Strain Prioritization and Genome Mining for Enediyne Natural Products.

PubMed

Yan, Xiaohui; Ge, Huiming; Huang, Tingting; Hindra; Yang, Dong; Teng, Qihui; Crnovčić, Ivana; Li, Xiuling; Rudolf, Jeffrey D; Lohman, Jeremy R; Gansemans, Yannick; Zhu, Xiangcheng; Huang, Yong; Zhao, Li-Xing; Jiang, Yi; Van Nieuwerburgh, Filip; Rader, Christoph; Duan, Yanwen; Shen, Ben

2016-12-20

The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the enediyne polyketide synthase cassettes that could be grouped into 28 distinct clades based on phylogenetic analysis. Genome sequencing of 31 representative strains confirmed that each clade harbors a distinct enediyne biosynthetic gene cluster. A genome neighborhood network allows prediction of new structural features and biosynthetic insights that could be exploited for enediyne discovery. We confirmed one clade as new C-1027 producers, with a significantly higher C-1027 titer than the original producer, and discovered a new family of enediyne natural products, the tiancimycins (TNMs), that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Our results demonstrate the feasibility of rapid discovery of new enediynes from a large strain collection. Recent advances in microbial genomics clearly revealed that the biosynthetic potential of soil actinomycetes to produce enediynes is underappreciated. A great challenge is to develop innovative methods to discover new enediynes and produce them in sufficient quantities for chemical, biological, and clinical investigations. This work demonstrated the feasibility of rapid discovery of new enediynes from a large strain collection. The new C-1027 producers, with a significantly higher C-1027 titer than the original producer, will impact the practical supply of this important drug lead. The TNMs, with their extremely potent cytotoxicity against various cancer cells and their rapid and complete cancer cell killing characteristics, in comparison with the payloads used in FDA-approved antibody-drug conjugates (ADCs), are poised to be exploited as payload candidates for the next generation of anticancer ADCs. Follow-up studies on the other identified hits promise the discovery of new enediynes, radically expanding the chemical space for the enediyne family. Copyright © 2016 Yan et al.

The Computer's Debt to Science.

ERIC Educational Resources Information Center

Branscomb, Lewis M.

1984-01-01

Discusses discoveries and applications of science that have enabled the computer industry to introduce new technology each year and produce 25 percent more for the customer at constant cost. Potential limits to progress, disc storage technology, programming and end-user interface, and designing for ease of use are considered. Glossary is included.…

Host responses to mycobacterial infections: Spotlight on biomarker discovery to predict vaccine

USDA-ARS?s Scientific Manuscript database

The global spread of tuberculosis (TB) in animals and humans result in enormous economic. social and public health burdens. TB vaccine development in both humans and animals has produced a growing portfolio of candidates with potential applicability across species. However, the lack of understandin...

Discovery of the leinamycin family of natural products by mining actinobacterial genomes

PubMed Central

Xu, Zhengren; Guo, Zhikai; Hindra; Ma, Ming; Zhou, Hao; Gansemans, Yannick; Zhu, Xiangcheng; Huang, Yong; Zhao, Li-Xing; Jiang, Yi; Cheng, Jinhua; Van Nieuwerburgh, Filip; Suh, Joo-Won; Duan, Yanwen

2017-01-01

Nature’s ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge-based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF–SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF–SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm-type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature’s rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature’s biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity. PMID:29229819

Discovery of the leinamycin family of natural products by mining actinobacterial genomes.

PubMed

Pan, Guohui; Xu, Zhengren; Guo, Zhikai; Hindra; Ma, Ming; Yang, Dong; Zhou, Hao; Gansemans, Yannick; Zhu, Xiangcheng; Huang, Yong; Zhao, Li-Xing; Jiang, Yi; Cheng, Jinhua; Van Nieuwerburgh, Filip; Suh, Joo-Won; Duan, Yanwen; Shen, Ben

2017-12-26

Nature's ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge-based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF-SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF-SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm -type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature's rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature's biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity.

Sweetening the pot: adding glycosylation to the biomarker discovery equation.

PubMed

Drake, Penelope M; Cho, Wonryeon; Li, Bensheng; Prakobphol, Akraporn; Johansen, Eric; Anderson, N Leigh; Regnier, Fred E; Gibson, Bradford W; Fisher, Susan J

2010-02-01

Cancer has profound effects on gene expression, including a cell's glycosylation machinery. Thus, tumors produce glycoproteins that carry oligosaccharides with structures that are markedly different from the same protein produced by a normal cell. A single protein can have many glycosylation sites that greatly amplify the signals they generate compared with their protein backbones. In this article, we survey clinical tests that target carbohydrate modifications for diagnosing and treating cancer. We present the biological relevance of glycosylation to disease progression by highlighting the role these structures play in adhesion, signaling, and metastasis and then address current methodological approaches to biomarker discovery that capitalize on selectively capturing tumor-associated glycoforms to enrich and identify disease-related candidate analytes. Finally, we discuss emerging technologies--multiple reaction monitoring and lectin-antibody arrays--as potential tools for biomarker validation studies in pursuit of clinically useful tests. The future of carbohydrate-based biomarker studies has arrived. At all stages, from discovery through verification and deployment into clinics, glycosylation should be considered a primary readout or a way of increasing the sensitivity and specificity of protein-based analyses.

Sweetening the pot: adding glycosylation to the biomarker discovery equation

PubMed Central

Drake, Penelope M.; Cho, Wonryeon; Li, Bensheng; Prakobphol, Akraporn; Johansen, Eric; Anderson, N. Leigh; Regnier, Fred E.; Gibson, Bradford W.; Fisher, Susan J.

2010-01-01

Background Cancer has profound effects on gene expression, including a cell’s glycosylation machinery. Thus, tumors produce glycoproteins that carry oligosaccharides with structures that are markedly different from the same protein produced by a normal cell. A single protein can have many glycosylation sites that greatly amplify the signals they generate as compared to their protein backbones. Content We survey clinical tests that target carbohydrate modifications. for diagnosing and treating cancer. Next, we present the biological relevance of glycosylation to disease progression by highlighting the role these structures play in adhesion, signaling and metastasis, and then address current methodological approaches to biomarker discovery that capitalize on selectively capturing tumor-associated glycoforms to enrich and identify disease-related candidate analytes. Finally, we discuss emerging technologies—multiple reaction monitoring and lectin-antibody arrays—as potential tools for biomarker validation studies in pursuit of clinically useful tests. Summary The future of carbohydrate-based biomarker studies has arrived. At all stages, from discovery through verification and deployment into clinics, glycosylation should be considered a primary readout or a way of increasing the sensitivity and specificity of protein-based analyses. PMID:19959616

HSQC-TOCSY Fingerprinting for Prioritization of Polyketide- and Peptide-Producing Microbial Isolates.

PubMed

Buedenbender, Larissa; Habener, Leesa J; Grkovic, Tanja; Kurtböke, D İpek; Duffy, Sandra; Avery, Vicky M; Carroll, Anthony R

2018-04-27

Microbial products are a promising source for drug leads as a result of their unique structural diversity. However, reisolation of already known natural products significantly hampers the discovery process, and it is therefore important to incorporate effective microbial isolate selection and dereplication protocols early in microbial natural product studies. We have developed a systematic approach for prioritization of microbial isolates for natural product discovery based on heteronuclear single-quantum correlation-total correlation spectroscopy (HSQC-TOCSY) nuclear magnetic resonance profiles in combination with antiplasmodial activity of extracts. The HSQC-TOCSY experiments allowed for unfractionated microbial extracts containing polyketide and peptidic natural products to be rapidly identified. Here, we highlight how this approach was used to prioritize extracts derived from a library of 119 ascidian-associated actinomycetes that possess a higher potential to produce bioactive polyketides and peptides.

Metabolomics-Driven Discovery of a Prenylated Isatin Antibiotic Produced by Streptomyces Species MBT28.

PubMed

Wu, Changsheng; Du, Chao; Gubbens, Jacob; Choi, Young Hae; van Wezel, Gilles P

2015-10-23

Actinomycetes are a major source of antimicrobials, anticancer compounds, and other medically important products, and their genomes harbor extensive biosynthetic potential. Major challenges in the screening of these microorganisms are to activate the expression of cryptic biosynthetic gene clusters and the development of technologies for efficient dereplication of known molecules. Here we report the identification of a previously unidentified isatin-type antibiotic produced by Streptomyces sp. MBT28, following a strategy based on NMR-based metabolomics combined with the introduction of streptomycin resistance in the producer strain. NMR-guided isolation by tracking the target proton signal resulted in the characterization of 7-prenylisatin (1) with antimicrobial activity against Bacillus subtilis. The metabolite-guided genome mining of Streptomyces sp. MBT28 combined with proteomics identified a gene cluster with an indole prenyltransferase that catalyzes the conversion of tryptophan into 7-prenylisatin. This study underlines the applicability of NMR-based metabolomics in facilitating the discovery of novel antibiotics.

Recent Advances in the Discovery and Development of Marine Microbial Natural Products

PubMed Central

Xiong, Zhi-Qiang; Wang, Jian-Feng; Hao, Yu-You; Wang, Yong

2013-01-01

Marine microbial natural products (MMNPs) have attracted increasing attention from microbiologists, taxonomists, ecologists, agronomists, chemists and evolutionary biologists during the last few decades. Numerous studies have indicated that diverse marine microbes appear to have the capacity to produce an impressive array of MMNPs exhibiting a wide variety of biological activities such as antimicrobial, anti-tumor, anti-inflammatory and anti-cardiovascular agents. Marine microorganisms represent an underexplored reservoir for the discovery of MMNPs with unique scaffolds and for exploitation in the pharmaceutical and agricultural industries. This review focuses on MMNPs discovery and development over the past decades, including innovative isolation and culture methods, strategies for discovering novel MMNPs via routine screenings, metagenomics, genomics, combinatorial biosynthesis, and synthetic biology. The potential problems and future directions for exploring MMNPs are also discussed. PMID:23528949

Recent advances in the discovery and development of marine microbial natural products.

PubMed

Xiong, Zhi-Qiang; Wang, Jian-Feng; Hao, Yu-You; Wang, Yong

2013-03-08

Marine microbial natural products (MMNPs) have attracted increasing attention from microbiologists, taxonomists, ecologists, agronomists, chemists and evolutionary biologists during the last few decades. Numerous studies have indicated that diverse marine microbes appear to have the capacity to produce an impressive array of MMNPs exhibiting a wide variety of biological activities such as antimicrobial, anti-tumor, anti-inflammatory and anti-cardiovascular agents. Marine microorganisms represent an underexplored reservoir for the discovery of MMNPs with unique scaffolds and for exploitation in the pharmaceutical and agricultural industries. This review focuses on MMNPs discovery and development over the past decades, including innovative isolation and culture methods, strategies for discovering novel MMNPs via routine screenings, metagenomics, genomics, combinatorial biosynthesis, and synthetic biology. The potential problems and future directions for exploring MMNPs are also discussed.

Natural product discovery: past, present, and future.

PubMed

Katz, Leonard; Baltz, Richard H

2016-03-01

Microorganisms have provided abundant sources of natural products which have been developed as commercial products for human medicine, animal health, and plant crop protection. In the early years of natural product discovery from microorganisms (The Golden Age), new antibiotics were found with relative ease from low-throughput fermentation and whole cell screening methods. Later, molecular genetic and medicinal chemistry approaches were applied to modify and improve the activities of important chemical scaffolds, and more sophisticated screening methods were directed at target disease states. In the 1990s, the pharmaceutical industry moved to high-throughput screening of synthetic chemical libraries against many potential therapeutic targets, including new targets identified from the human genome sequencing project, largely to the exclusion of natural products, and discovery rates dropped dramatically. Nonetheless, natural products continued to provide key scaffolds for drug development. In the current millennium, it was discovered from genome sequencing that microbes with large genomes have the capacity to produce about ten times as many secondary metabolites as was previously recognized. Indeed, the most gifted actinomycetes have the capacity to produce around 30-50 secondary metabolites. With the precipitous drop in cost for genome sequencing, it is now feasible to sequence thousands of actinomycete genomes to identify the "biosynthetic dark matter" as sources for the discovery of new and novel secondary metabolites. Advances in bioinformatics, mass spectrometry, proteomics, transcriptomics, metabolomics and gene expression are driving the new field of microbial genome mining for applications in natural product discovery and development.

