39A at NASA's Kennedy Space Center in Florida. Traveling from the Vehicle Assembly Building, the shuttle took nearly 12 hours on the journey as technicians stopped several times to clear mud from the crawler's treads and bearings caused by the waterlogged crawlerway. First motion out of the VAB was at 2:07 a.m. EDT Aug. 4. Rollout was delayed approximately 2 hours due to lightning in the area. In the foreground next to Discovery's main engines is one of the two tail masts, which provide several umbilical connections to the orbiter, including a liquid-oxygen line through one and a liquid-hydrogen line through another. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the International Space Station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for late August. Photo credit: NASA/Troy Cryder

KSC01padig074

NASA Image and Video Library

2001-02-12

KENNEDY SPACE CENTER, Fla. -- This closeup shows Space Shuttle Discovery as it travels to Launch Pad 39B. Underneath Discovery is the Mobile Launcher Platform, a two-story movable launch base. Part of the MPLM is the tail service mast, seen here at the bottom of the wind and next to the Shuttle’s main engines. The tail service mast is 31 feet high, 15 feet long and 9 feet wide. A second TSM is on the other side. They support the fluid, gas and electrical requirements of the orbiter’s liquid oxygen and liquid hydrogen aft T-0 umbilicals. Discovery will be flying on mission STS-102 to the International Space Station. Its payload is the Multi-Purpose Logistics Module Leonardo, a “moving van,” to carry laboratory racks filled with equipment, experiments and supplies to and from the Space Station aboard the Space Shuttle. The flight will also carry the Expedition Two crew up to the Space Station, replacing Expedition One, who will return to Earth on Discovery. Launch is scheduled for March 8 at 6:45 a.m. EST

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

Surrounded by work platforms, the full-scale Orion AFT crew module (center) is undergoing preparations for the first flight test of Orion's launch abort system.

NASA Image and Video Library

2008-05-20

Surrounded by work platforms, NASA's first full-scale Orion abort flight test (AFT) crew module (center) is undergoing preparations at the NASA Dryden Flight Research Center in California for the first flight test of Orion's launch abort system.

Lab on a CD.

PubMed

Madou, Marc; Zoval, Jim; Jia, Guangyao; Kido, Horacio; Kim, Jitae; Kim, Nahui

2006-01-01

In this paper, centrifuge-based microfluidic platforms are reviewed and compared with other popular microfluidic propulsion methods. The underlying physical principles of centrifugal pumping in microfluidic systems are presented and the various centrifuge fluidic functions, such as valving, decanting, calibration, mixing, metering, heating, sample splitting, and separation, are introduced. Those fluidic functions have been combined with analytical measurement techniques, such as optical imaging, absorbance, and fluorescence spectroscopy and mass spectrometry, to make the centrifugal platform a powerful solution for medical and clinical diagnostics and high throughput screening (HTS) in drug discovery. Applications of a compact disc (CD)-based centrifuge platform analyzed in this review include two-point calibration of an optode-based ion sensor, an automated immunoassay platform, multiple parallel screening assays, and cellular-based assays. The use of modified commercial CD drives for high-resolution optical imaging is discussed as well. From a broader perspective, we compare technical barriers involved in applying microfluidics for sensing and diagnostic use and applying such techniques to HTS. The latter poses less challenges and explains why HTS products based on a CD fluidic platform are already commercially available, whereas we might have to wait longer to see commercial CD-based diagnostics.

Knowledge discovery through games and game theory

NASA Astrophysics Data System (ADS)

Smith, James F., III; Rhyne, Robert D.

2001-03-01

A fuzzy logic based expert system has been developed that automatically allocates electronic attack (EA) resources in real-time over many dissimilar platforms. The platforms can be very general, e.g., ships, planes, robots, land based facilities, etc. Potential foes the platforms deal with can also be general. The initial version of the algorithm was optimized using a genetic algorithm employing fitness functions constructed based on expertise. A new approach is being explored that involves embedding the resource manager in a electronic game environment. The game allows a human expert to play against the resource manager in a simulated battlespace with each of the defending platforms being exclusively directed by the fuzzy resource manager and the attacking platforms being controlled by the human expert or operating autonomously under their own logic. This approach automates the data mining problem. The game automatically creates a database reflecting the domain expert's knowledge, it calls a data mining function, a genetic algorithm, for data mining of the database as required. The game allows easy evaluation of the information mined in the second step. The measure of effectiveness (MOE) for re-optimization is discussed. The mined information is extremely valuable as shown through demanding scenarios.

Carbon nanotubes (CNTs) based advanced dermal therapeutics: current trends and future potential.

PubMed

Kuche, Kaushik; Maheshwari, Rahul; Tambe, Vishakha; Mak, Kit-Kay; Jogi, Hardi; Raval, Nidhi; Pichika, Mallikarjuna Rao; Kumar Tekade, Rakesh

2018-05-17

The search for effective and non-invasive delivery modules to transport therapeutic molecules across skin has led to the discovery of a number of nanocarriers (viz.: liposomes, ethosomes, dendrimers, etc.) in the last few decades. However, available literature suggests that these delivery modules face several issues including poor stability, low encapsulation efficiency, and scale-up hurdles. Recently, carbon nanotubes (CNTs) emerged as a versatile tool to deliver therapeutics across skin. Superior stability, high loading capacity, well-developed synthesis protocol as well as ease of scale-up are some of the reason for growing interest in CNTs. CNTs have a unique physical architecture and a large surface area with unique surface chemistry that can be tailored for vivid biomedical applications. CNTs have been thus largely engaged in the development of transdermal systems such as tuneable hydrogels, programmable nonporous membranes, electroresponsive skin modalities, protein channel mimetic platforms, reverse iontophoresis, microneedles, and dermal buckypapers. In addition, CNTs were also employed in the development of RNA interference (RNAi) based therapeutics for correcting defective dermal genes. This review expounds the state-of-art synthesis methodologies, skin penetration mechanism, drug liberation profile, loading potential, characterization techniques, and transdermal applications along with a summary on patent/regulatory status and future scope of CNT based skin therapeutics.

Maximizing Academic Library Collections: Measuring Changes in Use Patterns Owing to EBSCO Discovery Service

ERIC Educational Resources Information Center

Calvert, Kristin

2015-01-01

Despite the prevalence of academic libraries adopting web-scale discovery tools, few studies have quantified their effect on the use of library collections. This study measures the impact that EBSCO Discovery Service has had on use of library resources through circulation statistics, use of electronic resources, and interlibrary loan requests.…

WholePathwayScope: a comprehensive pathway-based analysis tool for high-throughput data

PubMed Central

Yi, Ming; Horton, Jay D; Cohen, Jonathan C; Hobbs, Helen H; Stephens, Robert M

2006-01-01

Background Analysis of High Throughput (HTP) Data such as microarray and proteomics data has provided a powerful methodology to study patterns of gene regulation at genome scale. A major unresolved problem in the post-genomic era is to assemble the large amounts of data generated into a meaningful biological context. We have developed a comprehensive software tool, WholePathwayScope (WPS), for deriving biological insights from analysis of HTP data. Result WPS extracts gene lists with shared biological themes through color cue templates. WPS statistically evaluates global functional category enrichment of gene lists and pathway-level pattern enrichment of data. WPS incorporates well-known biological pathways from KEGG (Kyoto Encyclopedia of Genes and Genomes) and Biocarta, GO (Gene Ontology) terms as well as user-defined pathways or relevant gene clusters or groups, and explores gene-term relationships within the derived gene-term association networks (GTANs). WPS simultaneously compares multiple datasets within biological contexts either as pathways or as association networks. WPS also integrates Genetic Association Database and Partial MedGene Database for disease-association information. We have used this program to analyze and compare microarray and proteomics datasets derived from a variety of biological systems. Application examples demonstrated the capacity of WPS to significantly facilitate the analysis of HTP data for integrative discovery. Conclusion This tool represents a pathway-based platform for discovery integration to maximize analysis power. The tool is freely available at . PMID:16423281

Identification of widespread adenosine nucleotide binding in Mycobacterium tuberculosis

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

Ansong, Charles; Ortega, Corrie; Payne, Samuel H.

The annotation of protein function is almost completely performed by in silico approaches. However, computational prediction of protein function is frequently incomplete and error prone. In Mycobacterium tuberculosis (Mtb), ~25% of all genes have no predicted function and are annotated as hypothetical proteins. This lack of functional information severely limits our understanding of Mtb pathogenicity. Current tools for experimental functional annotation are limited and often do not scale to entire protein families. Here, we report a generally applicable chemical biology platform to functionally annotate bacterial proteins by combining activity-based protein profiling (ABPP) and quantitative LC-MS-based proteomics. As an example ofmore » this approach for high-throughput protein functional validation and discovery, we experimentally annotate the families of ATP-binding proteins in Mtb. Our data experimentally validate prior in silico predictions of >250 ATPases and adenosine nucleotide-binding proteins, and reveal 73 hypothetical proteins as novel ATP-binding proteins. We identify adenosine cofactor interactions with many hypothetical proteins containing a diversity of unrelated sequences, providing a new and expanded view of adenosine nucleotide binding in Mtb. Furthermore, many of these hypothetical proteins are both unique to Mycobacteria and essential for infection, suggesting specialized functions in mycobacterial physiology and pathogenicity. Thus, we provide a generally applicable approach for high throughput protein function discovery and validation, and highlight several ways in which application of activity-based proteomics data can improve the quality of functional annotations to facilitate novel biological insights.« less

Optimization and Pharmacological Validation of a Leukocyte Migration Assay in Zebrafish Larvae for the Rapid In Vivo Bioactivity Analysis of Anti-Inflammatory Secondary Metabolites

PubMed Central

Vicet-Muro, Liliana; Wilches-Arizábala, Isabel María; Esguerra, Camila V.; de Witte, Peter A. M.; Crawford, Alexander D.

2013-01-01

Over the past decade, zebrafish (Danio rerio) have emerged as an attractive model for in vivo drug discovery. In this study, we explore the suitability of zebrafish larvae to rapidly evaluate the anti-inflammatory activity of natural products (NPs) and medicinal plants used in traditional medicine for the treatment of inflammatory disorders. First, we optimized a zebrafish assay for leukocyte migration. Inflammation was induced in four days post-fertilization (dpf) zebrafish larvae by tail transection and co-incubation with bacterial lipopolysaccharides (LPS), resulting in a robust recruitment of leukocytes to the zone of injury. Migrating zebrafish leukocytes were detected in situ by myeloperoxidase (MPO) staining, and anti-inflammatory activity was semi-quantitatively scored using a standardized scale of relative leukocyte migration (RLM). Pharmacological validation of this optimized assay was performed with a panel of anti-inflammatory drugs, demonstrating a concentration-responsive inhibition of leukocyte migration for both steroidal and non-steroidal anti-inflammatory drugs (SAIDs and NSAIDs). Subsequently, we evaluated the bioactivity of structurally diverse NPs with well-documented anti-inflammatory properties. Finally, we further used this zebrafish-based assay to quantify the anti-inflammatory activity in the aqueous and methanolic extracts of several medicinal plants. Our results indicate the suitability of this LPS-enhanced leukocyte migration assay in zebrafish larvae as a front-line screening platform in NP discovery, including for the bioassay-guided isolation of anti-inflammatory secondary metabolites from complex NP extracts. PMID:24124487

The silicon chip: A versatile micro-scale platform for micro- and nano-scale systems

NASA Astrophysics Data System (ADS)

Choi, Edward

Cutting-edge advances in micro- and nano-scale technology require instrumentation to interface with the external world. While technology feature sizes are continually being reduced, the size of experimentalists and their instrumentation do not mirror this trend. Hence there is a need for effective application-specific instrumentation to bridge the gap from the micro and nano-scale phenomena being studied to the comparative macro-scale of the human interfaces. This dissertation puts forward the idea that the silicon CMOS integrated circuit, or microchip in short, serves as an excellent platform to perform this functionality. The electronic interfaces designed for the semiconductor industry are particularly attractive as development platforms, and the reduction in feature sizes that has been a hallmark of the industry suggests that chip-scale instrumentation may be more closely coupled to the phenomena of interest, allowing finer control or improved measurement capabilities. Compatibility with commercial processes will further enable economies of scale through mass production, another welcome feature of this approach. Thus chip-scale instrumentation may replace the bulky, expensive, cumbersome-to-operate macro-scale prototypes currently in use for many of these applications. The dissertation examines four specific applications in which the chip may serve as the ideal instrumentation platform. These are nanorod manipulation, polypyrrole bilayer hinge microactuator control, organic transistor hybrid circuits, and contact fluorescence imaging. The thesis is structured around chapters devoted to each of these projects, in addition to a chapter on preliminary work on an RFID system that serves as a wireless interface model. Each of these chapters contains tools and techniques developed for chip-scale instrumentation, from custom scripts for automated layout and data collection to microfabrication processes. Implementation of these tools to develop systems for the applications above is evaluated. The viability of this approach is not limited to the examples listed in this work, and innovative new methodologies beyond those included here may be developed in the future for other systems which would benefit from the versatility of chip-scale platforms.