Hydrocarbon potential assessment of Ngimbang formation, Rihen field of Northeast Java Basin

NASA Astrophysics Data System (ADS)

Pandito, R. H.; Haris, A.; Zainal, R. M.; Riyanto, A.

2017-07-01

The assessment of Ngimbang formation at Rihen field of Northeast Java Basin has been conducted to identify the hydrocarbon potential by analyzing the response of passive seismic on the proven reservoir zone and proposing a tectonic evolution model. In the case of petroleum exploration in Northeast Java basin, the Ngimbang formation cannot be simply overemphasized. East Java Basin has been well known as one of the mature basins producing hydrocarbons in Indonesia. This basin was stratigraphically composed of several formations from the old to the young i.e., the basement, Ngimbang, Kujung, Tuban, Ngerayong, Wonocolo, Kawengan and Lidah formation. All of these formations have proven to become hydrocarbon producer. The Ngrayong formation, which is geologically dominated by channels, has become a production formation. The Kujung formation that has been known with the reef build up has produced more than 102 million barrel of oil. The Ngimbang formation so far has not been comprehensively assessed in term its role as a source rock and a reservoir. In 2013, one exploratory well has been drilled at Ngimbang formation and shown a gas discovery, which is indicated on Drill Stem Test (DST) reading for more than 22 MMSCFD of gas. This discovery opens new prospect in exploring the Ngimbang formation.

Discovery of antimicrobial lipodepsipeptides produced by a Serratia sp. within mosquito microbiomes.

PubMed

Ganley, Jack; Carr, Gavin; Ioerger, Thomas; Sacchettini, James; Clardy, Jon; Derbyshire, Emily

2018-04-26

The Anopheles mosquito that harbors the Plasmodium parasite contains a microbiota that can influence both the vector and parasite. In recent years, insect-associated microbes have highlighted the untapped potential of exploiting interspecies interactions to discover bioactive compounds. In this study, we report the discovery of nonribosomal lipodepsipeptides that are produced by a Serratia sp. within the midgut and salivary glands of A. stephensi mosquitoes. The lipodepsipeptides, stephensiolides A-K, have antibiotic activity and facilitate bacterial surface motility. Bioinformatic analyses indicate that the stephensiolides are ubiquitous in nature and are likely important for Serratia spp. colonization within mosquitoes, humans, and other ecological niches. Our results demonstrate the usefulness of probing insect-microbiome interactions, enhance our understanding of the chemical ecology within Anopheles mosquitoes, and provide a secondary metabolite scaffold to further investigate this complex relationship. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Integrating mass spectrometry and genomics for cyanobacterial metabolite discovery

PubMed Central

Bertin, Matthew J.; Kleigrewe, Karin; Leão, Tiago F.; Gerwick, Lena

2016-01-01

Filamentous marine cyanobacteria produce bioactive natural products with both potential therapeutic value and capacity to be harmful to human health. Genome sequencing has revealed that cyanobacteria have the capacity to produce many more secondary metabolites than have been characterized. The biosynthetic pathways that encode cyanobacterial natural products are mostly uncharacterized, and lack of cyanobacterial genetic tools has largely prevented their heterologous expression. Hence, a combination of cutting edge and traditional techniques has been required to elucidate their secondary metabolite biosynthetic pathways. Here, we review the discovery and refined biochemical understanding of the olefin synthase and fatty acid ACP reductase/aldehyde deformylating oxygenase pathways to hydrocarbons, and the curacin A, jamaicamide A, lyngbyabellin, columbamide, and a trans-acyltransferase macrolactone pathway encoding phormidolide. We integrate into this discussion the use of genomics, mass spectrometric networking, biochemical characterization, and isolation and structure elucidation techniques. PMID:26578313

Probing TeV scale top-philic resonances with boosted top-tagging at the high luminosity LHC

DOE PAGES

Kim, Jeong Han; Kong, Kyoungchul; Lee, Seung J.; ...

2016-08-24

Here, we investigate the discovery potential of singly produced top-philic resonances at the high luminosity (HL) LHC in the four-top final state. Our analysis spans over the fully-hadronic, semi-leptonic, and same-sign dilepton channels where we present concrete search strategies adequate to a boosted kinematic regime and high jet-multiplicity environments. We utilize the Template Overlap Method (TOM) with newly developed template observables for tagging boosted top quarks, a large-radius jet variablemore » $$M_J$$ and customized b-tagging tactics for background discrimination. Our results show that the same-sign dilepton channel gives the best sensitivity among the considered channels, with an improvement of significance up to 10%-20% when combined with boosted-top tagging. Both the fully-hadronic and semi-leptonic channels yield comparable discovery potential and contribute to further enhancements in the sensitivity by combining all channels. Finally, we show the sensitivity of a top-philic resonance at the LHC and HL-LHC by showing the $$2\\sigma$$ exclusion limit and $$5\\sigma$$ discovery reach, including a combination of all three channels.« less

Solid-Phase Biological Assays for Drug Discovery

NASA Astrophysics Data System (ADS)

Forsberg, Erica M.; Sicard, Clémence; Brennan, John D.

2014-06-01

In the past 30 years, there has been a significant growth in the use of solid-phase assays in the area of drug discovery, with a range of new assays being used for both soluble and membrane-bound targets. In this review, we provide some basic background to typical drug targets and immobilization protocols used in solid-phase biological assays (SPBAs) for drug discovery, with emphasis on particularly labile biomolecular targets such as kinases and membrane-bound receptors, and highlight some of the more recent approaches for producing protein microarrays, bioaffinity columns, and other devices that are central to small molecule screening by SPBA. We then discuss key applications of such assays to identify drug leads, with an emphasis on the screening of mixtures. We conclude by highlighting specific advantages and potential disadvantages of SPBAs, particularly as they relate to particular assay formats.

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

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

Petzet, G.A.

1998-06-15

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

SALMON-TRINITY ALPS WILDERNESS, CALIFORNIA.

USGS Publications Warehouse

Hotz, Preston E.; Thurber, Horace K.

1984-01-01

The Salmon-Trinity Alps Wilderness in the Klamath Mountains province occupies an area of about 648 sq mi in parts of Trinity, Siskiyou, and Humboldt Counties, northwestern California. As a result of field studies it was determined that the Salmon-Trinity Alps Wilderness has an area with substantiated potential for gold resources in known lode deposits. Small amounts of quicksilver have been produced from one mine but there is little promise for the discovery of additional mercury resources. Geochemical sampling showed that anomalously high amounts of several other metals occur in a few places, but there is little promise for the discovery of energy or mineral resources other than mercury and gold.

[Adverse Effect Predictions Based on Computational Toxicology Techniques and Large-scale Databases].

PubMed

Uesawa, Yoshihiro

2018-01-01

　Understanding the features of chemical structures related to the adverse effects of drugs is useful for identifying potential adverse effects of new drugs. This can be based on the limited information available from post-marketing surveillance, assessment of the potential toxicities of metabolites and illegal drugs with unclear characteristics, screening of lead compounds at the drug discovery stage, and identification of leads for the discovery of new pharmacological mechanisms. This present paper describes techniques used in computational toxicology to investigate the content of large-scale spontaneous report databases of adverse effects, and it is illustrated with examples. Furthermore, volcano plotting, a new visualization method for clarifying the relationships between drugs and adverse effects via comprehensive analyses, will be introduced. These analyses may produce a great amount of data that can be applied to drug repositioning.

Current Soviet exploration plays: Success and potential

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

Grace, J.D.

1991-03-01

Soviet hydrocarbon exploration in the 1980s took four distinct directions. First was extension exploration and the search for smaller new fields in discrete traps in traditional producing regions, such as the Apsheron Peninsula, North Caucasus, and Volga-Urals. This strategy produced a large number of small discoveries close to established infrastructure. Second was new field exploration in West Siberia in the stratigraphically complex Jurassic and the lower Neocomian sections. Third was expansion of the prolific gas plays in northern West Siberia. Exploratory success in West Siberia has created a backlog of several hundred discoveries awaiting full delineation and development. Most ofmore » these fields are distant from the established oil production center in the Middle Ob region and, therefore, may remain in inventory. Fourth was initial tests of new exploration frontiers, most important, the Paleozoic and Mesozoic plays of the Barents and Kara seas and the subsalt plays of the North Caspian basin. While these plays have yielded very important discoveries, significant technological barriers impede their development. The outlook for Soviet oil exploration in the 1990s is for significant opportunities for discovery of large volumes of oil, but at radically increasing exploration and production costs. In established regions, these costs arise from small field sizes and low well productivities. In frontier regions, exploitation of new fields will require technology not currently available in the USSR. The outlook for gas exploration continues to be very bright, as the onshore northern West Siberia is not fully explored and initial results from the Barents and Kara seas promise more very large gas discoveries.« less

Regional stratigraphy and petroleum potential, Ghadames basin, Algeria

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

Emme, J.J.; Sunderland, B.L.

1991-03-01

The Ghadames basin in east-central Algeria extends over 65,000 km{sup 2} (25,000 mi{sup 2}), of which 90% is covered by dunes of the eastern Erg. This intracratonic basin consists of up to 6000 m (20,000 ft) of dominantly clastic Paleozoic through Mesozoic strata. The Ghadames basin is part of a larger, composite basin complex (Ilizzi-Ghadames-Triassic basins) where Paleozoic strata have been truncated during a Hercynian erosional event and subsequently overlain by a northward-thickening wedge of Mesozoic sediments. Major reservoir rocks include Triassic sandstones that produce oil, gas, and condensate in the western Ghadames basin, Siluro-Devonian sandstones that produce mostly oilmore » in the shallower Ilizzi basin to the south, and Cambro-Ordovician orthoquartzites that produce oil at Hassi Messaoud to the northwest. Organic shales of the Silurian and Middle-Upper Devonian are considered primary source rocks. Paleozoic shales and Triassic evaporite/red bed sequences act as seals for hydrocarbon accumulations. The central Ghadames basin is underexplored, with less than one wildcat well/1700 km{sup 2} (one well/420,000 ac). Recent Devonian and Triassic oil discoveries below 3500 m (11,500 ft) indicate that deep oil potential exists. Exploration to date has concentrated on structural traps. Subcrop and facies trends indicate that potential for giant stratigraphic or combination traps exists for both Siluro-Devonian and Triassic intervals. Modern seismic acquisition and processing techniques in high dune areas can be used to successfully identify critical unconformity-bound sequences with significant stratigraphic trap potential. Advances in seismic and drilling technology combined with creative exploration should result in major petroleum discoveries in the Ghadames basin.« less

Gas potential of the Rome Trough in Kentucky: Results of recent Cambrian exploration

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

Harris, D.C.; Drahovzal, J.A.