Platform for Automated Real-Time High Performance Analytics on Medical Image Data.

PubMed

Allen, William J; Gabr, Refaat E; Tefera, Getaneh B; Pednekar, Amol S; Vaughn, Matthew W; Narayana, Ponnada A

2018-03-01

Biomedical data are quickly growing in volume and in variety, providing clinicians an opportunity for better clinical decision support. Here, we demonstrate a robust platform that uses software automation and high performance computing (HPC) resources to achieve real-time analytics of clinical data, specifically magnetic resonance imaging (MRI) data. We used the Agave application programming interface to facilitate communication, data transfer, and job control between an MRI scanner and an off-site HPC resource. In this use case, Agave executed the graphical pipeline tool GRAphical Pipeline Environment (GRAPE) to perform automated, real-time, quantitative analysis of MRI scans. Same-session image processing will open the door for adaptive scanning and real-time quality control, potentially accelerating the discovery of pathologies and minimizing patient callbacks. We envision this platform can be adapted to other medical instruments, HPC resources, and analytics tools.

Development and Validation of an Automated High-Throughput System for Zebrafish In Vivo Screenings

PubMed Central

Virto, Juan M.; Holgado, Olaia; Diez, Maria; Izpisua Belmonte, Juan Carlos; Callol-Massot, Carles

2012-01-01

The zebrafish is a vertebrate model compatible with the paradigms of drug discovery. The small size and transparency of zebrafish embryos make them amenable for the automation necessary in high-throughput screenings. We have developed an automated high-throughput platform for in vivo chemical screenings on zebrafish embryos that includes automated methods for embryo dispensation, compound delivery, incubation, imaging and analysis of the results. At present, two different assays to detect cardiotoxic compounds and angiogenesis inhibitors can be automatically run in the platform, showing the versatility of the system. A validation of these two assays with known positive and negative compounds, as well as a screening for the detection of unknown anti-angiogenic compounds, have been successfully carried out in the system developed. We present a totally automated platform that allows for high-throughput screenings in a vertebrate organism. PMID:22615792

Pluripotent stem cells: the last 10 years.

PubMed

Kimbrel, Erin A; Lanza, Robert

2016-12-01

Pluripotent stem cells (PSCs) can differentiate into virtually any cell type in the body, making them attractive for both regenerative medicine and drug discovery. Over the past 10 years, technological advances and innovative platforms have yielded first-in-man PSC-based clinical trials and opened up new approaches for disease modeling and drug development. Induced PSCs have become the foremost alternative to embryonic stem cells and accelerated the development of disease-in-a-dish models. Over the years and with each new discovery, PSCs have proven to be extremely versatile. This review article highlights key advancements in PSC research, from 2006 to 2016, and how they will guide the direction of the field over the next decade.

Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors.

PubMed

Frett, Brendan; McConnell, Nick; Smith, Catherine C; Wang, Yuanxiang; Shah, Neil P; Li, Hong-yu

2015-04-13

The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Raffaello Multi-Purpose Logistics Module (MPLM) in Discovery Cargo Bay

NASA Technical Reports Server (NTRS)

2005-01-01

Launched on July 26, 2005 from the Kennedy Space Center in Florida, STS-114 was classified as Logistics Flight 1. Among the Station-related activities of the mission were the delivery of new supplies and the replacement of one of the orbital outpost's Control Moment Gyroscopes (CMGs). STS-114 also carried the Raffaello Multi-Purpose Logistics Module (MPLM) and the External Stowage Platform-2. Back dropped by popcorn-like clouds, the MPLM can be seen in the cargo bay as Discovery undergoes rendezvous and docking operations. Cosmonaut Sergei K. Kriklev, Expedition 11 Commander, and John L. Phillips, NASA Space Station officer and flight engineer photographed the spacecraft from the International Space Station (ISS).

Raffaello Multi-Purpose Logistics Module (MPLM) in Discovery Cargo Bay

NASA Technical Reports Server (NTRS)

2005-01-01

Launched on July 26 2005 from the Kennedy Space Center in Florida, STS-114 was classified as Logistics Flight 1. Among the Station-related activities of the mission were the delivery of new supplies and the replacement of one of the orbital outpost's Control Moment Gyroscopes (CMGs). STS-114 also carried the Raffaello Multi-Purpose Logistics Module (MPLM) and the External Stowage Platform-2. Back dropped by popcorn-like clouds, the MPLM can be seen in the cargo bay as Discovery undergoes rendezvous and docking operations. Cosmonaut Sergei K. Kriklev, Expedition 11 Commander, and John L. Phillips, NASA Space Station officer and flight engineer photographed the spacecraft from the International Space Station (ISS).

KSC-07pd2024

NASA Image and Video Library

2007-07-19

KENNEDY SPACE CENTER, Fla. -- In the Orbiter Processing Facility bay 3, a crane moves the main bus switching unit that will be installed in Discovery's payload bay. The unit is part of the payload on mission STS-120. A main bus switching unit is used for power distribution, circuit protection and fault isolation on the space station's power system. The units route power to proper locations in the space station, such as from solar arrays through umbilicals into the U.S. Lab. The unit will be installed on the external stowage platform 2 attached to the Quest airlock for temporary storage. Discovery is targeted to launch mission STS-120 no earlier than Oct. 20. Photo credit: NASA/Jim Grossmann

KSC-07pd2023

NASA Image and Video Library

2007-07-19

KENNEDY SPACE CENTER, Fla. -- In the Orbiter Processing Facility bay 3, a crane lifts the main bus switching unit that will be installed in Discovery's payload bay. The unit is part of the payload on mission STS-120. A main bus switching unit is used for power distribution, circuit protection and fault isolation on the space station's power system. The units route power to proper locations in the space station, such as from solar arrays through umbilicals into the U.S. Lab. The unit will be installed on the external stowage platform 2 attached to the Quest airlock for temporary storage. Discovery is targeted to launch mission STS-120 no earlier than Oct. 20. Photo credit: NASA/Jim Grossmann

Closeup view from the starboard side looking towards the port ...

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

Close-up view from the starboard side looking towards the port side of the Orbiter Discovery looking at the airlock and payload bay. The docking ring has been removed from the airlock prior to this photo being taken. Note that the Orbiter Boom Sensor System is still attached while the Remote Manipulator System has been removed. Also note the suspended protective panels and walkways in place to protect the interior surfaces of the payload bay doors while in their open position. This view was taken from a service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

KSC-08pd1109

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, dawn reveals the arrival of space shuttle Discovery, secured atop the mobile launch platform below, at Launch Pad 39A to begin prelaunch processing for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder

KSC-08pd1106

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, space shuttle Discovery, secured atop the mobile launch platform below, arrives at Launch Pad 39A to begin prelaunch processing for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder

KSC-08pd1105

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- This aerial view of NASA's Kennedy Space Center shows space shuttle Discovery, secured atop a mobile launch platform as it is moved into position at Launch Pad 39A to prepare for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder

KSC-08pd1110

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, the sun rises upon the arrival of space shuttle Discovery, secured atop the mobile launch platform below, at Launch Pad 39A to begin prelaunch processing for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder

Scalable Analysis Methods and In Situ Infrastructure for Extreme Scale Knowledge Discovery

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

Bethel, Wes

2016-07-24

The primary challenge motivating this team’s work is the widening gap between the ability to compute information and to store it for subsequent analysis. This gap adversely impacts science code teams, who are able to perform analysis only on a small fraction of the data they compute, resulting in the very real likelihood of lost or missed science, when results are computed but not analyzed. Our approach is to perform as much analysis or visualization processing on data while it is still resident in memory, an approach that is known as in situ processing. The idea in situ processing wasmore » not new at the time of the start of this effort in 2014, but efforts in that space were largely ad hoc, and there was no concerted effort within the research community that aimed to foster production-quality software tools suitable for use by DOE science projects. In large, our objective was produce and enable use of production-quality in situ methods and infrastructure, at scale, on DOE HPC facilities, though we expected to have impact beyond DOE due to the widespread nature of the challenges, which affect virtually all large-scale computational science efforts. To achieve that objective, we assembled a unique team of researchers consisting of representatives from DOE national laboratories, academia, and industry, and engaged in software technology R&D, as well as engaged in close partnerships with DOE science code teams, to produce software technologies that were shown to run effectively at scale on DOE HPC platforms.« less

Grid heterogeneity in in-silico experiments: an exploration of drug screening using DOCK on cloud environments.

PubMed

Yim, Wen-Wai; Chien, Shu; Kusumoto, Yasuyuki; Date, Susumu; Haga, Jason

2010-01-01

Large-scale in-silico screening is a necessary part of drug discovery and Grid computing is one answer to this demand. A disadvantage of using Grid computing is the heterogeneous computational environments characteristic of a Grid. In our study, we have found that for the molecular docking simulation program DOCK, different clusters within a Grid organization can yield inconsistent results. Because DOCK in-silico virtual screening (VS) is currently used to help select chemical compounds to test with in-vitro experiments, such differences have little effect on the validity of using virtual screening before subsequent steps in the drug discovery process. However, it is difficult to predict whether the accumulation of these discrepancies over sequentially repeated VS experiments will significantly alter the results if VS is used as the primary means for identifying potential drugs. Moreover, such discrepancies may be unacceptable for other applications requiring more stringent thresholds. This highlights the need for establishing a more complete solution to provide the best scientific accuracy when executing an application across Grids. One possible solution to platform heterogeneity in DOCK performance explored in our study involved the use of virtual machines as a layer of abstraction. This study investigated the feasibility and practicality of using virtual machine and recent cloud computing technologies in a biological research application. We examined the differences and variations of DOCK VS variables, across a Grid environment composed of different clusters, with and without virtualization. The uniform computer environment provided by virtual machines eliminated inconsistent DOCK VS results caused by heterogeneous clusters, however, the execution time for the DOCK VS increased. In our particular experiments, overhead costs were found to be an average of 41% and 2% in execution time for two different clusters, while the actual magnitudes of the execution time costs were minimal. Despite the increase in overhead, virtual clusters are an ideal solution for Grid heterogeneity. With greater development of virtual cluster technology in Grid environments, the problem of platform heterogeneity may be eliminated through virtualization, allowing greater usage of VS, and will benefit all Grid applications in general.

Regenerative Medicine Build-Out.

PubMed

Terzic, Andre; Pfenning, Michael A; Gores, Gregory J; Harper, C Michel

2015-12-01

Regenerative technologies strive to boost innate repair processes and restitute normative impact. Deployment of regenerative principles into practice is poised to usher in a new era in health care, driving radical innovation in patient management to address the needs of an aging population challenged by escalating chronic diseases. There is urgency to design, execute, and validate viable paradigms for translating and implementing the science of regenerative medicine into tangible health benefits that provide value to stakeholders. A regenerative medicine model of care would entail scalable production and standardized application of clinical grade biotherapies supported by comprehensive supply chain capabilities that integrate sourcing and manufacturing with care delivery. Mayo Clinic has rolled out a blueprint for discovery, translation, and application of regenerative medicine therapies for accelerated adoption into the standard of care. To establish regenerative medical and surgical service lines, the Mayo Clinic model incorporates patient access, enabling platforms and delivery. Access is coordinated through a designated portal, the Regenerative Medicine Consult Service, serving to facilitate patient/provider education, procurement of biomaterials, referral to specialty services, and/or regenerative interventions, often in clinical trials. Platforms include the Regenerative Medicine Biotrust and Good Manufacturing Practice facilities for manufacture of clinical grade products for cell-based, acellular, and/or biomaterial applications. Care delivery leverages dedicated interventional suites for provision of regenerative services. Performance is tracked using a scorecard system to inform decision making. The Mayo Clinic roadmap exemplifies an integrated organization in the discovery, development, and delivery of regenerative medicine within a growing community of practice at the core of modern health care. Regenerative medicine is at the vanguard of health care poised to offer solutions for many of today's incurable diseases. Accordingly, there is a pressing need to develop, deploy, and demonstrate a viable framework for rollout of a regenerative medicine model of care. Translation of regenerative medicine principles into practice is feasible, yet clinical validity and utility must be established to ensure approval and adoption. Standardized and scaled-up regenerative products and services across medical and surgical specialties must in turn achieve a value-added proposition, advancing intended outcome beyond current management strategies. ©AlphaMed Press.