1996-09-01

A recent gas discovery in the Rome Trough suggests the need to re-evaluate the deep Cambrian potential of eastern Kentucky. A new phase of Cambrian exploration began in mid-1994 with a new pool discovery by the Carson Associates No. 1 Kazee well in Elliott County, Ky. This well blew out and initially flowed 11 MMcfd of gas from the upper Conasauga Group/Rome Formation at 6,258 to 6,270 feet. After this discovery, a second exploratory well (the Blue Ridge No. 1Greene) was drilled on a separate structure in Elliott County in late 1995. The Blue Ridge well was temporarily abandoned, butmore » had shows of gas and condensate. In early 1996, Carson Associates offset their initial discovery well with the No. 33 Lawson Heirs well. This activity follows a frustrating exploration history in the Rome Trough that is marked by numerous gas and oil shows, but rare commercial production. Only three single-well pools have produced commercial gas from the trough, including the recent Kazee well. Stratigraphic units below the Cambrian-Ordovician Knox Group in the Rome Trough are dramatically thicker than their equivalents on the shelf to the north. The interval in the trough is thought to include rocks as old as Early Cambrian, consisting of a basal sandstone, equivalents of the Shady/Tomstown Dolomite, the Rome Formation, and the Conasauga Formation. Sandstones and fractured shales have been responsible for most of the production to date, but dolostone intervals may also have potential. Limited seismic data indicate possible fan-delta and basin-floor fan deposits that may have reservoir potential.« less

Culture-independent discovery of natural products from soil metagenomes.

PubMed

Katz, Micah; Hover, Bradley M; Brady, Sean F

2016-03-01

Bacterial natural products have proven to be invaluable starting points in the development of many currently used therapeutic agents. Unfortunately, traditional culture-based methods for natural product discovery have been deemphasized by pharmaceutical companies due in large part to high rediscovery rates. Culture-independent, or "metagenomic," methods, which rely on the heterologous expression of DNA extracted directly from environmental samples (eDNA), have the potential to provide access to metabolites encoded by a large fraction of the earth's microbial biosynthetic diversity. As soil is both ubiquitous and rich in bacterial diversity, it is an appealing starting point for culture-independent natural product discovery efforts. This review provides an overview of the history of soil metagenome-driven natural product discovery studies and elaborates on the recent development of new tools for sequence-based, high-throughput profiling of environmental samples used in discovering novel natural product biosynthetic gene clusters. We conclude with several examples of these new tools being employed to facilitate the recovery of novel secondary metabolite encoding gene clusters from soil metagenomes and the subsequent heterologous expression of these clusters to produce bioactive small molecules.

From Discovery to Production: Biotechnology of Marine Fungi for the Production of New Antibiotics.

PubMed

Silber, Johanna; Kramer, Annemarie; Labes, Antje; Tasdemir, Deniz

2016-07-21

Filamentous fungi are well known for their capability of producing antibiotic natural products. Recent studies have demonstrated the potential of antimicrobials with vast chemodiversity from marine fungi. Development of such natural products into lead compounds requires sustainable supply. Marine biotechnology can significantly contribute to the production of new antibiotics at various levels of the process chain including discovery, production, downstream processing, and lead development. However, the number of biotechnological processes described for large-scale production from marine fungi is far from the sum of the newly-discovered natural antibiotics. Methods and technologies applied in marine fungal biotechnology largely derive from analogous terrestrial processes and rarely reflect the specific demands of the marine fungi. The current developments in metabolic engineering and marine microbiology are not yet transferred into processes, but offer numerous options for improvement of production processes and establishment of new process chains. This review summarises the current state in biotechnological production of marine fungal antibiotics and points out the enormous potential of biotechnology in all stages of the discovery-to-development pipeline. At the same time, the literature survey reveals that more biotechnology transfer and method developments are needed for a sustainable and innovative production of marine fungal antibiotics.

Meeting the Needs of Data Management Training: The Federation of Earth Science Information Partners (ESIP) Data Management for Scientists Short Course

ERIC Educational Resources Information Center

Hou, Chung-Yi

2015-01-01

With the proliferation of digital technologies, scientists are exploring various methods for the integration of data to produce scientific discoveries. To maximize the potential of data for science advancement, proper stewardship must be provided to ensure data integrity and usability both for the short- and the long-term. In order to assist…

12 CFR 1209.29 - Discovery.

Code of Federal Regulations, 2014 CFR

2014-01-01

... the timely, cost-effective management of document discovery (including, if applicable, electronically... discovery plan shall specify the form of electronic productions, if any. Documents are to be produced in... proceeding under this part may obtain document discovery by serving upon any other party in the proceeding a...

12 CFR 1209.29 - Discovery.

Code of Federal Regulations, 2012 CFR

2012-01-01

... the timely, cost-effective management of document discovery (including, if applicable, electronically... discovery plan shall specify the form of electronic productions, if any. Documents are to be produced in... proceeding under this part may obtain document discovery by serving upon any other party in the proceeding a...

12 CFR 1209.29 - Discovery.

Code of Federal Regulations, 2013 CFR

2013-01-01

... the timely, cost-effective management of document discovery (including, if applicable, electronically... discovery plan shall specify the form of electronic productions, if any. Documents are to be produced in... proceeding under this part may obtain document discovery by serving upon any other party in the proceeding a...

A reservoir for solar-wind-produced water in lunar soils

NASA Astrophysics Data System (ADS)

Taylor, L.; Liu, Y.; Zent, A.; Quinn, R.; Ichimura, A.

2012-09-01

Discoveries of new sources of WATER on the Moon are becoming more numerous as our research progresses. All these recent discoveries of different forms of H (OH, HOH, and H2O ice) on the Moon, both endogenic and exogenic, have reshaped our view of "water" ON and IN the Moon Despite these discoveries, a potential large reservoir, LUNAR SOIL, has been largely overlooked until recently [1-2]. This was the first report and confirmation of OH in micro-meteoriteformed, impact glass in lunar soils; so-called "agglutinates", with abundances of up to 500 ppmw H2O, presents a medium for the accumulation of H from all the various sources. And the Lunar Soil Characterization Consortium (LSCC) [3-5] has demonstrated that the impact-melt glass portion of the fine-grain sizes of the lunar soil contains upwards of 70-80 % of such water-bearing glass. This could make for lunar soil feedstock with upwards of ~0.1 wt% H2O, in addition to any water produced solarwind hydrogen reduction of ilmenite, etc. Therefore, thermal rendering of the fine-portions of the soil for solar-wind volatiles (e.g., H, He-3, C, N) will encounter additional quantities of water, exceeding those of the absorbed solar-wind.

Computational databases, pathway and cheminformatics tools for tuberculosis drug discovery

PubMed Central

Ekins, Sean; Freundlich, Joel S.; Choi, Inhee; Sarker, Malabika; Talcott, Carolyn

2010-01-01

We are witnessing the growing menace of both increasing cases of drug-sensitive and drug-resistant Mycobacterium tuberculosis strains and the challenge to produce the first new tuberculosis (TB) drug in well over 40 years. The TB community, having invested in extensive high-throughput screening efforts, is faced with the question of how to optimally leverage this data in order to move from a hit to a lead to a clinical candidate and potentially a new drug. Complementing this approach, yet conducted on a much smaller scale, cheminformatic techniques have been leveraged and are herein reviewed. We suggest these computational approaches should be more optimally integrated in a workflow with experimental approaches to accelerate TB drug discovery. PMID:21129975

Induced Pluripotent Stem Cells in Dermatology: Potentials, Advances, and Limitations

PubMed Central

Bilousova, Ganna; Roop, Dennis R.

2014-01-01

The discovery of methods for reprogramming adult somatic cells into induced pluripotent stem cells (iPSCs) has raised the possibility of producing truly personalized treatment options for numerous diseases. Similar to embryonic stem cells (ESCs), iPSCs can give rise to any cell type in the body and are amenable to genetic correction by homologous recombination. These ESC properties of iPSCs allow for the development of permanent corrective therapies for many currently incurable disorders, including inherited skin diseases, without using embryonic tissues or oocytes. Here, we review recent progress and limitations of iPSC research with a focus on clinical applications of iPSCs and using iPSCs to model human diseases for drug discovery in the field of dermatology. PMID:25368014

Impedance-based cellular assay technologies: recent advances, future promise.

PubMed

McGuinness, Ryan

2007-10-01

Cell-based assays are continuing to grow in importance in the drug discovery workflow. Their early introduction holds the promise of limiting attrition in the later, more costly phases of the process. This article reviews recent advances in the development of impedance technologies for label-free cell-based assays. These systems are capable of monitoring endogenous receptor activation, and thus generate more physiologically relevant measures of pharmacological endpoints. Primary cells can be investigated as well, thus producing disease relevant information. Label-free assays significantly decrease assay development efforts and avoid many complications inherent in recombinant readout systems. Impedance-based systems have great potential to advance the utility of cell-based assays as they are applied to drug discovery and pharmacology.

Bone metabolism and adipokines: are there perspectives for bone diseases drug discovery?

PubMed

Scotece, Morena; Conde, Javier; Abella, Vanessa; López, Verónica; Pino, Jesús; Lago, Francisca; Gómez-Reino, Juan J; Gualillo, Oreste

2014-08-01

Over the past 20 years, the idea that white adipose tissue (WAT) is simply an energy depot organ has been radically changed. Indeed, present understanding suggests WAT to be an endocrine organ capable of producing and secreting a wide variety of proteins termed adipokines. These adipokines appear to be relevant factors involved in a number of different functions, including metabolism, immune response, inflammation and bone metabolism. In this review, the authors focus on the effects of several adipose tissue-derived factors in bone pathophysiology. They also consider how the modification of the adipokine network could potentially lead to promising treatment options for bone diseases. There are currently substantial developments being made in the understanding of the interplay between bone metabolism and the metabolic system. These insights could potentially lead to the development of new treatment strategies and interventions with the aim of successful outcomes in many people affected by bone disorders. Specifically, future research should look into the intimate mechanisms regulating peripheral and central activity of adipokines as it has potential for novel drug discovery.

Renaissance of the ~1 TeV Fixed-Target Program

NASA Astrophysics Data System (ADS)

Adams, T.; Appel, J. A.; Arms, K. E.; Balantekin, A. B.; Conrad, J. M.; Cooper, P. S.; Djurcic, Z.; Dunwoodie, W.; Engelfried, J.; Fisher, P. H.; Gottschalk, E.; de Gouvea, A.; Heller, K.; Ignarra, C. M.; Karagiorgi, G.; Kwan, S.; Loinaz, W. A.; Meadows, B.; Moore, R.; Morfín, J. G.; Naples, D.; Nienaber, P.; Pate, S. F.; Papavassiliou, V.; Petrov, A. A.; Purohit, M. V.; Ray, H.; Russ, J.; Schwartz, A. J.; Seligman, W. G.; Shaevitz, M. H.; Schellman, H.; Spitz, J.; Syphers, M. J.; Tait, T. M. P.; Vannucci, F.

This document describes the physics potential of a new fixed-target program based on a ~1 TeV proton source. Two proton sources are potentially available in the future: the existing Tevatron at Fermilab, which can provide 800 GeV protons for fixed-target physics, and a possible upgrade to the SPS at CERN, called SPS+, which would produce 1 TeV protons on target. In this paper we use an example Tevatron fixed-target program to illustrate the high discovery potential possible in the charm and neutrino sectors. We highlight examples which are either unique to the program or difficult to accomplish at other venues.

Renaissance of the ~ 1-TeV Fixed-Target Program

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

Adams, T.; /Florida State U.; Appel, J.A.

2011-12-02

This document describes the physics potential of a new fixed-target program based on a {approx}1 TeV proton source. Two proton sources are potentially available in the future: the existing Tevatron at Fermilab, which can provide 800 GeV protons for fixed-target physics, and a possible upgrade to the SPS at CERN, called SPS+, which would produce 1 TeV protons on target. In this paper we use an example Tevatron fixed-target program to illustrate the high discovery potential possible in the charm and neutrino sectors. We highlight examples which are either unique to the program or difficult to accomplish at other venues.

Chemical Analyses of Wasp-Associated Streptomyces Bacteria Reveal a Prolific Potential for Natural Products Discovery

PubMed Central

Clardy, Jon; Currie, Cameron R.

2011-01-01

Identifying new sources for small molecule discovery is necessary to help mitigate the continuous emergence of antibiotic-resistance in pathogenic microbes. Recent studies indicate that one potentially rich source of novel natural products is Actinobacterial symbionts associated with social and solitary Hymenoptera. Here we test this possibility by examining two species of solitary mud dauber wasps, Sceliphron caementarium and Chalybion californicum. We performed enrichment isolations from 33 wasps and obtained more than 200 isolates of Streptomyces Actinobacteria. Chemical analyses of 15 of these isolates identified 11 distinct and structurally diverse secondary metabolites, including a novel polyunsaturated and polyoxygenated macrocyclic lactam, which we name sceliphrolactam. By pairing the 15 Streptomyces strains against a collection of fungi and bacteria, we document their antifungal and antibacterial activity. The prevalence and anti-microbial properties of Actinobacteria associated with these two solitary wasp species suggest the potential role of these Streptomyces as antibiotic-producing symbionts, potentially helping defend their wasp hosts from pathogenic microbes. Finding phylogenetically diverse and chemically prolific Actinobacteria from solitary wasps suggests that insect-associated Actinobacteria can provide a valuable source of novel natural products of pharmaceutical interest. PMID:21364940

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

USGS Publications Warehouse

Attanasi, E.D.

2000-01-01

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

A total petroleum system of the Browse Basin, Australia; Late Jurassic, Early Cretaceous-Mesozoic

USGS Publications Warehouse

Bishop, M.G.

1999-01-01

The Browse Basin Province 3913, offshore northern Australia, contains one important petroleum system, Late Jurassic, Early Cretaceous-Mesozoic. It is comprised of Late Jurassic through Early Cretaceous source rocks deposited in restricted marine environments and various Mesozoic reservoir rocks deposited in deep-water fan to fluvial settings. Jurassic age intraformational shales and claystones and Cretaceous regional claystones seal the reservoirs. Since 1967, when exploration began in this 105,000 km2 area, fewer than 40 wells have been drilled and only one recent oil discovery is considered potentially commercial. Prior to the most recent oil discovery, on the eastern side of the basin, a giant gas field was discovered in 1971, under a modern reef on the west side of the basin. Several additional oil and gas discoveries and shows were made elsewhere. A portion of the Vulcan sub-basin lies within Province 3913 where a small field, confirmed in 1987, produced 18.8 million barrels of oil (MMBO) up to 1995 and has since been shut in.

Methods for Discovery of Novel Cellulosomal Cellulases Using Genomics and Biochemical Tools.

PubMed

Ben-David, Yonit; Dassa, Bareket; Bensoussan, Lizi; Bayer, Edward A; Moraïs, Sarah

2018-01-01

Cell wall degradation by cellulases is extensively explored owing to its potential contribution to biofuel production. The cellulosome is an extracellular multienzyme complex that can degrade the plant cell wall very efficiently, and cellulosomal enzymes are therefore of great interest. The cellulosomal cellulases are defined as enzymes that contain a dockerin module, which can interact with a cohesin module contained in multiple copies in a noncatalytic protein, termed scaffoldin. The assembly of the cellulosomal cellulases into the cellulosomal complex occurs via specific protein-protein interactions. Cellulosome systems have been described initially only in several anaerobic cellulolytic bacteria. However, owing to ongoing genome sequencing and metagenomic projects, the discovery of novel cellulosome-producing bacteria and the description of their cellulosomal genes have dramatically increased in the recent years. In this chapter, methods for discovery of novel cellulosomal cellulases from a DNA sequence by bioinformatics and biochemical tools are described. Their biochemical characterization is also described, including both the enzymatic activity of the putative cellulases and their assembly into mature designer cellulosomes.

Synthetic biology to access and expand nature’s chemical diversity

PubMed Central

Smanski, Michael J.; Zhou, Hui; Claesen, Jan; Shen, Ben; Fischbach, Michael; Voigt, Christopher A.

2016-01-01

Bacterial genomes encode the biosynthetic potential to produce hundreds of thousands of complex molecules with diverse applications, from medicine to agriculture and materials. Economically accessing the potential encoded within sequenced genomes promises to reinvigorate waning drug discovery pipelines and provide novel routes to intricate chemicals. This is a tremendous undertaking, as the pathways often comprise dozens of genes spanning as much as 100+ kiliobases of DNA, are controlled by complex regulatory networks, and the most interesting molecules are made by non-model organisms. Advances in synthetic biology address these issues, including DNA construction technologies, genetic parts for precision expression control, synthetic regulatory circuits, computer aided design, and multiplexed genome engineering. Collectively, these technologies are moving towards an era when chemicals can be accessed en mass based on sequence information alone. This will enable the harnessing of metagenomic data and massive strain banks for high-throughput molecular discovery and, ultimately, the ability to forward design pathways to complex chemicals not found in nature. PMID:26876034

From Discovery to Production: Biotechnology of Marine Fungi for the Production of New Antibiotics

PubMed Central

Silber, Johanna; Kramer, Annemarie; Labes, Antje; Tasdemir, Deniz

2016-01-01

Filamentous fungi are well known for their capability of producing antibiotic natural products. Recent studies have demonstrated the potential of antimicrobials with vast chemodiversity from marine fungi. Development of such natural products into lead compounds requires sustainable supply. Marine biotechnology can significantly contribute to the production of new antibiotics at various levels of the process chain including discovery, production, downstream processing, and lead development. However, the number of biotechnological processes described for large-scale production from marine fungi is far from the sum of the newly-discovered natural antibiotics. Methods and technologies applied in marine fungal biotechnology largely derive from analogous terrestrial processes and rarely reflect the specific demands of the marine fungi. The current developments in metabolic engineering and marine microbiology are not yet transferred into processes, but offer numerous options for improvement of production processes and establishment of new process chains. This review summarises the current state in biotechnological production of marine fungal antibiotics and points out the enormous potential of biotechnology in all stages of the discovery-to-development pipeline. At the same time, the literature survey reveals that more biotechnology transfer and method developments are needed for a sustainable and innovative production of marine fungal antibiotics. PMID:27455283

Rediscovering natural products as a source of new drugs.

PubMed

Koehn, Frank E; Carter, Guy T

2005-04-01

Extract: Since the very beginnings of human medicine, physicians have relied on chemical compounds produced by animals, plants and microorganisms, so-called natural products, to treat diseases. Natural products are directly or indirectly responsible for roughly one-half of all drugs currently in use. Of the 877 small-molecule new drug molecules introduced between 1981 and 2002, 49% were natural products or natural product analogs. Despite the great success of the 70s and 80s, the pharmaceutical industry de-emphasized natural products research during the following decade. In this article, we examine the underlying reasons for the decline, and assess future prospects for natural products research in drug discovery. In the 1990s, major pharmaceutical companies moved to a lead-finding strategy based on High Throughput Screening (HTS) of very large collections (libraries) of synthetic compounds. The move arose from the belief that techniques such as combinatorial chemistry could produce larger, more cost-effective libraries with improved hit rates and quality. Additionally, advances in molecular biology, cellular biology and genomics dramatically increased the number of molecular targets, prompting shorter drug discovery timelines. In today's drug discovery environment, rapid screening and identification of potential drug molecules is essential for success. This puts traditional natural products-based programs, with their reliance on the lengthy processes of the screening of extracts library, bioassay-guided isolation of the active components, structure elucidation and subsequent production scale-up, at a competitive disadvantage.

Information visualisation for science and policy: engaging users and avoiding bias.

PubMed

McInerny, Greg J; Chen, Min; Freeman, Robin; Gavaghan, David; Meyer, Miriah; Rowland, Francis; Spiegelhalter, David J; Stefaner, Moritz; Tessarolo, Geizi; Hortal, Joaquin

2014-03-01

Visualisations and graphics are fundamental to studying complex subject matter. However, beyond acknowledging this value, scientists and science-policy programmes rarely consider how visualisations can enable discovery, create engaging and robust reporting, or support online resources. Producing accessible and unbiased visualisations from complicated, uncertain data requires expertise and knowledge from science, policy, computing, and design. However, visualisation is rarely found in our scientific training, organisations, or collaborations. As new policy programmes develop [e.g., the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES)], we need information visualisation to permeate increasingly both the work of scientists and science policy. The alternative is increased potential for missed discoveries, miscommunications, and, at worst, creating a bias towards the research that is easiest to display. Copyright © 2014 Elsevier Ltd. All rights reserved.

Early Pottery Making in Northern Coastal Peru. Part II: Field Firing Experiments

NASA Astrophysics Data System (ADS)

Shimada, I.; Goldstein, D.; Sosa, J.; Wagner, U.

2003-09-01

We present data from three seasons of experimental field work designed to recreate ancient Andean coastal ceramic firing techniques. Based on the recent discovery of two different archaeological ceramic production sites in the La Leche river valley of northern coastal Peru, the opportunity arose to apply Mössbauer spectroscopy and other analytical methods to reconstruct ancient firing procedures. Two sets of firings took place in 1993 and 1997 in Batán Grande using a partially restored Formative kiln from about 800 BC, local hardwood and cow dung as fuel. A third experiment followed in 2000 after the discovery of a Middle Sicán ceramics workshop in use between ca. AD 950 and 1050 at Huaca Sialupe, where an exact replica of an ancient kiln was built from local clay, and fired with local wood and cow dung. Additionally, inverted urns found at Huaca Sialupe were tested for their potential use as furnaces for metal working. Mössbauer spectroscopy was used to compare the physical and chemical state of specimens produced in the field experiments with ancient ceramics and with specimens produced in controlled laboratory experiments.

Extraction of consensus protein patterns in regions containing non-proline cis peptide bonds and their functional assessment.

PubMed

Exarchos, Konstantinos P; Exarchos, Themis P; Rigas, Georgios; Papaloukas, Costas; Fotiadis, Dimitrios I

2011-05-10

In peptides and proteins, only a small percentile of peptide bonds adopts the cis configuration. Especially in the case of amide peptide bonds, the amount of cis conformations is quite limited thus hampering systematic studies, until recently. However, lately the emerging population of databases with more 3D structures of proteins has produced a considerable number of sequences containing non-proline cis formations (cis-nonPro). In our work, we extract regular expression-type patterns that are descriptive of regions surrounding the cis-nonPro formations. For this purpose, three types of pattern discovery are performed: i) exact pattern discovery, ii) pattern discovery using a chemical equivalency set, and iii) pattern discovery using a structural equivalency set. Afterwards, using each pattern as predicate, we search the Eukaryotic Linear Motif (ELM) resource to identify potential functional implications of regions with cis-nonPro peptide bonds. The patterns extracted from each type of pattern discovery are further employed, in order to formulate a pattern-based classifier, which is used to discriminate between cis-nonPro and trans-nonPro formations. In terms of functional implications, we observe a significant association of cis-nonPro peptide bonds towards ligand/binding functionalities. As for the pattern-based classification scheme, the highest results were obtained using the structural equivalency set, which yielded 70% accuracy, 77% sensitivity and 63% specificity.

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

USGS Publications Warehouse

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

2006-01-01

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

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, KSC employee Joel Smith prepares an area on the orbiter Discovery for blanket installation. The blankets are part of the Orbiter Thermal Protection System, thermal shields to protect against temperatures as high as 3,000° Fahrenheit, which are produced during descent for landing. Discovery is scheduled to fly on mission STS-121 to the International Space Station.

NASA Image and Video Library

2003-12-09

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, KSC employee Joel Smith prepares an area on the orbiter Discovery for blanket installation. The blankets are part of the Orbiter Thermal Protection System, thermal shields to protect against temperatures as high as 3,000° Fahrenheit, which are produced during descent for landing. Discovery is scheduled to fly on mission STS-121 to the International Space Station.