Regenerative Medicine Build-Out

PubMed Central

Pfenning, Michael A.; Gores, Gregory J.; Harper, C. Michel

2015-01-01

Summary Regenerative technologies strive to boost innate repair processes and restitute normative impact. Deployment of regenerative principles into practice is poised to usher in a new era in health care, driving radical innovation in patient management to address the needs of an aging population challenged by escalating chronic diseases. There is urgency to design, execute, and validate viable paradigms for translating and implementing the science of regenerative medicine into tangible health benefits that provide value to stakeholders. A regenerative medicine model of care would entail scalable production and standardized application of clinical grade biotherapies supported by comprehensive supply chain capabilities that integrate sourcing and manufacturing with care delivery. Mayo Clinic has rolled out a blueprint for discovery, translation, and application of regenerative medicine therapies for accelerated adoption into the standard of care. To establish regenerative medical and surgical service lines, the Mayo Clinic model incorporates patient access, enabling platforms and delivery. Access is coordinated through a designated portal, the Regenerative Medicine Consult Service, serving to facilitate patient/provider education, procurement of biomaterials, referral to specialty services, and/or regenerative interventions, often in clinical trials. Platforms include the Regenerative Medicine Biotrust and Good Manufacturing Practice facilities for manufacture of clinical grade products for cell-based, acellular, and/or biomaterial applications. Care delivery leverages dedicated interventional suites for provision of regenerative services. Performance is tracked using a scorecard system to inform decision making. The Mayo Clinic roadmap exemplifies an integrated organization in the discovery, development, and delivery of regenerative medicine within a growing community of practice at the core of modern health care. Significance Regenerative medicine is at the vanguard of health care poised to offer solutions for many of today’s incurable diseases. Accordingly, there is a pressing need to develop, deploy, and demonstrate a viable framework for rollout of a regenerative medicine model of care. Translation of regenerative medicine principles into practice is feasible, yet clinical validity and utility must be established to ensure approval and adoption. Standardized and scaled-up regenerative products and services across medical and surgical specialties must in turn achieve a value-added proposition, advancing intended outcome beyond current management strategies. PMID:26537392

A Technology-Enriched Active Learning Space for a New Gateway Education Programme in Hong Kong: A Platform for Nurturing Student Innovations

ERIC Educational Resources Information Center

Chiu, Pit Ho Patrio

2016-01-01

A Gateway Education Programme is established in Hong Kong that aims to broaden students' interdisciplinary knowledge and nurture student innovations under the Discovery-enriched Curriculum. To support the initiative, a novel idea was proposed for the creation of a Gateway Education Laboratory (GE Lab) with a highly configurable layout equipped…

Discovery of a small-molecule HIV-1 integrase inhibitor-binding site | Center for Cancer Research

Cancer.gov

The lowest energy-binding conformation of an inhibitor bound to the dimeric interface of HIV-1 integrase core domain. The yellow region represents a unique allosteric binding site identified by affinity labeling and mass spectrometry and validated through mutagenesis. This site can provide a potential platform for the rational design of inhibitors selective for disruption of

Single nucleotide polymorphism (SNP) discovery in rainbow trout using restriction site associated DNA (RAD) sequencing of doubled haploids and assessment of polymorphism in a population survey

USDA-ARS?s Scientific Manuscript database

Background: Our goal is to produce a high-throughput SNP genotyping platform for genomic analyses in rainbow trout that will enable fine mapping of QTL, whole genome association studies, genomic selection for improved aquaculture production traits, and genetic analyses of wild populations that aid ...

Applications of microarray technology in breast cancer research

PubMed Central

Cooper, Colin S

2001-01-01

Microarrays provide a versatile platform for utilizing information from the Human Genome Project to benefit human health. This article reviews the ways in which microarray technology may be used in breast cancer research. Its diverse applications include monitoring chromosome gains and losses, tumour classification, drug discovery and development, DNA resequencing, mutation detection and investigating the mechanism of tumour development. PMID:11305951

General Platform for Systematic Quantitative Evaluation of Small-Molecule Permeability in Bacteria

PubMed Central

2015-01-01

The chemical features that impact small-molecule permeability across bacterial membranes are poorly understood, and the resulting lack of tools to predict permeability presents a major obstacle to the discovery and development of novel antibiotics. Antibacterials are known to have vastly different structural and physicochemical properties compared to nonantiinfective drugs, as illustrated herein by principal component analysis (PCA). To understand how these properties influence bacterial permeability, we have developed a systematic approach to evaluate the penetration of diverse compounds into bacteria with distinct cellular envelopes. Intracellular compound accumulation is quantitated using LC-MS/MS, then PCA and Pearson pairwise correlations are used to identify structural and physicochemical parameters that correlate with accumulation. An initial study using 10 sulfonyladenosines in Escherichia coli, Bacillus subtilis, and Mycobacterium smegmatis has identified nonobvious correlations between chemical structure and permeability that differ among the various bacteria. Effects of cotreatment with efflux pump inhibitors were also investigated. This sets the stage for use of this platform in larger prospective analyses of diverse chemotypes to identify global relationships between chemical structure and bacterial permeability that would enable the development of predictive tools to accelerate antibiotic drug discovery. PMID:25198656

Multiplexing of miniaturized planar antibody arrays for serum protein profiling--a biomarker discovery in SLE nephritis.

PubMed

Petersson, Linn; Dexlin-Mellby, Linda; Bengtsson, Anders A; Sturfelt, Gunnar; Borrebaeck, Carl A K; Wingren, Christer

2014-06-07

In the quest to decipher disease-associated biomarkers, miniaturized and multiplexed antibody arrays may play a central role in generating protein expression profiles, or protein maps, of crude serum samples. In this conceptual study, we explored a novel, 4-times larger pen design, enabling us to, in a unique manner, simultaneously print 48 different reagents (antibodies) as individual 78.5 μm(2) (10 μm in diameter) sized spots at a density of 38,000 spots cm(-2) using dip-pen nanolithography technology. The antibody array set-up was interfaced with a high-resolution fluorescent-based scanner for sensitive sensing. The performance and applicability of this novel 48-plex recombinant antibody array platform design was demonstrated in a first clinical application targeting SLE nephritis, a severe chronic autoimmune connective tissue disorder, as the model disease. To this end, crude, directly biotinylated serum samples were targeted. The results showed that the miniaturized and multiplexed array platform displayed adequate performance, and that SLE-associated serum biomarker panels reflecting the disease process could be deciphered, outlining the use of miniaturized antibody arrays for disease proteomics and biomarker discovery.

KENNEDY SPACE CENTER, FLA. - The STS-114 crew stands underneath Discovery in the Orbiter Processing Facility. From left are Mission Specialist Stephen Robinson, Pilot James Kelly, Mission Specialist Charles Camarda, astronaut John Young, Commander Eileen Collins and Mission Specialists Andrew Thomas, Wendy Lawrence and Soichi Noguchi, who is with the Japanese Aerospace and Exploration Agency. Young is associate director, Technical, at Johnson Space Center. The crew is spending time becoming familiar with Shuttle and mission equipment. The mission is Logistics Flight 1, which is scheduled to deliver supplies and equipment plus the external stowage platform to the International Space Station.

NASA Image and Video Library

2004-03-05

KENNEDY SPACE CENTER, FLA. - The STS-114 crew stands underneath Discovery in the Orbiter Processing Facility. From left are Mission Specialist Stephen Robinson, Pilot James Kelly, Mission Specialist Charles Camarda, astronaut John Young, Commander Eileen Collins and Mission Specialists Andrew Thomas, Wendy Lawrence and Soichi Noguchi, who is with the Japanese Aerospace and Exploration Agency. Young is associate director, Technical, at Johnson Space Center. The crew is spending time becoming familiar with Shuttle and mission equipment. The mission is Logistics Flight 1, which is scheduled to deliver supplies and equipment plus the external stowage platform to the International Space Station.

Harnessing the power of emerging petascale platforms

NASA Astrophysics Data System (ADS)

Mellor-Crummey, John

2007-07-01

As part of the US Department of Energy's Scientific Discovery through Advanced Computing (SciDAC-2) program, science teams are tackling problems that require computational simulation and modeling at the petascale. A grand challenge for computer science is to develop software technology that makes it easier to harness the power of these systems to aid scientific discovery. As part of its activities, the SciDAC-2 Center for Scalable Application Development Software (CScADS) is building open source software tools to support efficient scientific computing on the emerging leadership-class platforms. In this paper, we describe two tools for performance analysis and tuning that are being developed as part of CScADS: a tool for analyzing scalability and performance, and a tool for optimizing loop nests for better node performance. We motivate these tools by showing how they apply to S3D, a turbulent combustion code under development at Sandia National Laboratory. For S3D, our node performance analysis tool helped uncover several performance bottlenecks. Using our loop nest optimization tool, we transformed S3D's most costly loop nest to reduce execution time by a factor of 2.94 for a processor working on a 503 domain.

Developing a novel fiber optic fluorescence device for multiplexed high-throughput cytotoxic screening.

PubMed

Lee, Dennis; Barnes, Stephen

2010-01-01

The need for new pharmacological agents is unending. Yet the drug discovery process has changed substantially over the past decade and continues to evolve in response to new technologies. There is presently a high demand to reduce discovery time by improving specific lab disciplines and developing new technology platforms in the area of cell-based assay screening. Here we present the developmental concept and early stage testing of the Ab-Sniffer, a novel fiber optic fluorescence device for high-throughput cytotoxicity screening using an immobilized whole cell approach. The fused silica fibers are chemically functionalized with biotin to provide interaction with fluorescently labeled, streptavidin functionalized alginate-chitosan microspheres. The microspheres are also functionalized with Concanavalin A to facilitate binding to living cells. By using lymphoma cells and rituximab in an adaptation of a well-known cytotoxicity protocol we demonstrate the utility of the Ab-Sniffer for functional screening of potential drug compounds rather than indirect, non-functional screening via binding assay. The platform can be extended to any assay capable of being tied to a fluorescence response including multiple target cells in each well of a multi-well plate for high-throughput screening.

A machine learning approach for viral genome classification.

PubMed

Remita, Mohamed Amine; Halioui, Ahmed; Malick Diouara, Abou Abdallah; Daigle, Bruno; Kiani, Golrokh; Diallo, Abdoulaye Baniré

2017-04-11

Advances in cloning and sequencing technology are yielding a massive number of viral genomes. The classification and annotation of these genomes constitute important assets in the discovery of genomic variability, taxonomic characteristics and disease mechanisms. Existing classification methods are often designed for specific well-studied family of viruses. Thus, the viral comparative genomic studies could benefit from more generic, fast and accurate tools for classifying and typing newly sequenced strains of diverse virus families. Here, we introduce a virus classification platform, CASTOR, based on machine learning methods. CASTOR is inspired by a well-known technique in molecular biology: restriction fragment length polymorphism (RFLP). It simulates, in silico, the restriction digestion of genomic material by different enzymes into fragments. It uses two metrics to construct feature vectors for machine learning algorithms in the classification step. We benchmark CASTOR for the classification of distinct datasets of human papillomaviruses (HPV), hepatitis B viruses (HBV) and human immunodeficiency viruses type 1 (HIV-1). Results reveal true positive rates of 99%, 99% and 98% for HPV Alpha species, HBV genotyping and HIV-1 M subtyping, respectively. Furthermore, CASTOR shows a competitive performance compared to well-known HIV-1 specific classifiers (REGA and COMET) on whole genomes and pol fragments. The performance of CASTOR, its genericity and robustness could permit to perform novel and accurate large scale virus studies. The CASTOR web platform provides an open access, collaborative and reproducible machine learning classifiers. CASTOR can be accessed at http://castor.bioinfo.uqam.ca .

Tectonic setting and hydrocarbon habitat of external Carpathian basins in Romania

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

Dicea, O.; Morariu, D.C.

1993-09-01

During the Alpine evolution of Romania, two distinct depositional areas evolved in the external zones of the Carpathians: the Paleogene flysch and Neogene Molasse basin of the eastern Carpathians, and the Paleogene and Neogene Molasse basin of the southern Carpathians. Both basins were compressionally deformed during the Neogene, giving rise to the development of a succession of nappes and thrust sheets. The internal elements of the external Carpathians corresponding to the Tarcau and marginal folds nappes and the external elements forming the sub-carpathian nappe and foredeep were thrusted over significant distances onto the European platform. Intense exploration of the externalmore » Carpathian thrustbelt has led to the discovery of more than 100 oil and gas pools. Reservoirs are provided by Oligocene, Burdigalian, Sarmatian, and Pliocene clastic rocks. A prolific hydrocarbon charge is derived from regionally distributed Oligocene oil source rocks. Traps are mainly of the structural type and involve faulted anticlines, [open quotes]scale folds,[close quotes] and compressional structures modified by salt; stratigraphic pinch-out and unconformity related traps play a secondary role. On the basis of selected examples, the development and distribution of hydrocarbon pools will be discussed in terms of thrust kinematics and the structure of different platform blocks. The philosophy of past exploration activities will be reviewed, and both success cases and failures will be discussed. Remaining oil and gas plays, aimed at shallow as well as at deep objectives, will be highlighted.« less

Purdue ionomics information management system. An integrated functional genomics platform.