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, KSC employee Nadine Phillips prepares an area on the orbiter Discovery for blanket installation. The blankets are part of the Orbiter Thermal Protection System, thermal shields to protect against temperatures as high as 3,000° Fahrenheit, which are produced during descent for landing. Discovery is scheduled to fly on mission STS-121 to the International Space Station.

NASA Image and Video Library

2003-12-09

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, KSC employee Nadine Phillips prepares an area on the orbiter Discovery for blanket installation. The blankets are part of the Orbiter Thermal Protection System, thermal shields to protect against temperatures as high as 3,000° Fahrenheit, which are produced during descent for landing. Discovery is scheduled to fly on mission STS-121 to the International Space Station.

Natural products discovery from micro-organisms in the post-genome era.

PubMed

Ikeda, Haruo

2017-01-01

With the decision to award the Nobel Prize in Physiology or Medicine to Drs. S. Ōmura, W.C. Campbell, and Y. Tu, the importance and usefulness of natural drug discovery and development have been revalidated. Since the end of the twentieth century, many genome analyses of organisms have been conducted, and accordingly, numerous microbial genomes have been decoded. In particular, genomic studies of actinomycetes, micro-organisms that readily produce natural products, led to the discovery of biosynthetic gene clusters responsible for producing natural products. New explorations for natural products through a comprehensive approach combining genomic information with conventional methods show great promise for the discovery of new natural products and even systematic generation of unnaturally occurring compounds.

Scenario Educational Software: Design and Development of Discovery Learning.

ERIC Educational Resources Information Center

Keegan, Mark

This book shows how and why the computer is so well suited to producing discovery learning environments. An examination of the literature outlines four basic modes of instruction: didactic, Socratic, inquiry, and discovery. Research from the fields of education, psychology, and physiology is presented to demonstrate the many strengths of…

International Astronomical Search Collaboration: Online Educational Outreach Program in Astronomical Discovery for Middle School, High School, & College Students and Citizen Scientists

NASA Astrophysics Data System (ADS)

Miller, P.

2016-12-01

The International Astronomical Search Collaboration (IASC = "Isaac") in an online educational outreach program in planetary science. Citizen scientists and students from middle schools, high schools, and colleges make original discoveries of Main Belt asteroids. They discover trans-Neptunian objects and near-Earth objects. To date there have been discoveries of 1300 provisional MBAs, 7 TNOs, 2 potentially hazardous NEOs, and one Jupiter-family comet 276P/Vorobjov. IASC receives images from the Institute for Astronomy, University of Hawaii. Images are provided by the 1.8-m Pan-STARRS telescopes (PS1, PS2). These telescopes have the world's largest CCD cameras that produce 3o fields containing 1.4 billion pixels. These images are partitioned into 208 sub-images that are distributed online to the participating citizen scientists and schools (see http://iasc.hsutx.edu). Using the software Astrometrica, the sub-images are searched for moving object discoveries that are recorded with astrometry then reported to the Minor Planet Center (Smithsonian Astrophysical Observatory, Harvard). There are >5,000 citizen scientists and 700 schools that participate in the IASC asteroid searches. They come from more than 80 countries. And, the cost to participate…is free. Of the 1300 provisional MBA discoveries, 39 have been numbered and cataloged by the International Astronomical Union (Paris). The numbered discoveries are named by their citizen scientist and student discoverers. IASC works in conjunction with the NASA Asteroid Grand Challenge providing digital badging to the students (https://www.nasa.gov/feature/the-asteroid-grand-challenge-digital-badging-effort). IASC works online with the teachers from the participating schools, training them using videoconferencing to use Astrometrica in the search for, measurement of, and reporting of MBA discoveries by their students.

Assessment of the petroleum, coal, and geothermal resources of the Economic Community of West African States (ECOWAS) region

USGS Publications Warehouse

Mattick, R. E.

1982-01-01

Approximately 85 percent of the land area of the ECOWAS (Economic Community of West African States) region is covered by basement rocks (igneous and highly metamorphosed rocks) or relatively thin layers of Paleozoic, Upper Precambrian, and 'Continental Intercalaire? sedimentary rocks. These areas have little or no petroleum potential. Areas of the ECOWAS region that have potential for petroleum production or potential for increased petroleum production include the narrow belt of sedimentary rocks that stretches along the continental margin from Mauritania to Nigeria and the Niger Delta and the Benue depression. The Senegal Basin, located on the continental margin of Mauritania, Senegal, Gambia, Guinea Bissau, and Guinea, has been intensely explored by the oil industry and most of the larger structures onshore and on the shelf probably have been tested by drilling with little or no resulting commercial production. Unless basic ideas pertaining to the petroleum geology of the Senegal Basin are revised, future discoveries are expected to be limited to small fields overlooked by industry at a time when petroleum prices were low. On the continental shelf of Sierra Leone and the continental shelf of northeast and central Liberia, the sedimentary rocks are relatively thin, and industry has shown little interest in the area. On the continental rise of these countries, however, the sedimentary section, deposited in a complex fault-block system, increases in thickness. A renewal of industry interest in this deep-water area will probably follow further development of deep-water production technology. A recent oil discovery on the continental slope off the Ivory Coast is expected to spur further exploration offshore of southeastern Liberia, Ivory Coast, Ghana, Togo, and Benin. This relatively unexplored area in the Gulf of Guinea has good possibilities .for the discovery of giant oil fields. Nigeria's oil development from the Niger Delta may have peaked, as 13 of 14 giant oil fields were discovered prior to 1969 and the greatest number of fields were discovered in the period 1965 through 1967. Like delta regions in other parts of the world, individual oil fields of the Niger Delta are small to medium by world standards and future discoveries, therefore, are likely to reflect this reality. The natural gas resources of the Niger Delta, unlike its oil resources, are comparatively underdeveloped. Parts of the Benue depression in Nigeria and Niger could contain significant deposits of petroleum. The lower Benue depression, immediately north of the Niger Delta, has been extensively explored by drilling. Except for noncommercial discoveries of oil and gas and traces of oil and gas on the ground surface, the results of exploration in the lower Benue depression were negative. However, in the Lake Chad area of Chad and in southern Chad near the Central African Republic boundary, oil and gas discoveries were made just prior to the cessation of all drilling and exploration activity in early 1979. It is rumored that these discoveries may be large although little information is available. The relation between the two areas in Chad and their overall relation to the Benue depression is poorly understood; however, the possibility of thick sedimentary sections containing Cretaceous marine source rock and Tertiary reservoir beds-all contained within grabens in a highly faulted failed-arm system subjected to high heat flow--is attractive. Of the ECOWAS countries, only Nigeria and Niger produce coal commercially. Nigeria produces subbituminous coal from Paleocene-Maestrichtian and Maestrichtian (Late Cretaceous) age rocks of the Niger Delta region; reserves are estimated, on the basis of extensive drilling, to be 350 million tons (standard coal equivalent). In addition, lignite deposits of the Niger Delta appear to be large but have not been developed. Niger produces small amounts of coal used locally by uranium mine and mill operations from C

The Discovery of Extrasolar Planets by Backyard Astronomers

NASA Technical Reports Server (NTRS)

Castellano, Tim; Laughlin, Greg; DeVincenzi, D. (Technical Monitor)

2002-01-01

The discovery since 1995 of more than 80 planets around nearby solar-like stars and the photometric measurement of a transit of the jovian mass planet orbiting the solar-like star HD 209458 (producing a more than 1% drop in brightness that lasts 3 hours) has heralded a new era in astronomy. It has now been demonstrated that small telescopes equipped with sensitive and stable electronic detectors can produce fundamental scientific discoveries regarding the frequency and nature of planets outside the solar system. The modest equipment requirements for the discovery of extrasolar planetary transits of jovian mass planets in short period orbits around solar-like stars are fulfilled by commercial small aperture telescopes and CCD (charge coupled device) imagers common among amateur astronomers. With equipment already in hand and armed with target lists, observing techniques and software procedures developed by scientists at NASA's Ames Research Center and the University of California at Santa Cruz, non-professional astronomers can contribute significantly to the discovery and study of planets around others stars. In this way, we may resume (after a two century interruption!) the tradition of planet discoveries by amateur astronomers begun with William Herschel's 1787 discovery of the 'solar' planet Uranus.

Drugs from the Oceans: Marine Natural Products as Leads for Drug Discovery.

PubMed

Altmann, Karl-Heinz

2017-10-25

The marine environment harbors a vast number of species that are the source of a wide array of structurally diverse bioactive secondary metabolites. At this point in time, roughly 27'000 marine natural products are known, of which eight are (were) at the origin of seven marketed drugs, mostly for the treatment of cancer. The majority of these drugs and also of drug candidates currently undergoing clinical evaluation (excluding antibody-drug conjugates) are unmodified natural products, but synthetic chemistry has played a central role in the discovery and/or development of all but one of the approved marine-derived drugs. More than 1000 new marine natural products have been isolated per year over the last decade, but the pool of new and unique structures is far from exhausted. To fully leverage the potential offered by the structural diversity of marine-produced secondary metabolites for drug discovery will require their broad assessment for different bioactivities and the productive interplay between new fermentation technologies, synthetic organic chemistry, and medicinal chemistry, in order to secure compound supply and enable lead optimization.

Peptide-based antibody alternatives for biological sensing in austere environments

NASA Astrophysics Data System (ADS)

Coppock, Matthew B.; Sarkes, Deborah A.; Hurley, Margaret M.; Stratis-Cullum, Dimitra N.

2017-02-01

The most critical component of a biosensor, the biorecognition element, must exhibit high selectivity and strong affinity for a target of interest in operational sensing. Monoclonal antibodies are the current standard reagents for such devices, but their adaptability, manufacturability, and stability greatly limit their effectiveness in fieldable sensors. Peptides have emerged as potential antibody replacements in such applications due to their similar binding performance, extreme chemical and thermal stabilities, and on-demand scalability. In conjunction with modeling capabilities, work at the Army Research Lab focuses on protein catalyzed capture (PCC) agent technology and bacterial display for the discovery of these novel peptide binding reagents. The synthetic, bottom-up PCC agent technology uses an iterative, in situ "click chemistry" approach to produce high performing peptides against specific epitopes translatable to the protein target. Bacterial display allows rapid reagent discovery due to the combination of fast bacterial growth and effective peptide sequence enrichment through multiple rounds of biopanning. Recent advances in both methods are highlighted in regards to the discovery of reagents against Army high priority protein targets for soldier safety, performance, and diagnostics.

Knowledge Discovery/A Collaborative Approach, an Innovative Solution

NASA Technical Reports Server (NTRS)

Fitts, Mary A.

2009-01-01

Collaboration between Medical Informatics and Healthcare Systems (MIHCS) at NASA/Johnson Space Center (JSC) and the Texas Medical Center (TMC) Library was established to investigate technologies for facilitating knowledge discovery across multiple life sciences research disciplines in multiple repositories. After reviewing 14 potential Enterprise Search System (ESS) solutions, Collexis was determined to best meet the expressed needs. A three month pilot evaluation of Collexis produced positive reports from multiple scientists across 12 research disciplines. The joint venture and a pilot-phased approach achieved the desired results without the high cost of purchasing software, hardware or additional resources to conduct the task. Medical research is highly compartmentalized by discipline, e.g. cardiology, immunology, neurology. The medical research community at large, as well as at JSC, recognizes the need for cross-referencing relevant information to generate best evidence. Cross-discipline collaboration at JSC is specifically required to close knowledge gaps affecting space exploration. To facilitate knowledge discovery across these communities, MIHCS combined expertise with the TMC library and found Collexis to best fit the needs of our researchers including:

Adobe unlocks Cherry Canyon, other zones in prolific Barstow unit

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

Brewster, J.