PubMed

Baxter, Ivan; Ouzzani, Mourad; Orcun, Seza; Kennedy, Brad; Jandhyala, Shrinivas S; Salt, David E

2007-02-01

The advent of high-throughput phenotyping technologies has created a deluge of information that is difficult to deal with without the appropriate data management tools. These data management tools should integrate defined workflow controls for genomic-scale data acquisition and validation, data storage and retrieval, and data analysis, indexed around the genomic information of the organism of interest. To maximize the impact of these large datasets, it is critical that they are rapidly disseminated to the broader research community, allowing open access for data mining and discovery. We describe here a system that incorporates such functionalities developed around the Purdue University high-throughput ionomics phenotyping platform. The Purdue Ionomics Information Management System (PiiMS) provides integrated workflow control, data storage, and analysis to facilitate high-throughput data acquisition, along with integrated tools for data search, retrieval, and visualization for hypothesis development. PiiMS is deployed as a World Wide Web-enabled system, allowing for integration of distributed workflow processes and open access to raw data for analysis by numerous laboratories. PiiMS currently contains data on shoot concentrations of P, Ca, K, Mg, Cu, Fe, Zn, Mn, Co, Ni, B, Se, Mo, Na, As, and Cd in over 60,000 shoot tissue samples of Arabidopsis (Arabidopsis thaliana), including ethyl methanesulfonate, fast-neutron and defined T-DNA mutants, and natural accession and populations of recombinant inbred lines from over 800 separate experiments, representing over 1,000,000 fully quantitative elemental concentrations. PiiMS is accessible at www.purdue.edu/dp/ionomics.

Analytical validation considerations of multiplex mass-spectrometry-based proteomic platforms for measuring protein biomarkers.

PubMed

Boja, Emily S; Fehniger, Thomas E; Baker, Mark S; Marko-Varga, György; Rodriguez, Henry

2014-12-05

Protein biomarker discovery and validation in current omics era are vital for healthcare professionals to improve diagnosis, detect cancers at an early stage, identify the likelihood of cancer recurrence, stratify stages with differential survival outcomes, and monitor therapeutic responses. The success of such biomarkers would have a huge impact on how we improve the diagnosis and treatment of patients and alleviate the financial burden of healthcare systems. In the past, the genomics community (mostly through large-scale, deep genomic sequencing technologies) has been steadily improving our understanding of the molecular basis of disease, with a number of biomarker panels already authorized by the U.S. Food and Drug Administration (FDA) for clinical use (e.g., MammaPrint, two recently cleared devices using next-generation sequencing platforms to detect DNA changes in the cystic fibrosis transmembrane conductance regulator (CFTR) gene). Clinical proteomics, on the other hand, albeit its ability to delineate the functional units of a cell, more likely driving the phenotypic differences of a disease (i.e., proteins and protein-protein interaction networks and signaling pathways underlying the disease), "staggers" to make a significant impact with only an average ∼ 1.5 protein biomarkers per year approved by the FDA over the past 15-20 years. This statistic itself raises the concern that major roadblocks have been impeding an efficient transition of protein marker candidates in biomarker development despite major technological advances in proteomics in recent years.

Rapid Sequential in Situ Multiplexing with DNA Exchange Imaging in Neuronal Cells and Tissues.

PubMed

Wang, Yu; Woehrstein, Johannes B; Donoghue, Noah; Dai, Mingjie; Avendaño, Maier S; Schackmann, Ron C J; Zoeller, Jason J; Wang, Shan Shan H; Tillberg, Paul W; Park, Demian; Lapan, Sylvain W; Boyden, Edward S; Brugge, Joan S; Kaeser, Pascal S; Church, George M; Agasti, Sarit S; Jungmann, Ralf; Yin, Peng

2017-10-11

To decipher the molecular mechanisms of biological function, it is critical to map the molecular composition of individual cells or even more importantly tissue samples in the context of their biological environment in situ. Immunofluorescence (IF) provides specific labeling for molecular profiling. However, conventional IF methods have finite multiplexing capabilities due to spectral overlap of the fluorophores. Various sequential imaging methods have been developed to circumvent this spectral limit but are not widely adopted due to the common limitation of requiring multirounds of slow (typically over 2 h at room temperature to overnight at 4 °C in practice) immunostaining. We present here a practical and robust method, which we call DNA Exchange Imaging (DEI), for rapid in situ spectrally unlimited multiplexing. This technique overcomes speed restrictions by allowing for single-round immunostaining with DNA-barcoded antibodies, followed by rapid (less than 10 min) buffer exchange of fluorophore-bearing DNA imager strands. The programmability of DEI allows us to apply it to diverse microscopy platforms (with Exchange Confocal, Exchange-SIM, Exchange-STED, and Exchange-PAINT demonstrated here) at multiple desired resolution scales (from ∼300 nm down to sub-20 nm). We optimized and validated the use of DEI in complex biological samples, including primary neuron cultures and tissue sections. These results collectively suggest DNA exchange as a versatile, practical platform for rapid, highly multiplexed in situ imaging, potentially enabling new applications ranging from basic science, to drug discovery, and to clinical pathology.

Next-generation sequencing library preparation method for identification of RNA viruses on the Ion Torrent Sequencing Platform.

PubMed

Chen, Guiqian; Qiu, Yuan; Zhuang, Qingye; Wang, Suchun; Wang, Tong; Chen, Jiming; Wang, Kaicheng

2018-05-09

Next generation sequencing (NGS) is a powerful tool for the characterization, discovery, and molecular identification of RNA viruses. There were multiple NGS library preparation methods published for strand-specific RNA-seq, but some methods are not suitable for identifying and characterizing RNA viruses. In this study, we report a NGS library preparation method to identify RNA viruses using the Ion Torrent PGM platform. The NGS sequencing adapters were directly inserted into the sequencing library through reverse transcription and polymerase chain reaction, without fragmentation and ligation of nucleic acids. The results show that this method is simple to perform, able to identify multiple species of RNA viruses in clinical samples.

Flow Cytometry: Impact on Early Drug Discovery.

PubMed

Edwards, Bruce S; Sklar, Larry A

2015-07-01

Modern flow cytometers can make optical measurements of 10 or more parameters per cell at tens of thousands of cells per second and more than five orders of magnitude dynamic range. Although flow cytometry is used in most drug discovery stages, "sip-and-spit" sampling technology has restricted it to low-sample-throughput applications. The advent of HyperCyt sampling technology has recently made possible primary screening applications in which tens of thousands of compounds are analyzed per day. Target-multiplexing methodologies in combination with extended multiparameter analyses enable profiling of lead candidates early in the discovery process, when the greatest numbers of candidates are available for evaluation. The ability to sample small volumes with negligible waste reduces reagent costs, compound usage, and consumption of cells. Improved compound library formatting strategies can further extend primary screening opportunities when samples are scarce. Dozens of targets have been screened in 384- and 1536-well assay formats, predominantly in academic screening lab settings. In concert with commercial platform evolution and trending drug discovery strategies, HyperCyt-based systems are now finding their way into mainstream screening labs. Recent advances in flow-based imaging, mass spectrometry, and parallel sample processing promise dramatically expanded single-cell profiling capabilities to bolster systems-level approaches to drug discovery. © 2015 Society for Laboratory Automation and Screening.

Flow Cytometry: Impact On Early Drug Discovery

PubMed Central

Edwards, Bruce S.; Sklar, Larry A.

2015-01-01

Summary Modern flow cytometers can make optical measurements of 10 or more parameters per cell at tens-of-thousands of cells per second and over five orders of magnitude dynamic range. Although flow cytometry is used in most drug discovery stages, “sip-and-spit” sampling technology has restricted it to low sample throughput applications. The advent of HyperCyt sampling technology has recently made possible primary screening applications in which tens-of-thousands of compounds are analyzed per day. Target-multiplexing methodologies in combination with extended multi-parameter analyses enable profiling of lead candidates early in the discovery process, when the greatest numbers of candidates are available for evaluation. The ability to sample small volumes with negligible waste reduces reagent costs, compound usage and consumption of cells. Improved compound library formatting strategies can further extend primary screening opportunities when samples are scarce. Dozens of targets have been screened in 384- and 1536-well assay formats, predominantly in academic screening lab settings. In concert with commercial platform evolution and trending drug discovery strategies, HyperCyt-based systems are now finding their way into mainstream screening labs. Recent advances in flow-based imaging, mass spectrometry and parallel sample processing promise dramatically expanded single cell profiling capabilities to bolster systems level approaches to drug discovery. PMID:25805180

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

DTIC Science & Technology

2016-11-01

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

Web-scale discovery in an academic health sciences library: development and implementation of the EBSCO Discovery Service.

PubMed

Thompson, Jolinda L; Obrig, Kathe S; Abate, Laura E

2013-01-01

Funds made available at the close of the 2010-11 fiscal year allowed purchase of the EBSCO Discovery Service (EDS) for a year-long trial. The appeal of this web-scale discovery product that offers a Google-like interface to library resources was counter-balanced by concerns about quality of search results in an academic health science setting and the challenge of configuring an interface that serves the needs of a diverse group of library users. After initial configuration, usability testing with library users revealed the need for further work before general release. Of greatest concern were continuing issues with the relevance of items retrieved, appropriateness of system-supplied facet terms, and user difficulties with navigating the interface. EBSCO has worked with the library to better understand and identify problems and solutions. External roll-out to users occurred in June 2012.

Analysis of Human Plasma Metabolites across Different Liquid Chromatography - Mass Spectrometry Platforms: Cross-platform Transferable Chemical Signatures

PubMed Central

Telu, Kelly H.; Yan, Xinjian; Wallace, William E.; Stein, Stephen E.; Simón-Manso, Yamil

2016-01-01

RATIONALE The metabolite profiling of a NIST plasma Standard Reference Material (SRM 1950) on different LC-MS platforms showed significant differences. Although these findings suggest caution when interpreting metabolomics results, the degree of overlap of both profiles allowed us to use tandem mass spectral libraries of recurrent spectra to evaluate to what extent these results are transferable across platforms and to develop cross-platform chemical signatures. METHODS Non-targeted global metabolite profiles of SRM 1950 were obtained on different LC-MS platforms using reversed phase chromatography and different chromatographic scales (nano, conventional and UHPLC). The data processing and the metabolite differential analysis were carried out using publically available (XCMS), proprietary (Mass Profiler Professional) and in-house software (NIST pipeline). RESULTS Repeatability and intermediate precision showed that the non-targeted SRM 1950 profiling was highly reproducible when working on the same platform (RSD < 2%); however, substantial differences were found in the LC-MS patterns originating on different platforms or even using different chromatographic scales (conventional HPLC, UHPLC and nanoLC) on the same platform. A substantial degree of overlap (common molecular features) was also found. A procedure to generate consistent chemical signatures using tandem mass spectral libraries of recurrent spectra is proposed. CONLUSIONS Different platforms rendered significantly different metabolite profiles, but the results were highly reproducible when working within one platform. Tandem mass spectral libraries of recurrent spectra are proposed to evaluate the degree of transferability of chemical signatures generated on different platforms. Chemical signatures based on our procedure are most likely cross-platform transferable. PMID:26842580

Bioelectronic platforms for optimal bio-anode of bio-electrochemical systems: From nano- to macro scopes.

PubMed

Kim, Bongkyu; An, Junyeong; Fapyane, Deby; Chang, In Seop

2015-11-01

The current trend of bio-electrochemical systems is to improve strategies related to their applicability and potential for scaling-up. To date, literature has suggested strategies, but the proposal of correlations between each research field remains insufficient. This review paper provides a correlation based on platform techniques, referred to as bio-electronics platforms (BEPs). These BEPs consist of three platforms divided by scope scale: nano-, micro-, and macro-BEPs. In the nano-BEP, several types of electron transfer mechanisms used by electrochemically active bacteria are discussed. In the micro-BEP, factors affecting the formation of conductive biofilms and transport of electrons in the conductive biofilm are investigated. In the macro-BEP, electrodes and separators in bio-anode are debated in terms of real applications, and a scale-up strategy is discussed. Overall, the challenges of each BEP are highlighted, and potential solutions are suggested. In addition, future research directions are provided and research ideas proposed to develop research interest. Copyright © 2015 Elsevier Ltd. All rights reserved.

Precision medicine in the age of big data: The present and future role of large-scale unbiased sequencing in drug discovery and development.

PubMed

Vicini, P; Fields, O; Lai, E; Litwack, E D; Martin, A-M; Morgan, T M; Pacanowski, M A; Papaluca, M; Perez, O D; Ringel, M S; Robson, M; Sakul, H; Vockley, J; Zaks, T; Dolsten, M; Søgaard, M

2016-02-01

High throughput molecular and functional profiling of patients is a key driver of precision medicine. DNA and RNA characterization has been enabled at unprecedented cost and scale through rapid, disruptive progress in sequencing technology, but challenges persist in data management and interpretation. We analyze the state-of-the-art of large-scale unbiased sequencing in drug discovery and development, including technology, application, ethical, regulatory, policy and commercial considerations, and discuss issues of LUS implementation in clinical and regulatory practice. © 2015 American Society for Clinical Pharmacology and Therapeutics.

Throttleable GOX/ABS launch assist hybrid rocket motor for small scale air launch platform

NASA Astrophysics Data System (ADS)

Spurrier, Zachary S.