1979-08-01

Recent discoveries by Adobe Oil and Gas Corp. in the Barstow unit skirting the Pecos River near Pecos, Texas have extended the Cherry Canyon play approx. 10 miles west in Ward County. In February, Adobe reported an oil discovery, 10 Barstow, drilled between No. 9 and No. 11 (gas wells) in section 34. The well reestablished Cherry Canyon oil production in the Scott field with a potential of 149 bpd of oil and a gor of 1540:1 or gas flow of 230 mcfd. Perforations were from 5827 to 6092 ft. The explanation of the anomaly of an oil well sandwichedmore » between 2 gas wells all producing from the same formation, is that Cherry Canyon consists of lensitic sands, not necessarily connected, that can yield gas and oil in substantially different proportions.« less

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, KSC employee Duane Williams prepares the blanket insulation to be installed on the body flap on orbiter Discovery. The blankets are part of the Orbiter Thermal Protection System, thermal shields to protect against temperatures as high as 3,000° Fahrenheit, which are produced during descent for landing. Discovery is scheduled to fly on mission STS-121 to the International Space Station.

NASA Image and Video Library

2003-12-09

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, KSC employee Duane Williams prepares the blanket insulation to be installed on the body flap on orbiter Discovery. The blankets are part of the Orbiter Thermal Protection System, thermal shields to protect against temperatures as high as 3,000° Fahrenheit, which are produced during descent for landing. Discovery is scheduled to fly on mission STS-121 to the International Space Station.

76 FR 44645 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-26

... Change To Amend FINRA Rule 9251 to Explicitly Protect From Discovery Those Documents That Federal Law... to amend FINRA Rule 9251 to explicitly protect from discovery those documents that federal law... produce to respondents during the discovery phase of a disciplinary proceeding. The rule also explicitly...

Fungal Peptaibiotics: Assessing Potential Meteoritic Amino Acid Contamination

NASA Technical Reports Server (NTRS)

Elsila, J. E.; Callahan, M. P.; Glavin, D. P.; Dworkin, J. P.; Bruckner, H.

2010-01-01

The presence of non-protein alpha-dialkyl-amino acids such as alpha-aminoisobutyric acid (alpha-A1B) and isovaline (Iva), which are relatively rare in the terrestrial biosphere, has long been used as an indication of the indigeneity of meteoritic amino acids, however, the discovery of alpha-AIB in peptides producers by a widespread group of filamentous fungi indicates the possibility of a terrestrial biotic source for the alpha-AIB observed in some meteorites. The alpha-AIB-containing peptides produced by these fungi are dubbed peptaibiotics. We measured the molecular distribution and stable carbon and nitrogen isotopic ratios for amino acids found in the total hydrolysates of four biologically synthesized peptaibiotics. We compared these aneasurenetts with those from the CM2 carbonaceous chondrite Murchison and from three Antarctic CR2 carbonaceous chondrites in order to understand the peptaibiotics as a potential source of meteoritic contamination.

A digital atlas of hydrocarbon accumulations within and adjacent to the National Petroleum Reserve - Alaska (NPRA)

USGS Publications Warehouse

Kumar, Naresh; Bird, Kenneth J.; Nelson, Philip H.; Grow, John A.; Evans, Kevin R.

2002-01-01

The United States Geological Survey (USGS) has initiated a project to reassess the hydrocarbon potential of the NPRA. Although exploration for hydrocarbons in the NPRA was initiated in 1944, it has taken fifty years for the first commercial discovery to be made. That discovery, the Alpine field (projected recoverable reserves of 430 million barrels), was made in 1994 along the eastern boundary of the NPRA. This field produces from a formation heretofore considered to be mostly a source rock. The Alpine discovery made such a reassessment necessary. As part of this assessment, we have compiled stratigraphic, structural, petrophysical, and seismic data related to nineteen accumulations within and nearby the NPRA. The goal is to provide basic documentation and a set of analog accumulations for the new assessment. The first two displays of this atlas consist of a location map and a stratigraphic column showing the stratigraphic settings for the primary reservoir and source rocks for these accumulations. The third display is a table listing each accumulation and providing the hydrocarbon fluid type, reservoir, operator, status, and discovery well and date for each. Compilation of basic information for each individual accumulation follows these displays. A typical compilation includes a structurecontour map on or near the reservoir horizon, a log display of the discovery well with reservoir characteristics along with figures for recoverable volumes, and one or two seismic lines across or near the accumulation.

Biotechnology of polyketides: New breath of life for the novel antibiotic genetic pathways discovery through metagenomics

PubMed Central

Gomes, Elisângela Soares; Schuch, Viviane; de Macedo Lemos, Eliana Gertrudes

2013-01-01

The discovery of secondary metabolites produced by microorganisms (e.g., penicillin in 1928) and the beginning of their industrial application (1940) opened new doors to what has been the main medication source for the treatment of infectious diseases and tumors. In fact, approximately 80 years after the discovery of the first antibiotic compound, and despite all of the warnings about the failure of the “goose that laid the golden egg,” the potential of this wealth is still inexorable: simply adjust the focus from “micro” to “nano”, that means changing the look from microorganisms to nanograms of DNA. Then, the search for new drugs, driven by genetic engineering combined with metagenomic strategies, shows us a way to bypass the barriers imposed by methodologies limited to isolation and culturing. However, we are far from solving the problem of supplying new molecules that are effective against the plasticity of multi- or pan-drug-resistant pathogens. Although the first advances in genetic engineering date back to 1990, there is still a lack of high-throughput methods to speed up the screening of new genes and design new molecules by recombination of pathways. In addition, it is necessary an increase in the variety of heterologous hosts and improvements throughout the full drug discovery pipeline. Among numerous studies focused on this subject, those on polyketide antibiotics stand out for the large technical-scientific efforts that established novel solutions for the transfer/engineering of major metabolic pathways using transposons and other episomes, overcoming one of the main methodological constraints for the heterologous expression of major pathways. In silico prediction analysis of three-dimensional enzymatic structures and advances in sequencing technologies have expanded access to the metabolic potential of microorganisms. PMID:24688489

The prepared mind. [Serendipitous discovery of demulsifier

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

Thompson, N.E.S.

Products derived from the work of scientists with serendipity, or an imagined faculty for making fluke discoveries by looking for one thing and finding another, include the well-known examples of Teflon, penicillin, X-rays, Velcro, nylon, saccharin, and Nutrasweet. This dream of every scientist came true for the author in the discovery of a dithiocarbamate compound that could be used as a water-clarifying agent for oil fields that produce water. The new agent enables oil companies to discharge water produced in offshore drilling facilities without upsetting the clarity of the aquatic environment. The EPA limit for oil in discharged water ismore » 48 ppm. Failure to maintain this limit will result in shutdown of the platform. The alternative is to pipe the produced water to onshore facilities for treatment before discharge, which costs a good bit more. The serendipitous discovery of the dithiocarbamate compound discussed here as a unique water-clarifying agent has also led to important fundamental advances. The new agent allows producers to use existing water treatment equipment and remain in compliance with the latest limits on oil content. This compound has made it more economical to operate offshore oil and gas production facilities in the Gulf of Mexico and the North Sea.« less

Salem limestone oil and gas production in the Keenville field, Wayne County, Illinois

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

Stevenson, D.L.

Oil has been produced from the Salem Limestone of Valmeyeran (middle Mississippian) age in Illinois since 1939. In 1972 the discovery of Salem oil at Zenith North field in Wayne County, Illinois, stimulated a resurgence of Salem exploration in the Illinois Basin. By the end of 1977, activity had resulted in 3 new field discoveries and 24 new pool discoveries in the Salem of Illinois. One of the most promising of these discoveries was in the Keenville field in T. 1 S., R. 5 E., Wayne County, Illinois. The discovery well was completed early in January 1977, and by themore » end of the year 40 wells had produced approximately 760,000 barrels of Salem oil. The oil is produced from a biocalcarenite (predominatly sand-sized fossils and fossil fragments), with highly variable porosity and permeability, which lies about midway between the top and bottom of the formation. No structural closure is evident on key marker beds above the Salem, but some closure is created by the tendency of the producing zone to occur increasingly lower in the section in an up-dip direction. Water-free oil production was obtained in many wells by setting pipe through the reservoir and perforating above the oil-water contact, as determined by examination of drill cuttings. The oil produced is accompanied by gas with a heating value of about 1500 Btu/ft/sup 3/. To date, most of the oil accumulations in the Salem have been found by drilling below shallower, producing zones on prominent structures. The presence of reservoirs within the Salem, such as the one at Keenville has been difficult to predict prior to drilling. The recent increase in the number of holes drilled to or through the Salem should add to our knowledge of its depositional and diagenetic history and help in further oil exploration.« less

Application of a Bacillus subtilis Whole-Cell Biosensor (PliaI-lux) for the Identification of Cell Wall Active Antibacterial Compounds.

PubMed

Kobras, Carolin Martina; Mascher, Thorsten; Gebhard, Susanne

2017-01-01

Whole-cell biosensors, based on the visualization of a reporter strain's response to a particular stimulus, are a robust and cost-effective means to monitor defined environmental conditions or the presence of chemical compounds. One specific field in which such biosensors are frequently applied is drug discovery, i.e., the screening of large numbers of bacterial or fungal strains for the production of antimicrobial compounds. We here describe the application of a luminescence-based Bacillus subtilis biosensor for the discovery of cell wall active substances. The system is based on the well-characterized promoter P liaI , which is induced in response to a wide range of conditions that cause cell envelope stress, particularly antibiotics that interfere with the membrane-anchored steps of cell wall biosynthesis. A simple "spot-on-lawn" assay, where colonies of potential producer strains are grown directly on a lawn of the reporter strain, allows for quantitative and time-resolved detection of antimicrobial compounds. Due to the very low technical demands of this procedure, we expect it to be easily applicable to a large variety of candidate producer strains and growth conditions.

Rational Design of Novel 1,3-Oxazine Based β-Secretase (BACE1) Inhibitors: Incorporation of a Double Bond To Reduce P-gp Efflux Leading to Robust Aβ Reduction in the Brain.

PubMed

Fuchino, Kouki; Mitsuoka, Yasunori; Masui, Moriyasu; Kurose, Noriyuki; Yoshida, Shuhei; Komano, Kazuo; Yamamoto, Takahiko; Ogawa, Masayoshi; Unemura, Chie; Hosono, Motoko; Ito, Hisanori; Sakaguchi, Gaku; Ando, Shigeru; Ohnishi, Shuichi; Kido, Yasuto; Fukushima, Tamio; Miyajima, Hirofumi; Hiroyama, Shuichi; Koyabu, Kiyotaka; Dhuyvetter, Deborah; Borghys, Herman; Gijsen, Harrie J M; Yamano, Yoshinori; Iso, Yasuyoshi; Kusakabe, Ken-Ichi

2018-05-23

Accumulation of Aβ peptides is a hallmark of Alzheimer's disease (AD) and is considered a causal factor in the pathogenesis of AD. β-Secretase (BACE1) is a key enzyme responsible for producing Aβ peptides, and thus agents that inhibit BACE1 should be beneficial for disease-modifying treatment of AD. Here we describe the discovery and optimization of novel oxazine-based BACE1 inhibitors by lowering amidine basicity with the incorporation of a double bond to improve brain penetration. Starting from a 1,3-dihydrooxazine lead 6 identified by a hit-to-lead SAR following HTS, we adopted a p K a lowering strategy to reduce the P-gp efflux and the high hERG potential leading to the discovery of 15 that produced significant Aβ reduction with long duration in pharmacodynamic models and exhibited wide safety margins in cardiovascular safety models. This compound improved the brain-to-plasma ratio relative to 6 by reducing P-gp recognition, which was demonstrated by a P-gp knockout mouse model.

Perceptual learning modules in mathematics: enhancing students' pattern recognition, structure extraction, and fluency.