Aircraft-based space-launch platforms allow operational flexibility and offer the potential for significant propellant savings for small-to-medium orbital payloads. The NASA Armstrong Flight Research Center's Towed Glider Air-Launch System (TGALS) is a small-scale flight research project investigating the feasibility for a remotely-piloted, towed, glider system to act as a versatile air launch platform for nano-scale satellites. Removing the crew from the launch vehicle means that the system does not have to be human rated, and offers a potential for considerable cost savings. Utah State University is developing a small throttled launch-assist system for the TGALS platform. This "stage zero" design allows the TGALS platform to achieve the required flight path angle for the launch point, a condition that the TGALS cannot achieve without external propulsion. Throttling is required in order to achieve and sustain the proper launch attitude without structurally overloading the airframe. The hybrid rocket system employs gaseous-oxygen and acrylonitrile butadiene styrene (ABS) as propellants. This thesis summarizes the development and testing campaign, and presents results from the clean-sheet design through ground-based static fire testing. Development of the closed-loop throttle control system is presented.

ProteoLens: a visual analytic tool for multi-scale database-driven biological network data mining.

PubMed

Huan, Tianxiao; Sivachenko, Andrey Y; Harrison, Scott H; Chen, Jake Y

2008-08-12

New systems biology studies require researchers to understand how interplay among myriads of biomolecular entities is orchestrated in order to achieve high-level cellular and physiological functions. Many software tools have been developed in the past decade to help researchers visually navigate large networks of biomolecular interactions with built-in template-based query capabilities. To further advance researchers' ability to interrogate global physiological states of cells through multi-scale visual network explorations, new visualization software tools still need to be developed to empower the analysis. A robust visual data analysis platform driven by database management systems to perform bi-directional data processing-to-visualizations with declarative querying capabilities is needed. We developed ProteoLens as a JAVA-based visual analytic software tool for creating, annotating and exploring multi-scale biological networks. It supports direct database connectivity to either Oracle or PostgreSQL database tables/views, on which SQL statements using both Data Definition Languages (DDL) and Data Manipulation languages (DML) may be specified. The robust query languages embedded directly within the visualization software help users to bring their network data into a visualization context for annotation and exploration. ProteoLens supports graph/network represented data in standard Graph Modeling Language (GML) formats, and this enables interoperation with a wide range of other visual layout tools. The architectural design of ProteoLens enables the de-coupling of complex network data visualization tasks into two distinct phases: 1) creating network data association rules, which are mapping rules between network node IDs or edge IDs and data attributes such as functional annotations, expression levels, scores, synonyms, descriptions etc; 2) applying network data association rules to build the network and perform the visual annotation of graph nodes and edges according to associated data values. We demonstrated the advantages of these new capabilities through three biological network visualization case studies: human disease association network, drug-target interaction network and protein-peptide mapping network. The architectural design of ProteoLens makes it suitable for bioinformatics expert data analysts who are experienced with relational database management to perform large-scale integrated network visual explorations. ProteoLens is a promising visual analytic platform that will facilitate knowledge discoveries in future network and systems biology studies.

OpenQuake, a platform for collaborative seismic hazard and risk assessment

NASA Astrophysics Data System (ADS)

Henshaw, Paul; Burton, Christopher; Butler, Lars; Crowley, Helen; Danciu, Laurentiu; Nastasi, Matteo; Monelli, Damiano; Pagani, Marco; Panzeri, Luigi; Simionato, Michele; Silva, Vitor; Vallarelli, Giuseppe; Weatherill, Graeme; Wyss, Ben

2013-04-01

Sharing of data and risk information, best practices, and approaches across the globe is key to assessing risk more effectively. Through global projects, open-source IT development and collaborations with more than 10 regions, leading experts are collaboratively developing unique global datasets, best practice, tools and models for global seismic hazard and risk assessment, within the context of the Global Earthquake Model (GEM). Guided by the needs and experiences of governments, companies and international organisations, all contributions are being integrated into OpenQuake: a web-based platform that - together with other resources - will become accessible in 2014. With OpenQuake, stakeholders worldwide will be able to calculate, visualize and investigate earthquake hazard and risk, capture new data and share findings for joint learning. The platform is envisaged as a collaborative hub for earthquake risk assessment, used at global and local scales, around which an active network of users has formed. OpenQuake will comprise both online and offline tools, many of which can also be used independently. One of the first steps in OpenQuake development was the creation of open-source software for advanced seismic hazard and risk calculations at any scale, the OpenQuake Engine. Although in continuous development, a command-line version of the software is already being test-driven and used by hundreds worldwide; from non-profits in Central Asia, seismologists in sub-Saharan Africa and companies in South Asia to the European seismic hazard harmonization programme (SHARE). In addition, several technical trainings were organized with scientists from different regions of the world (sub-Saharan Africa, Central Asia, Asia-Pacific) to introduce the engine and other OpenQuake tools to the community, something that will continue to happen over the coming years. Other tools that are being developed of direct interest to the hazard community are: • OpenQuake Modeller; fundamental instruments for the creation of seismogenic input models for seismic hazard assessment, a critical input to the OpenQuake Engine. OpenQuake Modeller will consist of a suite of tools (Hazard Modellers Toolkit) for characterizing the seismogenic sources of earthquakes and their models of earthquakes recurrence. An earthquake catalogue homogenization tool, for integration, statistical comparison and user-defined harmonization of multiple catalogues of earthquakes is also included in the OpenQuake modeling tools. • A data capture tool for active faults; a tool that allows geologists to draw (new) fault discoveries on a map in an intuitive GIS-environment and add details on the fault through the tool. This data, once quality checked, can then be integrated with the global active faults database, which will increase in value with every new fault insertion. Building on many ongoing efforts and the knowledge of scientists worldwide, GEM will for the first time integrate state-of-the-art data, models, results and open-source tools into a single platform. The platform will continue to increase in value, in particular for use in local contexts, through contributions from and collaborations with scientists and organisations worldwide. This presentation will showcase the OpenQuake Platform, focusing on the IT solutions that have been adopted as well as the added value that the platform will bring to scientists worldwide.

NASA's Space Shuttle Discovery is raised to allow ample clearance for the modified 747 Shuttle Carrier Aircraft to position underneath for attachment

NASA Image and Video Library

2005-08-18

NASA's specially modified 747 Shuttle Carrier Aircraft, or SCA, is positioned under the Space Shuttle Discovery to be attached for their ferry flight to the Kennedy Space Center in Florida. After its post-flight servicing and preparation at NASA Dryden in California, Discovery's return flight to Kennedy aboard the 747 will take approximately 2 days, with stops at several intermediate points for refueling. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.

NASA's modified 747 Shuttle Carrier Aircraft is positioned under the Space Shuttle Discovery to be attached for their ferry flight to the Kennedy Space Center

NASA Image and Video Library

2005-08-18

NASA's specially modified 747 Shuttle Carrier Aircraft, or SCA, is positioned under the Space Shuttle Discovery to be attached for their ferry flight to the Kennedy Space Center in Florida. After its post-flight servicing and preparation at NASA Dryden in California, Discovery's return flight to Kennedy aboard the 747 will take approximately 2 days, with stops at several intermediate points for refueling. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.

The Space Shuttle Discovery hitched a ride on a special 747 carrier aircraft for the flight from California to the Kennedy Space Center, FL, on August 19, 2005

NASA Image and Video Library

2005-08-19

The Space Shuttle Discovery hitched a ride on NASA's modified Boeing 747 Shuttle Carrier Aircraft for the flight from the Dryden Flight Research Center in California, to Kennedy Space Center, Florida, on August 19, 2005. The cross-country ferry flight to return Discovery to Florida after it's landing in California will take two days, with stops at several intermediate points for refueling. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.

Genomic Analysis of Childhood Brain Tumors: Methods for Genome-Wide Discovery and Precision Medicine Become Mainstream.

PubMed

Mack, Stephen C; Northcott, Paul A

2017-07-20

Recent breakthroughs in next-generation sequencing technology and complementary genomic platforms have transformed our capacity to interrogate the molecular landscapes of human cancers, including childhood brain tumors. Numerous high-throughput genomic studies have been reported for the major histologic brain tumor entities diagnosed in children, including interrogations at the level of the genome, epigenome, and transcriptome, many of which have yielded essential new insights into disease biology. The nature of these discoveries has been largely platform dependent, exemplifying the usefulness of applying different genomic and computational strategies, or integrative approaches, to address specific biologic and/or clinical questions. The goal of this article is to summarize the spectrum of molecular profiling methods available for investigating genomic aspects of childhood brain tumors in both the research and the clinical setting. We provide an overview of the main next-generation sequencing and array-based technologies currently being applied in this field and draw from key examples in the recent neuro-oncology literature to illustrate how these genomic approaches have profoundly advanced our understanding of individual tumor entities. Moreover, we discuss the current status of genomic profiling in the clinic and how different platforms are being used to improve patient diagnosis and stratification, as well as to identify actionable targets for informing molecularly guided therapies, especially for patients for whom conventional standard-of-care treatments have failed. Both the demand for genomic testing and the main challenges associated with incorporating genomics into the clinical management of pediatric patients with brain tumors are discussed, as are recommendations for incorporating these assays into future clinical trials.

The Turkish Version of Web-Based Learning Platform Evaluation Scale: Reliability and Validity Study

ERIC Educational Resources Information Center

Dag, Funda

2016-01-01

The purpose of this study is to determine the language equivalence and the validity and reliability of the Turkish version of the "Web-Based Learning Platform Evaluation Scale" ("Web Tabanli Ögrenme Ortami Degerlendirme Ölçegi" [WTÖODÖ]) used in the selection and evaluation of web-based learning environments. Within this scope,…

A genome-wide association study platform built on iPlant cyber-infrastructure

USDA-ARS?s Scientific Manuscript database

We demonstrated a flexible Genome-Wide Association (GWA) Study (GWAS) platform built upon the iPlant Collaborative Cyber-infrastructure. The platform supports big data management, sharing, and large scale study of both genotype and phenotype data on clusters. End users can add their own analysis too...

Scientific Workflows and the Sensor Web for Virtual Environmental Observatories

NASA Astrophysics Data System (ADS)

Simonis, I.; Vahed, A.

2008-12-01

Virtual observatories mature from their original domain and become common practice for earth observation research and policy building. The term Virtual Observatory originally came from the astronomical research community. Here, virtual observatories provide universal access to the available astronomical data archives of space and ground-based observatories. Further on, as those virtual observatories aim at integrating heterogeneous ressources provided by a number of participating organizations, the virtual observatory acts as a coordinating entity that strives for common data analysis techniques and tools based on common standards. The Sensor Web is on its way to become one of the major virtual observatories outside of the astronomical research community. Like the original observatory that consists of a number of telescopes, each observing a specific part of the wave spectrum and with a collection of astronomical instruments, the Sensor Web provides a multi-eyes perspective on the current, past, as well as future situation of our planet and its surrounding spheres. The current view of the Sensor Web is that of a single worldwide collaborative, coherent, consistent and consolidated sensor data collection, fusion and distribution system. The Sensor Web can perform as an extensive monitoring and sensing system that provides timely, comprehensive, continuous and multi-mode observations. This technology is key to monitoring and understanding our natural environment, including key areas such as climate change, biodiversity, or natural disasters on local, regional, and global scales. The Sensor Web concept has been well established with ongoing global research and deployment of Sensor Web middleware and standards and represents the foundation layer of systems like the Global Earth Observation System of Systems (GEOSS). The Sensor Web consists of a huge variety of physical and virtual sensors as well as observational data, made available on the Internet at standardized interfaces. All data sets and sensor communication follow well-defined abstract models and corresponding encodings, mostly developed by the OGC Sensor Web Enablement initiative. Scientific progress is currently accelerated by an emerging new concept called scientific workflows, which organize and manage complex distributed computations. A scientific workflow represents and records the highly complex processes that a domain scientist typically would follow in exploration, discovery and ultimately, transformation of raw data to publishable results. The challenge is now to integrate the benefits of scientific workflows with those provided by the Sensor Web in order to leverage all resources for scientific exploration, problem solving, and knowledge generation. Scientific workflows for the Sensor Web represent the next evolutionary step towards efficient, powerful, and flexible earth observation frameworks and platforms. Those platforms support the entire process from capturing data, sharing and integrating, to requesting additional observations. Multiple sites and organizations will participate on single platforms and scientists from different countries and organizations interact and contribute to large-scale research projects. Simultaneously, the data- and information overload becomes manageable, as multiple layers of abstraction will free scientists to deal with underlying data-, processing or storage peculiarities. The vision are automated investigation and discovery mechanisms that allow scientists to pose queries to the system, which in turn would identify potentially related resources, schedules processing tasks and assembles all parts in workflows that may satisfy the query.

Application of industrial scale genomics to discovery of therapeutic targets in heart failure.

PubMed

Mehraban, F; Tomlinson, J E

2001-12-01

In recent years intense activity in both academic and industrial sectors has provided a wealth of information on the human genome with an associated impressive increase in the number of novel gene sequences deposited in sequence data repositories and patent applications. This genomic industrial revolution has transformed the way in which drug target discovery is now approached. In this article we discuss how various differential gene expression (DGE) technologies are being utilized for cardiovascular disease (CVD) drug target discovery. Other approaches such as sequencing cDNA from cardiovascular derived tissues and cells coupled with bioinformatic sequence analysis are used with the aim of identifying novel gene sequences that may be exploited towards target discovery. Additional leverage from gene sequence information is obtained through identification of polymorphisms that may confer disease susceptibility and/or affect drug responsiveness. Pharmacogenomic studies are described wherein gene expression-based techniques are used to evaluate drug response and/or efficacy. Industrial-scale genomics supports and addresses not only novel target gene discovery but also the burgeoning issues in pharmaceutical and clinical cardiovascular medicine relative to polymorphic gene responses.

Description of web-enhanced virtual character simulation system to standardize patient hand-offs.

PubMed

Filichia, Lori; Halan, Shivashankar; Blackwelder, Ethan; Rossen, Brent; Lok, Benjamin; Korndorffer, James; Cendan, Juan

2011-04-01

The 80-h work week has increased discontinuity of patient care resulting in reports of increased medication errors and preventable adverse events. Graduate medical programs are addressing these shortcomings in a number of ways. We have developed a computer simulation platform called the Virtual People Factory (VPF), which allows us to capture and simulate the dialogue between a real user and a virtual character. We have converted the system to reflect a physician in the process of "checking-out" a patient to a covering physician. The responses are tracked and matched to educator-defined information termed "discoveries." Our proof of concept represented a typical post-operative patient with tachycardia. The system is web enabled. So far, 26 resident users at two institutions have completed the module. The critical discovery of tachycardia was identified by 62% of users. Residents spend 85% of the time asking intraoperative, postoperative, and past medical history questions. The system improves over time such that there is a near-doubling of questions that yield appropriate answers between users 13 and 22. Users who identified the virtual patient's underlying tachycardia expressed more concern and were more likely to order further testing for the patient in a post-module questionnaire (P = 0.13 and 0.08, respectively, NS). The VPF system can capture unique details about the hand-off interchange. The system improves with sequential users such that better matching of questions and answers occurs within the initial 25 users allowing rapid development of new modules. A catalog of hand-off modules could be easily developed. Wide-scale web-based deployment was uncomplicated. Identification of the critical findings appropriately translated to user concern for the patient though our series was too small to reach significance. Performance metrics based on the identification of critical discoveries could be used to assess readiness of the user to carry off a successful hand-off. Copyright © 2011 Elsevier Inc. All rights reserved.

Energy-Water Nexus Knowledge Discovery Framework

NASA Astrophysics Data System (ADS)

Bhaduri, B. L.; Foster, I.; Chandola, V.; Chen, B.; Sanyal, J.; Allen, M.; McManamay, R.

2017-12-01

As demand for energy grows, the energy sector is experiencing increasing competition for water. With increasing population and changing environmental, socioeconomic scenarios, new technology and investment decisions must be made for optimized and sustainable energy-water resource management. This requires novel scientific insights into the complex interdependencies of energy-water infrastructures across multiple space and time scales. An integrated data driven modeling, analysis, and visualization capability is needed to understand, design, and develop efficient local and regional practices for the energy-water infrastructure components that can be guided with strategic (federal) policy decisions to ensure national energy resilience. To meet this need of the energy-water nexus (EWN) community, an Energy-Water Knowledge Discovery Framework (EWN-KDF) is being proposed to accomplish two objectives: Development of a robust data management and geovisual analytics platform that provides access to disparate and distributed physiographic, critical infrastructure, and socioeconomic data, along with emergent ad-hoc sensor data to provide a powerful toolkit of analysis algorithms and compute resources to empower user-guided data analysis and inquiries; and Demonstration of knowledge generation with selected illustrative use cases for the implications of climate variability for coupled land-water-energy systems through the application of state-of-the art data integration, analysis, and synthesis. Oak Ridge National Laboratory (ORNL), in partnership with Argonne National Laboratory (ANL) and researchers affiliated with the Center for International Earth Science Information Partnership (CIESIN) at Columbia University and State University of New York-Buffalo (SUNY), propose to develop this Energy-Water Knowledge Discovery Framework to generate new, critical insights regarding the complex dynamics of the EWN and its interactions with climate variability and change. An overarching objective of this project is to integrate impacts, adaptation, and vulnerability (IAV) science with emerging data science to meet the data analysis needs of the U.S. Department of Energy and partner federal agencies with respect to the EWN.

Ligand-based receptor tyrosine kinase partial agonists: New paradigm for cancer drug discovery?

PubMed

Riese, David J

2011-02-01

INTRODUCTION: Receptor tyrosine kinases (RTKs) are validated targets for oncology drug discovery and several RTK antagonists have been approved for the treatment of human malignancies. Nonetheless, the discovery and development of RTK antagonists has lagged behind the discovery and development of agents that target G-protein coupled receptors. In part, this is because it has been difficult to discover analogs of naturally-occurring RTK agonists that function as antagonists. AREAS COVERED: Here we describe ligands of ErbB receptors that function as partial agonists for these receptors, thereby enabling these ligands to antagonize the activity of full agonists for these receptors. We provide insights into the mechanisms by which these ligands function as antagonists. We discuss how information concerning these mechanisms can be translated into screens for novel small molecule- and antibody-based antagonists of ErbB receptors and how such antagonists hold great potential as targeted cancer chemotherapeutics. EXPERT OPINION: While there have been a number of important key findings into this field, the identification of the structural basis of ligand functional specificity is still of the greatest importance. While it is true that, with some notable exceptions, peptide hormones and growth factors have not proven to be good platforms for oncology drug discovery; addressing the fundamental issues of antagonistic partial agonists for receptor tyrosine kinases has the potential to steer oncology drug discovery in new directions. Mechanism based approaches are now emerging to enable the discovery of RTK partial agonists that may antagonize both agonist-dependent and -independent RTK signaling and may hold tremendous promise as targeted cancer chemotherapeutics.

The sun rises on the Space Shuttle Discovery as it rests on the runway at Edwards Air Force Base, California, after a safe landing August 9, 2005

NASA Image and Video Library

2005-08-09

The sun rises on the Space Shuttle Discovery as it rests on the runway at Edwards Air Force Base, California, after a safe landing August 9, 2005 to complete the STS-114 mission. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT this morning, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.

High-throughput screening based on label-free detection of small molecule microarrays

NASA Astrophysics Data System (ADS)

Zhu, Chenggang; Fei, Yiyan; Zhu, Xiangdong

2017-02-01

Based on small-molecule microarrays (SMMs) and oblique-incidence reflectivity difference (OI-RD) scanner, we have developed a novel high-throughput drug preliminary screening platform based on label-free monitoring of direct interactions between target proteins and immobilized small molecules. The screening platform is especially attractive for screening compounds against targets of unknown function and/or structure that are not compatible with functional assay development. In this screening platform, OI-RD scanner serves as a label-free detection instrument which is able to monitor about 15,000 biomolecular interactions in a single experiment without the need to label any biomolecule. Besides, SMMs serves as a novel format for high-throughput screening by immobilization of tens of thousands of different compounds on a single phenyl-isocyanate functionalized glass slide. Based on the high-throughput screening platform, we sequentially screened five target proteins (purified target proteins or cell lysate containing target protein) in high-throughput and label-free mode. We found hits for respective target protein and the inhibition effects for some hits were confirmed by following functional assays. Compared to traditional high-throughput screening assay, the novel high-throughput screening platform has many advantages, including minimal sample consumption, minimal distortion of interactions through label-free detection, multi-target screening analysis, which has a great potential to be a complementary screening platform in the field of drug discovery.

NETL's Energy Data Exchange (EDX) - a coordination, collaboration, and data resource discovery platform for energy science

NASA Astrophysics Data System (ADS)

Rose, K.; Rowan, C.; Rager, D.; Dehlin, M.; Baker, D. V.; McIntyre, D.

2015-12-01

Multi-organizational research teams working jointly on projects often encounter problems with discovery, access to relevant existing resources, and data sharing due to large file sizes, inappropriate file formats, or other inefficient options that make collaboration difficult. The Energy Data eXchange (EDX) from Department of Energy's (DOE) National Energy Technology Laboratory (NETL) is an evolving online research environment designed to overcome these challenges in support of DOE's fossil energy goals while offering improved access to data driven products of fossil energy R&D such as datasets, tools, and web applications. In 2011, development of NETL's Energy Data eXchange (EDX) was initiated and offers i) a means for better preserving of NETL's research and development products for future access and re-use, ii) efficient, discoverable access to authoritative, relevant, external resources, and iii) an improved approach and tools to support secure, private collaboration and coordination between multi-organizational teams to meet DOE mission and goals. EDX presently supports fossil energy and SubTER Crosscut research activities, with an ever-growing user base. EDX is built on a heavily customized instance of the open source platform, Comprehensive Knowledge Archive Network (CKAN). EDX connects users to externally relevant data and tools through connecting to external data repositories built on different platforms and other CKAN platforms (e.g. Data.gov). EDX does not download and repost data or tools that already have an online presence. This leads to redundancy and even error. If a relevant resource already has an online instance, is hosted by another online entity, EDX will point users to that external host either using web services, inventorying URLs and other methods. EDX offers users the ability to leverage private-secure capabilities custom built into the system. The team is presently working on version 3 of EDX which will incorporate big data analytical capabilities amongst other advanced features.

Megatux

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

2012-09-25

The Megatux platform enables the emulation of large scale (multi-million node) distributed systems. In particular, it allows for the emulation of large-scale networks interconnecting a very large number of emulated computer systems. It does this by leveraging virtualization and associated technologies to allow hundreds of virtual computers to be hosted on a single moderately sized server or workstation. Virtualization technology provided by modern processors allows for multiple guest OSs to run at the same time, sharing the hardware resources. The Megatux platform can be deployed on a single PC, a small cluster of a few boxes or a large clustermore » of computers. With a modest cluster, the Megatux platform can emulate complex organizational networks. By using virtualization, we emulate the hardware, but run actual software enabling large scale without sacrificing fidelity.« less

Bench-Scale Filtration Testing in Support of the Pretreatment Engineering Platform (PEP)

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

Billing, Justin M.; Daniel, Richard C.; Kurath, Dean E.

Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed, constructed and operated as part of a plan to respond to issue M12, “Undemonstrated Leaching Processes.” The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP testing program specifies that bench-scale testing is to bemore » performed in support of specific operations, including filtration, caustic leaching, and oxidative leaching.« less

Ultrafast Microfluidic Cellular Imaging by Optical Time-Stretch.

PubMed

Lau, Andy K S; Wong, Terence T W; Shum, Ho Cheung; Wong, Kenneth K Y; Tsia, Kevin K

2016-01-01

There is an unmet need in biomedicine for measuring a multitude of parameters of individual cells (i.e., high content) in a large population efficiently (i.e., high throughput). This is particularly driven by the emerging interest in bringing Big-Data analysis into this arena, encompassing pathology, drug discovery, rare cancer cell detection, emulsion microdroplet assays, to name a few. This momentum is particularly evident in recent advancements in flow cytometry. They include scaling of the number of measurable colors from the labeled cells and incorporation of imaging capability to access the morphological information of the cells. However, an unspoken predicament appears in the current technologies: higher content comes at the expense of lower throughput, and vice versa. For example, accessing additional spatial information of individual cells, imaging flow cytometers only achieve an imaging throughput ~1000 cells/s, orders of magnitude slower than the non-imaging flow cytometers. In this chapter, we introduce an entirely new imaging platform, namely optical time-stretch microscopy, for ultrahigh speed and high contrast label-free single-cell (in a ultrafast microfluidic flow up to 10 m/s) imaging and analysis with an ultra-fast imaging line-scan rate as high as tens of MHz. Based on this technique, not only morphological information of the individual cells can be obtained in an ultrafast manner, quantitative evaluation of cellular information (e.g., cell volume, mass, refractive index, stiffness, membrane tension) at nanometer scale based on the optical phase is also possible. The technology can also be integrated with conventional fluorescence measurements widely adopted in the non-imaging flow cytometers. Therefore, these two combinatorial and complementary measurement capabilities in long run is an attractive platform for addressing the pressing need for expanding the "parameter space" in high-throughput single-cell analysis. This chapter provides the general guidelines of constructing the optical system for time stretch imaging, fabrication and design of the microfluidic chip for ultrafast fluidic flow, as well as the image acquisition and processing.

Standardised online data access and publishing for Earth Systems and Climate data in Australia

NASA Astrophysics Data System (ADS)

Evans, B. J. K.; Druken, K. A.; Trenham, C.; Wang, J.; Wyborn, L. A.; Smillie, J.; Allen, C.; Porter, D.