PubMed

Kellman, Philip J; Massey, Christine M; Son, Ji Y

2010-04-01

Learning in educational settings emphasizes declarative and procedural knowledge. Studies of expertise, however, point to other crucial components of learning, especially improvements produced by experience in the extraction of information: perceptual learning (PL). We suggest that such improvements characterize both simple sensory and complex cognitive, even symbolic, tasks through common processes of discovery and selection. We apply these ideas in the form of perceptual learning modules (PLMs) to mathematics learning. We tested three PLMs, each emphasizing different aspects of complex task performance, in middle and high school mathematics. In the MultiRep PLM, practice in matching function information across multiple representations improved students' abilities to generate correct graphs and equations from word problems. In the Algebraic Transformations PLM, practice in seeing equation structure across transformations (but not solving equations) led to dramatic improvements in the speed of equation solving. In the Linear Measurement PLM, interactive trials involving extraction of information about units and lengths produced successful transfer to novel measurement problems and fraction problem solving. Taken together, these results suggest (a) that PL techniques have the potential to address crucial, neglected dimensions of learning, including discovery and fluent processing of relations; (b) PL effects apply even to complex tasks that involve symbolic processing; and (c) appropriately designed PL technology can produce rapid and enduring advances in learning. Copyright © 2009 Cognitive Science Society, Inc.

Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders

PubMed Central

Yi, Bitna; Jahangir, Alam; Evans, Andrew K.; Briggs, Denise; Ravina, Kristine; Ernest, Jacqueline; Farimani, Amir B.; Sun, Wenchao; Rajadas, Jayakumar; Green, Michael; Feinberg, Evan N.; Pande, Vijay S.

2017-01-01

The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer’s disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction. PMID:28746336

Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders.

PubMed

Yi, Bitna; Jahangir, Alam; Evans, Andrew K; Briggs, Denise; Ravina, Kristine; Ernest, Jacqueline; Farimani, Amir B; Sun, Wenchao; Rajadas, Jayakumar; Green, Michael; Feinberg, Evan N; Pande, Vijay S; Shamloo, Mehrdad

2017-01-01

The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer's disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.

Rapid discovery and functional characterization of terpene synthases from four endophytic xylariaceae

DOE PAGES

Wu, Weihua; Tran, William; Taatjes, Craig A.; ...

2016-02-17

Endophytic fungi are ubiquitous plant endosymbionts that establish complex and poorly understood relationships with their host organisms. Many endophytic fungi are known to produce a wide spectrum of volatile organic compounds (VOCs) with potential energy applications, which have been described as "mycodiesel". Many of these mycodiesel hydrocarbons are terpenes, a chemically diverse class of compounds produced by many plants, fungi, and bacteria. Due to their high energy densities, terpenes, such as pinene and bisabolene, are actively being investigated as potential "drop-in" biofuels for replacing diesel and aviation fuel. In this study, we rapidly discovered and characterized 26 terpene synthases (TPSs)more » derived from four endophytic fungi known to produce mycodiesel hydrocarbons. The TPS genes were expressed in an E. coli strain harboring a heterologous mevalonate pathway designed to enhance terpene production, and their product profiles were determined using Solid Phase Micro-Extraction (SPME) and GC-MS. Lastly, out of the 26 TPS’s profiled, 12 TPS’s were functional, with the majority of them exhibiting both monoterpene and sesquiterpene synthase activity.« less

Rapid discovery and functional characterization of terpene synthases from four endophytic xylariaceae

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

Wu, Weihua; Tran, William; Taatjes, Craig A.

Endophytic fungi are ubiquitous plant endosymbionts that establish complex and poorly understood relationships with their host organisms. Many endophytic fungi are known to produce a wide spectrum of volatile organic compounds (VOCs) with potential energy applications, which have been described as "mycodiesel". Many of these mycodiesel hydrocarbons are terpenes, a chemically diverse class of compounds produced by many plants, fungi, and bacteria. Due to their high energy densities, terpenes, such as pinene and bisabolene, are actively being investigated as potential "drop-in" biofuels for replacing diesel and aviation fuel. In this study, we rapidly discovered and characterized 26 terpene synthases (TPSs)more » derived from four endophytic fungi known to produce mycodiesel hydrocarbons. The TPS genes were expressed in an E. coli strain harboring a heterologous mevalonate pathway designed to enhance terpene production, and their product profiles were determined using Solid Phase Micro-Extraction (SPME) and GC-MS. Lastly, out of the 26 TPS’s profiled, 12 TPS’s were functional, with the majority of them exhibiting both monoterpene and sesquiterpene synthase activity.« less

Protection conferred by recombinant Yersinia pestis antigens produced by a rapid and highly scalable plant expression system

PubMed Central

Santi, Luca; Giritch, Anatoli; Roy, Chad J.; Marillonnet, Sylvestre; Klimyuk, Victor; Gleba, Yuri; Webb, Robert; Arntzen, Charles J.; Mason, Hugh S.

2006-01-01

Plague is still an endemic disease in different regions of the world. Increasing reports of incidence, the discovery of antibiotic resistance strains, and concern about a potential use of the causative bacteria Yersinia pestis as an agent of biological warfare have highlighted the need for a safe, efficacious, and rapidly producible vaccine. The use of F1 and V antigens and the derived protein fusion F1-V has shown great potential as a protective vaccine in animal studies. Plants have been extensively studied for the production of pharmaceutical proteins as an inexpensive and scalable alternative to common expression systems. In the current study the recombinant plague antigens F1, V, and fusion protein F1-V were produced by transient expression in Nicotiana benthamiana by using a deconstructed tobacco mosaic virus-based system that allowed very rapid and extremely high levels of expression. All of the plant-derived purified antigens, administered s.c. to guinea pigs, generated systemic immune responses and provided protection against an aerosol challenge of virulent Y. pestis. PMID:16410352

Marennine, Promising Blue Pigments from a Widespread Haslea Diatom Species Complex

PubMed Central

Gastineau, Romain; Turcotte, François; Pouvreau, Jean-Bernard; Morançais, Michèle; Fleurence, Joël; Windarto, Eko; Semba Prasetiya, Fiddy; Arsad, Sulastri; Jaouen, Pascal; Babin, Mathieu; Coiffard, Laurence; Couteau, Céline; Bardeau, Jean-François; Jacquette, Boris; Leignel, Vincent; Hardivillier, Yann; Marcotte, Isabelle; Bourgougnon, Nathalie; Tremblay, Réjean; Deschênes, Jean-Sébastien; Badawy, Hope; Pasetto, Pamela; Davidovich, Nikolai; Hansen, Gert; Dittmer, Jens; Mouget, Jean-Luc

2014-01-01

In diatoms, the main photosynthetic pigments are chlorophylls a and c, fucoxanthin, diadinoxanthin and diatoxanthin. The marine pennate diatom Haslea ostrearia has long been known for producing, in addition to these generic pigments, a water-soluble blue pigment, marennine. This pigment, responsible for the greening of oysters in western France, presents different biological activities: allelopathic, antioxidant, antibacterial, antiviral, and growth-inhibiting. A method to extract and purify marennine has been developed, but its chemical structure could hitherto not be resolved. For decades, H. ostrearia was the only organism known to produce marennine, and can be found worldwide. Our knowledge about H. ostrearia-like diatom biodiversity has recently been extended with the discovery of several new species of blue diatoms, the recently described H. karadagensis, H. silbo sp. inedit. and H. provincialis sp. inedit. These blue diatoms produce different marennine-like pigments, which belong to the same chemical family and present similar biological activities. Aside from being a potential source of natural blue pigments, H. ostrearia-like diatoms thus present a commercial potential for aquaculture, cosmetics, food and health industries. PMID:24879542

TINS, target immobilized NMR screening: an efficient and sensitive method for ligand discovery.

PubMed

Vanwetswinkel, Sophie; Heetebrij, Robert J; van Duynhoven, John; Hollander, Johan G; Filippov, Dmitri V; Hajduk, Philip J; Siegal, Gregg

2005-02-01

We propose a ligand screening method, called TINS (target immobilized NMR screening), which reduces the amount of target required for the fragment-based approach to drug discovery. Binding is detected by comparing 1D NMR spectra of compound mixtures in the presence of a target immobilized on a solid support to a control sample. The method has been validated by the detection of a variety of ligands for protein and nucleic acid targets (K(D) from 60 to 5000 muM). The ligand binding capacity of a protein was undiminished after 2000 different compounds had been applied, indicating the potential to apply the assay for screening typical fragment libraries. TINS can be used in competition mode, allowing rapid characterization of the ligand binding site. TINS may allow screening of targets that are difficult to produce or that are insoluble, such as membrane proteins.

Bioactive compounds synthesized by non-ribosomal peptide synthetases and type-I polyketide synthases discovered through genome-mining and metagenomics.

PubMed

Nikolouli, Katerina; Mossialos, Dimitris

2012-08-01

Non-ribosomal peptide synthetases (NRPS) and type-I polyketide synthases (PKS-I) are multimodular enzymes involved in biosynthesis of oligopeptide and polyketide secondary metabolites produced by microorganisms such as bacteria and fungi. New findings regarding the mechanisms underlying NRPS and PKS-I evolution illustrate how microorganisms expand their metabolic potential. During the last decade rapid development of bioinformatics tools as well as improved sequencing and annotation of microbial genomes led to discovery of novel bioactive compounds synthesized by NRPS and PKS-I through genome-mining. Taking advantage of these technological developments metagenomics is a fast growing research field which directly studies microbial genomes or specific gene groups and their products. Discovery of novel bioactive compounds synthesized by NRPS and PKS-I will certainly be accelerated through metagenomics, allowing the exploitation of so far untapped microbial resources in biotechnology and medicine.

Genalogical approaches to ethical implications of informational assimilative integrated discovery systems (AIDS) in business

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

Pharhizgar, K.D.; Lunce, S.E.

1994-12-31

Development of knowledge-based technological acquisition techniques and customers` information profiles are known as assimilative integrated discovery systems (AIDS) in modern organizations. These systems have access through processing to both deep and broad domains of information in modern societies. Through these systems organizations and individuals can predict future trend probabilities and events concerning their customers. AIDSs are new techniques which produce new information which informants can use without the help of the knowledge sources because of the existence of highly sophisticated computerized networks. This paper has analyzed the danger and side effects of misuse of information through the illegal, unethical andmore » immoral access to the data-base in an integrated and assimilative information system as described above. Cognivistic mapping, pragmatistic informational design gathering, and holistic classifiable and distributive techniques are potentially abusive systems whose outputs can be easily misused by businesses when researching the firm`s customers.« less

An overview of rapamycin: from discovery to future perspectives.

PubMed

Yoo, Young Ji; Kim, Hanseong; Park, Sung Ryeol; Yoon, Yeo Joon

2017-05-01

Rapamycin is an immunosuppressive metabolite produced from several actinomycete species. Besides its immunosuppressive activity, rapamycin and its analogs have additional therapeutic potentials, including antifungal, antitumor, neuroprotective/neuroregenerative, and lifespan extension activities. The core structure of rapamycin is derived from (4R,5R)-4,5-dihydrocyclohex-1-ene-carboxylic acid that is extended by polyketide synthase. The resulting linear polyketide chain is cyclized by incorporating pipecolate and further decorated by post-PKS modification enzymes. Herein, we review the discovery and biological activities of rapamycin as well as its mechanism of action, mechanistic target, biosynthesis, and regulation. In addition, we introduce the many efforts directed at enhancing the production of rapamycin and generating diverse analogs and also explore future perspectives in rapamycin research. This review will also emphasize the remarkable pilot studies on the biosynthesis and production improvement of rapamycin by Dr. Demain, one of the world's distinguished scientists in industrial microbiology and biotechnology.