2015-12-01

The National Computational Infrastructure (NCI) hosts Australia's largest repository (10+ PB) of research data collections spanning a wide range of fields from climate, coasts, oceans, and geophysics through to astronomy, bioinformatics, and the social sciences. Spatial scales range from global to local ultra-high resolution, requiring storage volumes from MB to PB. The data have been organised to be highly connected to both the NCI HPC and cloud resources (e.g., interactive visualisation and analysis environments). Researchers can login to utilise the high performance infrastructure for these data collections, or access the data via standards-based web services. Our aim is to provide a trusted platform to support interdisciplinary research across all the collections as well as services for use of the data within individual communities. We thus cater to a wide range of researcher needs, whilst needing to maintain a consistent approach to data management and publishing. All research data collections hosted at NCI are governed by a data management plan, prior to being published through a variety of platforms and web services such as OPeNDAP, HTTP, and WMS. The data management plan ensures the use of standard formats (when available) that comply with relevant data conventions (e.g., CF-Convention) and metadata standards (e.g., ISO19115). Digital Object Identifiers (DOIs) can be minted at NCI and assigned to datasets and collections. Large scale data growth and use in a variety of research fields has led to a rise in, and acceptance of, open spatial data formats such as NetCDF4/HDF5, prompting a need to extend these data conventions to fields such as geophysics and satellite Earth observations. The fusion of DOI-minted data that is discoverable and accessible via metadata and web services, creates a complete picture of data hosting, discovery, use, and citation. This enables standardised and reproducible data analysis.

Continuous measurement of breast tumor hormone receptor expression: a comparison of two computational pathology platforms

PubMed Central

Ahern, Thomas P.; Beck, Andrew H.; Rosner, Bernard A.; Glass, Ben; Frieling, Gretchen; Collins, Laura C.; Tamimi, Rulla M.

2017-01-01

Background Computational pathology platforms incorporate digital microscopy with sophisticated image analysis to permit rapid, continuous measurement of protein expression. We compared two computational pathology platforms on their measurement of breast tumor estrogen receptor (ER) and progesterone receptor (PR) expression. Methods Breast tumor microarrays from the Nurses’ Health Study were stained for ER (n=592) and PR (n=187). One expert pathologist scored cases as positive if ≥1% of tumor nuclei exhibited stain. ER and PR were then measured with the Definiens Tissue Studio (automated) and Aperio Digital Pathology (user-supervised) platforms. Platform-specific measurements were compared using boxplots, scatter plots, and correlation statistics. Classification of ER and PR positivity by platform-specific measurements was evaluated with areas under receiver operating characteristic curves (AUC) from univariable logistic regression models, using expert pathologist classification as the standard. Results Both platforms showed considerable overlap in continuous measurements of ER and PR between positive and negative groups classified by expert pathologist. Platform-specific measurements were strongly and positively correlated with one another (rho≥0.77). The user-supervised Aperio workflow performed slightly better than the automated Definiens workflow at classifying ER positivity (AUCAperio=0.97; AUCDefiniens=0.90; difference=0.07, 95% CI: 0.05, 0.09) and PR positivity (AUCAperio=0.94; AUCDefiniens=0.87; difference=0.07, 95% CI: 0.03, 0.12). Conclusion Paired hormone receptor expression measurements from two different computational pathology platforms agreed well with one another. The user-supervised workflow yielded better classification accuracy than the automated workflow. Appropriately validated computational pathology algorithms enrich molecular epidemiology studies with continuous protein expression data and may accelerate tumor biomarker discovery. PMID:27729430

Zooniverse - Web scale citizen science with people and machines. (Invited)

NASA Astrophysics Data System (ADS)

Smith, A.; Lynn, S.; Lintott, C.; Simpson, R.

2013-12-01

The Zooniverse (zooniverse.org) began in 2007 with the launch of Galaxy Zoo, a project in which more than 175,000 people provided shape analyses of more than 1 million galaxy images sourced from the Sloan Digital Sky Survey. These galaxy 'classifications', some 60 million in total, have since been used to produce more than 50 peer-reviewed publications based not only on the original research goals of the project but also because of serendipitous discoveries made by the volunteer community. Based upon the success of Galaxy Zoo the team have gone on to develop more than 25 web-based citizen science projects, all with a strong research focus in a range of subjects from astronomy to zoology where human-based analysis still exceeds that of machine intelligence. Over the past 6 years Zooniverse projects have collected more than 300 million data analyses from over 1 million volunteers providing fantastically rich datasets for not only the individuals working to produce research from their project but also the machine learning and computer vision research communities. The Zooniverse platform has always been developed to be the 'simplest thing that works' implementing only the most rudimentary algorithms for functionality such as task allocation and user-performance metrics - simplifications necessary to scale the Zooniverse such that the core team of developers and data scientists can remain small and the cost of running the computing infrastructure relatively modest. To date these simplifications have been appropriate for the data volumes and analysis tasks being addressed. This situation however is changing: next generation telescopes such as the Large Synoptic Sky Telescope (LSST) will produce data volumes dwarfing those previously analyzed. If citizen science is to have a part to play in analyzing these next-generation datasets then the Zooniverse will need to evolve into a smarter system capable for example of modeling the abilities of users and the complexities of the data being classified in real time. In this session I will outline the current architecture of the Zooniverse platform and introduce new functionality being developed to enable the development of a true 'social machines'. Our platform is evolving into a system capable of integrating human and machine intelligence in a live environment thus capable of addressing some of the biggest challenges in big-data science.

Application of Large-Scale Aptamer-Based Proteomic Profiling to Planned Myocardial Infarctions.

PubMed

Jacob, Jaison; Ngo, Debby; Finkel, Nancy; Pitts, Rebecca; Gleim, Scott; Benson, Mark D; Keyes, Michelle J; Farrell, Laurie A; Morgan, Thomas; Jennings, Lori L; Gerszten, Robert E

2018-03-20

Emerging proteomic technologies using novel affinity-based reagents allow for efficient multiplexing with high-sample throughput. To identify early biomarkers of myocardial injury, we recently applied an aptamer-based proteomic profiling platform that measures 1129 proteins to samples from patients undergoing septal alcohol ablation for hypertrophic cardiomyopathy, a human model of planned myocardial injury. Here, we examined the scalability of this approach using a markedly expanded platform to study a far broader range of human proteins in the context of myocardial injury. We applied a highly multiplexed, expanded proteomic technique that uses single-stranded DNA aptamers to assay 4783 human proteins (4137 distinct human gene targets) to derivation and validation cohorts of planned myocardial injury, individuals with spontaneous myocardial infarction, and at-risk controls. We found 376 target proteins that significantly changed in the blood after planned myocardial injury in a derivation cohort (n=20; P <1.05E-05, 1-way repeated measures analysis of variance, Bonferroni threshold). Two hundred forty-seven of these proteins were validated in an independent planned myocardial injury cohort (n=15; P <1.33E-04, 1-way repeated measures analysis of variance); >90% were directionally consistent and reached nominal significance in the validation cohort. Among the validated proteins that were increased within 1 hour after planned myocardial injury, 29 were also elevated in patients with spontaneous myocardial infarction (n=63; P <6.17E-04). Many of the novel markers identified in our study are intracellular proteins not previously identified in the peripheral circulation or have functional roles relevant to myocardial injury. For example, the cardiac LIM protein, cysteine- and glycine-rich protein 3, is thought to mediate cardiac mechanotransduction and stress responses, whereas the mitochondrial ATP synthase F 0 subunit component is a vasoactive peptide on its release from cells. Last, we performed aptamer-affinity enrichment coupled with mass spectrometry to technically verify aptamer specificity for a subset of the new biomarkers. Our results demonstrate the feasibility of large-scale aptamer multiplexing at a level that has not previously been reported and with sample throughput that greatly exceeds other existing proteomic methods. The expanded aptamer-based proteomic platform provides a unique opportunity for biomarker and pathway discovery after myocardial injury. © 2017 American Heart Association, Inc.

General view looking forward from the starboard side of the ...

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

General view looking forward from the starboard side of the Orbiter Discovery looking into the payload bay and the bulkhead of the forward fuselage with the airlock. The docking ring and airlock hatches have been removed from the airlock prior to this photo being taken. Note that the Orbiter Boom Sensor System is still attached while the Remote Manipulator System has been removed. Also note the suspended protective panels and walkways in place to protect the interior surfaces of the payload bay doors while in their open position. This view was taken from a service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Experiences with Deriva: An Asset Management Platform for Accelerating eScience.

PubMed

Bugacov, Alejandro; Czajkowski, Karl; Kesselman, Carl; Kumar, Anoop; Schuler, Robert E; Tangmunarunkit, Hongsuda

2017-10-01

The pace of discovery in eScience is increasingly dependent on a scientist's ability to acquire, curate, integrate, analyze, and share large and diverse collections of data. It is all too common for investigators to spend inordinate amounts of time developing ad hoc procedures to manage their data. In previous work, we presented Deriva, a Scientific Asset Management System, designed to accelerate data driven discovery. In this paper, we report on the use of Deriva in a number of substantial and diverse eScience applications. We describe the lessons we have learned, both from the perspective of the Deriva technology, as well as the ability and willingness of scientists to incorporate Scientific Asset Management into their daily workflows.

KSC-08pd1113

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, the rotating service structure, at left, at Launch Pad 39A has been rolled back for the delivery of space shuttle Discovery, secured atop the mobile launch platform below, for final prelaunch processing for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder

KSC-08pd1101

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, a crawler transporter moves space shuttle Discovery, secured atop a mobile launch platform, along the crawlerway from the Vehicle Assembly Building to Launch Pad 39A to prepare for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder

KSC-08pd1111

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, access arms from the fixed service structure at Launch Pad 39A are in place against space shuttle Discovery, secured atop the mobile launch platform below, as final prelaunch processing for the STS-124 mission begins at the pad. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder

Carbohydrates in diversity-oriented synthesis: challenges and opportunities.

PubMed

Lenci, E; Menchi, G; Trabocchi, A

2016-01-21

Over the last decade, Diversity-Oriented Synthesis (DOS) has become a new paradigm for developing large collections of structurally diverse small molecules as probes to investigate biological pathways, and to provide a larger array of the chemical space. Drug discovery and chemical biology are taking advantage of DOS approaches to exploit highly-diverse and complex molecular platforms, producing advances in both target and ligand discovery. In this view, carbohydrates are attractive building blocks for DOS libraries, due to their stereochemical diversity and high density of polar functional groups, thus offering many possibilities for chemical manipulation and scaffold decoration. This review will discuss research contributions and perspectives on the application of carbohydrate chemistry to explore the accessible chemical space through appendage, stereochemical and scaffold diversity.

KSC-08pd1102

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, space shuttle Discovery, secured atop a mobile launch platform, is reflected in water beside the crawlerway as it is moved from the Vehicle Assembly Building to Launch Pad 39A to prepare for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder

From Protein Structure to Small-Molecules: Recent Advances and Applications to Fragment-Based Drug Discovery.

PubMed

Ferreira, Leonardo G; Andricopulo, Adriano D

2017-01-01

Fragment-based drug discovery (FBDD) is a broadly used strategy in structure-guided ligand design, whereby low-molecular weight hits move from lead-like to drug-like compounds. Over the past 15 years, an increasingly important role of the integration of these strategies into industrial and academic research platforms has been successfully established, allowing outstanding contributions to drug discovery. One important factor for the current prominence of FBDD is the better coverage of the chemical space provided by fragment-like libraries. The development of the field relies on two features: (i) the growing number of structurally characterized drug targets and (ii) the enormous chemical diversity available for experimental and virtual screenings. Indeed, fragment-based campaigns have contributed to address major challenges in lead optimization, such as the appropriate physicochemical profile of clinical candidates. This perspective paper outlines the usefulness and applications of FBDD approaches in medicinal chemistry and drug design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Yeast as a potential vehicle for neglected tropical disease drug discovery.

PubMed

Denny, P W; Steel, P G

2015-01-01

High-throughput screening (HTS) efforts for neglected tropical disease (NTD) drug discovery have recently received increased attention because several initiatives have begun to attempt to reduce the deficit in new and clinically acceptable therapies for this spectrum of infectious diseases. HTS primarily uses two basic approaches, cell-based and in vitro target-directed screening. Both of these approaches have problems; for example, cell-based screening does not reveal the target or targets that are hit, whereas in vitro methodologies lack a cellular context. Furthermore, both can be technically challenging, expensive, and difficult to miniaturize for ultra-HTS [(u)HTS]. The application of yeast-based systems may overcome some of these problems and offer a cost-effective platform for target-directed screening within a eukaryotic cell context. Here, we review the advantages and limitations of the technologies that may be used in yeast cell-based, target-directed screening protocols, and we discuss how these are beginning to be used in NTD drug discovery. © 2014 Society for Laboratory Automation and Screening.

Leveraging the Thousands of Known Planets to Inform TESS Follow-Up

NASA Astrophysics Data System (ADS)

Ballard, Sarah

2017-10-01

The Solar System furnishes our most familiar planetary architecture: many planets, orbiting nearly coplanar to one another. However, a typical system of planets in the Milky Way orbits a much smaller M dwarf star, and these stars furnish a different blueprint in key ways than the conditions that nourished evolution of life on Earth. With ensemble studies of hundreds-to-thousands of exoplanets, I will describe the emerging links between planet formation from disks, orbital dynamics of planets, and the content and observability of planetary atmospheres. These quantities can be tied to observables even in discovery light curves, to enable judicious selection of follow-up targets from the ground and from space. After TESS exoplanet discoveries start in earnest, the studies of individual planets with large, space-based platforms comprise the clear next step toward understanding the hospitability of the Milky Way to life. Our success hinges upon leveraging the many thousands of planet discoveries in hand to determine how to use these precious and limited resources.

Induced Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Neurodegenerative Diseases.

PubMed

Cao, Lei; Tan, Lan; Jiang, Teng; Zhu, Xi-Chen; Yu, Jin-Tai

2015-08-01

Although most neurodegenerative diseases have been closely related to aberrant accumulation of aggregation-prone proteins in neurons, understanding their pathogenesis remains incomplete, and there is no treatment to delay the onset or slow the progression of many neurodegenerative diseases. The availability of induced pluripotent stem cells (iPSCs) in recapitulating the phenotypes of several late-onset neurodegenerative diseases marks the new era in in vitro modeling. The iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in these diseases and provides a novel human stem cell platform for screening new candidate therapeutics. Modeling human diseases using iPSCs has created novel opportunities for both mechanistic studies as well as for the discovery of new disease therapies. In this review, we introduce iPSC-based disease modeling in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In addition, we discuss the implementation of iPSCs in drug discovery associated with some new techniques.

Space Shuttle Discovery lifts off successfully

NASA Technical Reports Server (NTRS)

1998-01-01

Framed by the foliage of the Canaveral National Sea Shore, Space Shuttle Discovery soars through bright blue skies as it lifts off from Launch Pad 39B at 2:19 p.m. EST Oct. 29 on mission STS-95. Making his second voyage into space after 36 years is Payload Specialist John H. Glenn Jr., senator from Ohio. Other crew members are Mission Commander Curtis L. Brown Jr., Pilot Steven W. Lindsey, Payload Specialist Chiaki Mukai, (M.D., Ph.D.), with the National agency for Space Development (NASDA), Mission Specialist Stephen K. Robinson, Mission Specialist Pedro Duque of Spain, representing the European Space Agency (ESA), and Mission Specialist Scott E. Parazynski. The STS-95 mission includes research payloads such as the Spartan solar-observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process. Discovery is expected to return to KSC at 11:49 a.m. EST on Nov. 7.

Space Shuttle Discovery lifts off successfully

NASA Technical Reports Server (NTRS)

1998-01-01

Clouds of exhaust and blazing light fill Launch Pad 39B as Space Shuttle Discovery lifts off at 2:19 p.m. EST Oct. 29 on mission STS-95. Making his second voyage into space after 36 years is Payload Specialist John H. Glenn Jr., senator from Ohio. Other crew members are Mission Commander Curtis L. Brown Jr., Pilot Steven W. Lindsey, Payload Specialist Chiaki Mukai, (M.D., Ph.D.), with the National Space Development Agency of Japan (NASDA), Mission Specialist Stephen K. Robinson, Mission Specialist Pedro Duque of Spain, representing the European Space Agency (ESA), and Mission Specialist Scott E. Parazynski. The STS-95 mission includes research payloads such as the Spartan solar-observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process. Discovery is expected to return to KSC at 11:49 a.m. EST on Nov. 7.

Space Shuttle Discovery lifts off successfully

NASA Technical Reports Server (NTRS)

1998-01-01

Clouds of exhaust seem to fill the marsh near Launch Pad 39B as Space Shuttle Discovery lifts off at 2:19 p.m. EST Oct. 29 on mission STS-95. Making his second voyage into space after 36 years is Payload Specialist John H. Glenn Jr., senator from Ohio. Other crew members are Mission Commander Curtis L. Brown Jr., Pilot Steven W. Lindsey, Payload Specialist Chiaki Mukai, (M.D., Ph.D.), with the National Space Development Agency of Japan (NASDA), Mission Specialist Stephen K. Robinson, Mission Specialist Pedro Duque of Spain, representing the European Space Agency (ESA), and Mission Specialist Scott E. Parazynski. The STS-95 mission includes research payloads such as the Spartan solar-observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process. Discovery is expected to return to KSC at 11:49 a.m. EST on Nov. 7.

Advanced biological and chemical discovery (ABCD): centralizing discovery knowledge in an inherently decentralized world.

PubMed

Agrafiotis, Dimitris K; Alex, Simson; Dai, Heng; Derkinderen, An; Farnum, Michael; Gates, Peter; Izrailev, Sergei; Jaeger, Edward P; Konstant, Paul; Leung, Albert; Lobanov, Victor S; Marichal, Patrick; Martin, Douglas; Rassokhin, Dmitrii N; Shemanarev, Maxim; Skalkin, Andrew; Stong, John; Tabruyn, Tom; Vermeiren, Marleen; Wan, Jackson; Xu, Xiang Yang; Yao, Xiang

2007-01-01

We present ABCD, an integrated drug discovery informatics platform developed at Johnson & Johnson Pharmaceutical Research & Development, L.L.C. ABCD is an attempt to bridge multiple continents, data systems, and cultures using modern information technology and to provide scientists with tools that allow them to analyze multifactorial SAR and make informed, data-driven decisions. The system consists of three major components: (1) a data warehouse, which combines data from multiple chemical and pharmacological transactional databases, designed for supreme query performance; (2) a state-of-the-art application suite, which facilitates data upload, retrieval, mining, and reporting, and (3) a workspace, which facilitates collaboration and data sharing by allowing users to share queries, templates, results, and reports across project teams, campuses, and other organizational units. Chemical intelligence, performance, and analytical sophistication lie at the heart of the new system, which was developed entirely in-house. ABCD is used routinely by more than 1000 scientists around the world and is rapidly expanding into other functional areas within the J&J organization.

KSC-06pd0484

NASA Image and Video Library

2006-03-14

KENNEDY SPACE CENTER, FLA. - Inside the Orbiter Processing Facility bay 3 at NASA's Kennedy Space Center, workers lower Discovery's robotic arm onto a flat bed in a work area. The arm was removed from Discovery's payload bay. The arm was removed due to damage found on the arm after it was accidentally bumped by a bridge bucket in the payload bay. Ultrasound inspections revealed a small crack, measuring 1.25 inches by 0.015 inch deep. The arm will be sent back to the vendor for repair. The bucket was being used by technicians cleaning the area and was in the process of being stowed. A bridge bucket is a personnel transport device that is suspended from an overhead bridge that moves back and forth above the shuttle's mid-body. It allows workers to access the payload bay area without walking or standing on the payload bay floor or on the fixed platforms. Space Shuttle Discovery is scheduled for launch on mission STS-121 during a launch planning window of July 1-19. Photo credit: NASA/Kim Shiflett

KSC-2009-4422

NASA Image and Video Library

2009-08-04

CAPE CANAVERAL, Fla. –At NASA's Kennedy Space Center in Florida, the crawler-transporter delivers space shuttle Discovery atop the mobile launcher platform onto Launch Pad 39A. The shuttle nears the flame trench, which channels the flames and smoke exhaust of the shuttle's solid rocket boosters away from the space shuttle during liftoff. Traveling from the Vehicle Assembly Building, the shuttle took nearly 12 hours on the journey as technicians stopped several times to clear mud from the crawler's treads and bearings caused by the waterlogged crawlerway. First motion out of the VAB was at 2:07 a.m. EDT Aug. 4. Rollout was delayed approximately 2 hours due to lightning in the area. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the International Space Station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for late August. Photo credit: NASA/Troy Cryder

KSC-2009-4421

NASA Image and Video Library

2009-08-04

CAPE CANAVERAL, Fla. –Sitting on top of the mobile launcher platform and propelled by the crawler-transporter, space shuttle Discovery rolls up Launch Pad 39A at NASA's Kennedy Space Center in Florida after a nearly 12-hour journey from the Vehicle Assembly Building. First motion out of the VAB was at 2:07 a.m. EDT Aug. 4. Rollout was delayed approximately 2 hours due to lightning in the area. The rollout was slower than usual as technicians stopped several times to clear mud from the crawler's treads and bearings caused by the waterlogged crawlerway. The drying mud of the crawlerway is evident in the foreground. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the International Space Station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for late August. Photo credit: NASA/Troy Cryder

KSC-2009-4418

NASA Image and Video Library

2009-08-04

CAPE CANAVERAL, Fla. – At NASA's Kennedy Space Center in Florida, the crawler-transporter delivers space shuttle Discovery atop the mobile launcher platform onto Launch Pad 39A. The shuttle spans the flame trench, which channels the flames and smoke exhaust of the shuttle's solid rocket boosters away from the space shuttle during liftoff. Traveling from the Vehicle Assembly Building, the shuttle took nearly 12 hours on the journey as technicians stopped several times to clear mud from the crawler's treads and bearings caused by the waterlogged crawlerway. First motion out of the VAB was at 2:07 a.m. EDT Aug. 4. Rollout was delayed approximately 2 hours due to lightning in the area. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the International Space Station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for late August. Photo credit: NASA/Troy Cryder

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.

Design and construction of the Discovery Channel Telescope enclosure

NASA Astrophysics Data System (ADS)

Marshall, Heather K.; Teran, Jose U.; Bond, Kevin

2010-07-01

The Discovery Channel Telescope (DCT) is a project of Lowell Observatory, undertaken with support from Discovery Communications, Inc., to design and construct a 4-meter class telescope and support facility on a site approximately 40 miles southeast of Flagstaff, Arizona. The Discovery Channel Telescope Enclosure was completed in November, 2009. The DCT Enclosure is an octagonal steel structure with insulated composite panel skin. The structure rotates on sixteen compliant bogie assemblies attached to the stationary facility. The shutter is composed of two independently actuated, bi-parting structures that provide a viewing aperture. To improve seeing, the skin is covered with adhesive aluminum foil tape and the enclosed observing area is passively ventilated via rollup doors. The observing area can also be actively ventilated using a downdraft fan, and there are provisions for upgrades to active air conditioning. The enclosure also includes operational equipment such as a bridge crane, personnel lift, and access platforms. This paper discusses some of the design trades as well as the construction challenges and lessons learned by the DCT Project, its designer M3 Engineering and Technology Corporation (M3), and its general contractor, Building and Engineering Contractors, Southwest (BEC Southwest).

A Fully Automated High-Throughput Flow Cytometry Screening System Enabling Phenotypic Drug Discovery.

PubMed

Joslin, John; Gilligan, James; Anderson, Paul; Garcia, Catherine; Sharif, Orzala; Hampton, Janice; Cohen, Steven; King, Miranda; Zhou, Bin; Jiang, Shumei; Trussell, Christopher; Dunn, Robert; Fathman, John W; Snead, Jennifer L; Boitano, Anthony E; Nguyen, Tommy; Conner, Michael; Cooke, Mike; Harris, Jennifer; Ainscow, Ed; Zhou, Yingyao; Shaw, Chris; Sipes, Dan; Mainquist, James; Lesley, Scott

2018-05-01

The goal of high-throughput screening is to enable screening of compound libraries in an automated manner to identify quality starting points for optimization. This often involves screening a large diversity of compounds in an assay that preserves a connection to the disease pathology. Phenotypic screening is a powerful tool for drug identification, in that assays can be run without prior understanding of the target and with primary cells that closely mimic the therapeutic setting. Advanced automation and high-content imaging have enabled many complex assays, but these are still relatively slow and low throughput. To address this limitation, we have developed an automated workflow that is dedicated to processing complex phenotypic assays for flow cytometry. The system can achieve a throughput of 50,000 wells per day, resulting in a fully automated platform that enables robust phenotypic drug discovery. Over the past 5 years, this screening system has been used for a variety of drug discovery programs, across many disease areas, with many molecules advancing quickly into preclinical development and into the clinic. This report will highlight a diversity of approaches that automated flow cytometry has enabled for phenotypic drug discovery.

Discovering Drugs with DNA-Encoded Library Technology: From Concept to Clinic with an Inhibitor of Soluble Epoxide Hydrolase.

PubMed

Belyanskaya, Svetlana L; Ding, Yun; Callahan, James F; Lazaar, Aili L; Israel, David I

2017-05-04

DNA-encoded chemical library technology was developed with the vision of its becoming a transformational platform for drug discovery. The hope was that a new paradigm for the discovery of low-molecular-weight drugs would be enabled by combining the vast molecular diversity achievable with combinatorial chemistry, the information-encoding attributes of DNA, the power of molecular biology, and a streamlined selection-based discovery process. Here, we describe the discovery and early clinical development of GSK2256294, an inhibitor of soluble epoxide hydrolase (sEH, EPHX2), by using encoded-library technology (ELT). GSK2256294 is an orally bioavailable, potent and selective inhibitor of sEH that has a long half life and produced no serious adverse events in a first-time-in-human clinical study. To our knowledge, GSK2256294 is the first molecule discovered from this technology to enter human clinical testing and represents a realization of the vision that DNA-encoded chemical library technology can efficiently yield molecules with favorable properties that can be readily progressed into high-quality drugs. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.