Discovery and resupply of pharmacologically active plant-derived natural products: A review

PubMed Central

Linder, Thomas; Wawrosch, Christoph; Uhrin, Pavel; Temml, Veronika; Wang, Limei; Schwaiger, Stefan; Heiss, Elke H.; Rollinger, Judith M.; Schuster, Daniela; Breuss, Johannes M.; Bochkov, Valery; Mihovilovic, Marko D.; Kopp, Brigitte; Bauer, Rudolf; Dirsch, Verena M.; Stuppner, Hermann

2016-01-01

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future. PMID:26281720

Discovery and resupply of pharmacologically active plant-derived natural products: A review.

PubMed

Atanasov, Atanas G; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Linder, Thomas; Wawrosch, Christoph; Uhrin, Pavel; Temml, Veronika; Wang, Limei; Schwaiger, Stefan; Heiss, Elke H; Rollinger, Judith M; Schuster, Daniela; Breuss, Johannes M; Bochkov, Valery; Mihovilovic, Marko D; Kopp, Brigitte; Bauer, Rudolf; Dirsch, Verena M; Stuppner, Hermann

2015-12-01

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a "screening hit" through a "drug lead" to a "marketed drug" is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Identification of Secondary Metabolite Gene Clusters in the Pseudovibrio Genus Reveals Encouraging Biosynthetic Potential toward the Production of Novel Bioactive Compounds.

PubMed

Naughton, Lynn M; Romano, Stefano; O'Gara, Fergal; Dobson, Alan D W

2017-01-01

Increased incidences of antimicrobial resistance and the emergence of pan-resistant 'superbugs' have provoked an extreme sense of urgency amongst researchers focusing on the discovery of potentially novel antimicrobial compounds. A strategic shift in focus from the terrestrial to the marine environment has resulted in the discovery of a wide variety of structurally and functionally diverse bioactive compounds from numerous marine sources, including sponges. Bacteria found in close association with sponges and other marine invertebrates have recently gained much attention as potential sources of many of these novel bioactive compounds. Members of the genus Pseudovibrio are one such group of organisms. In this study, we interrogate the genomes of 21 Pseudovibrio strains isolated from a variety of marine sources, for the presence, diversity and distribution of biosynthetic gene clusters (BGCs). We expand on results obtained from antiSMASH analysis to demonstrate the similarity between the Pseudovibrio -related BGCs and those characterized in other bacteria and corroborate our findings with phylogenetic analysis. We assess how domain organization of the most abundant type of BGCs present among the isolates (Non-ribosomal peptide synthetases and Polyketide synthases) may influence the diversity of compounds produced by these organisms and highlight for the first time the potential for novel compound production from this genus of bacteria, using a genome guided approach.

Progressing from programmatic to discovery research: a case example with the overjustification effect.

PubMed

Roane, Henry S; Fisher, Wayne W; McDonough, Erin M

2003-01-01

Scientific research progresses along planned (programmatic research) and unplanned (discovery research) paths. In the current investigation, we attempted to conduct a single-case evaluation of the overjustification effect (i.e., programmatic research). Results of the initial analysis were contrary to the overjustification hypothesis in that removal of the reward contingency produced an increase in responding. Based on this unexpected finding, we conducted subsequent analyses to further evaluate the mechanisms underlying these results (i.e., discovery research). Results of the additional analyses suggested that the reward contingency functioned as punishment (because the participant preferred the task to the rewards) and that withdrawal of the contingency produced punishment contrast.

Progressing from programmatic to discovery research: a case example with the overjustification effect.

PubMed Central

Roane, Henry S; Fisher, Wayne W; McDonough, Erin M

2003-01-01

Scientific research progresses along planned (programmatic research) and unplanned (discovery research) paths. In the current investigation, we attempted to conduct a single-case evaluation of the overjustification effect (i.e., programmatic research). Results of the initial analysis were contrary to the overjustification hypothesis in that removal of the reward contingency produced an increase in responding. Based on this unexpected finding, we conducted subsequent analyses to further evaluate the mechanisms underlying these results (i.e., discovery research). Results of the additional analyses suggested that the reward contingency functioned as punishment (because the participant preferred the task to the rewards) and that withdrawal of the contingency produced punishment contrast. PMID:12723865

Fatal methane and cyanide poisoning as a result of handling industrial fish: a case report and review of the literature.

PubMed

Cherian, M A; Richmond, I

2000-10-01

The potential health hazards of handling industrial fish are well documented. Wet fish in storage consume oxygen and produce poisonous gases as they spoil. In addition to oxygen depletion, various noxious agents have been demonstrated in association with spoilage including carbon dioxide, sulphur dioxide, and ammonia. A fatal case of methane and cyanide poisoning among a group of deep sea trawler men is described. Subsequent independent investigation as a result of this case led to the discovery of cyanides as a further potential noxious agent. This is thus the first case in which cyanide poisoning has been recognised as a potentially fatal complication of handling spoiled fish. The previous literature is reviewed and the implications of the current case are discussed.

Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool?

PubMed

Florez, Jose C

2017-05-01

In recent years, technological and analytical advances have led to an explosion in the discovery of genetic loci associated with type 2 diabetes. However, their ability to improve prediction of disease outcomes beyond standard clinical risk factors has been limited. On the other hand, genetic effects on drug response may be stronger than those commonly seen for disease incidence. Pharmacogenetic findings may aid in identifying new drug targets, elucidate pathophysiology, unravel disease heterogeneity, help prioritise specific genes in regions of genetic association, and contribute to personalised or precision treatment. In diabetes, precedent for the successful application of pharmacogenetic concepts exists in its monogenic subtypes, such as MODY or neonatal diabetes. Whether similar insights will emerge for the much more common entity of type 2 diabetes remains to be seen. As genetic approaches advance, the progressive deployment of candidate gene, large-scale genotyping and genome-wide association studies has begun to produce suggestive results that may transform clinical practice. However, many barriers to the translation of diabetes pharmacogenetic discoveries to the clinic still remain. This perspective offers a contemporary overview of the field with a focus on sulfonylureas and metformin, identifies the major uses of pharmacogenetics, and highlights potential limitations and future directions.

Strategies to potentiate antimicrobial photoinactivation by overcoming resistant phenotypes†

PubMed Central

Vera, D. Mariano A.; Haynes, Mark H; Ball, Anthony R.; Dai, D. Tianhong; Astrakas, Christos; Kelso, Michael J; Hamblin, Michael R; Tegos, George P.

2012-01-01

Conventional antimicrobial strategies have become increasingly ineffective due to the emergence of multidrug resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered the exploration of alternative treatments and unconventional approaches towards controlling microbial infections. Photodynamic therapy was originally established as an anti-cancer modality and is currently used in the treatment of age related macular degeneration. The concept of photodynamic inactivation requires cell exposure to light energy, typically wavelengths in the visible region that causes the excitation of photosensitizer molecules either exogenous or endogenous, which results in the production of reactive oxygen species. ROS produce cell inactivation and death through modification of intracellular components. The versatile characteristics of PDT prompted its investigation as an anti-infective discovery platform. Advances in understanding of microbial physiology have shed light on a series of pathways, and phenotypes that serve as putative targets for antimicrobial drug discovery. Investigations of these phenotypic elements in concert with PDT have been reported focused on multidrug efflux systems, biofilms, virulence and pathogenesis determinants. In many instances the results are promising but only preliminary and require further investigation. This review discusses the different antimicrobial PDT strategies and highlights the need for highly informative and comprehensive discovery approaches. PMID:22242675

SemaTyP: a knowledge graph based literature mining method for drug discovery.

PubMed

Sang, Shengtian; Yang, Zhihao; Wang, Lei; Liu, Xiaoxia; Lin, Hongfei; Wang, Jian

2018-05-30

Drug discovery is the process through which potential new medicines are identified. High-throughput screening and computer-aided drug discovery/design are the two main drug discovery methods for now, which have successfully discovered a series of drugs. However, development of new drugs is still an extremely time-consuming and expensive process. Biomedical literature contains important clues for the identification of potential treatments. It could support experts in biomedicine on their way towards new discoveries. Here, we propose a biomedical knowledge graph-based drug discovery method called SemaTyP, which discovers candidate drugs for diseases by mining published biomedical literature. We first construct a biomedical knowledge graph with the relations extracted from biomedical abstracts, then a logistic regression model is trained by learning the semantic types of paths of known drug therapies' existing in the biomedical knowledge graph, finally the learned model is used to discover drug therapies for new diseases. The experimental results show that our method could not only effectively discover new drug therapies for new diseases, but also could provide the potential mechanism of action of the candidate drugs. In this paper we propose a novel knowledge graph based literature mining method for drug discovery. It could be a supplementary method for current drug discovery methods.

Radon gas: contractor liability for an indoor health hazard.

PubMed

Shuko, C M

1986-01-01

Many families throughout the United States have recently detected dangerously high concentrations of radon gas inside their homes. Radon, a carcinogenic gas produced from uranium, has been discovered in structures overlying uranium-bearing rock. This discovery may result in litigation to determine contractor liability for building upon radon-releasing rock sites. This Note examines the strengths and weaknesses of the various theories of contractor liability and considers potential statutory claims under the Clean Air Act. The Note suggests, as an alternative approach to recovery, a proposed regulatory scheme and implementation plan.

Mississippian Lodgepole Play, Williston Basin: A review

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

Montgomery, S.L.

1996-06-01

Waulsortian-type carbonate mud mounds in the lower Mississippian Lodgepole formation (Bottineau interval, Madison Group) comprise an important new oil play in the Williston basin with strong regional potential. The play is typified by wells capable of producing 1000-2500 bbl of oil per day and by reserves that have as much as 0.5-3.0 million bbl of oil per well. Currently centered in Stark County, North Dakota, along the southern flank of the basin, the play includes 38 wells, with 21 producers and 6 new fields. Initial discovery was made at a Silurian test in Dickinson field, traditionally productive from Pennsylvanian sands.more » The largest pool discovered to date is Eland field, which has 15 producers and estimated total reserves of 12-15 million bbl. This report summarizes geologic, well-log, seismic, and production data for this play, which promises to expand considerably in the years to come.« less

Rethinking production of Taxol® (paclitaxel) using endophyte biotechnology.

PubMed

Kusari, Souvik; Singh, Satpal; Jayabaskaran, Chelliah

2014-06-01

Taxol® (generic name paclitaxel) represents one of the most clinically valuable natural products known to mankind in the recent past. More than two decades have elapsed since the notable discovery of the first Taxol®-producing endophytic fungus, which was followed by a plethora of reports on other endophytes possessing similar biosynthetic potential. However, industrial-scale Taxol® production using fungal endophytes, although seemingly promising, has not seen the light of the day. In this opinion article, we embark on the current state of knowledge on Taxol® biosynthesis focusing on the chemical ecology of its producers, and ask whether it is actually possible to produce Taxol® using endophyte biotechnology. The key problems that have prevented the exploitation of potent endophytic fungi by industrial bioprocesses for sustained production of Taxol® are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Source rock potential in Pakistan

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

Raza, H.A.

1991-03-01

Pakistan contains two sedimentary basins: Indus in the east and Balochistan in the west. The Indus basin has received sediments from precambrian until Recent, albeit with breaks. It has been producing hydrocarbons since 1914 from three main producing regions, namely, the Potwar, Sulaisman, and Kirthar. In the Potwar, oil has been discovered in Cambrian, Permian, Jurassic, and Tertiary rocks. Potential source rocks are identified in Infra-Cambrian, Permian, Paleocene, and Eocene successions, but Paleocene/Eocene Patala Formation seems to be the main source of most of the oil. In the Sulaiman, gas has been found in Cretaceous and Tertiary; condensate in Cretaceousmore » rocks. Potential source rocks are indicated in Cretaceous, Paleocene, and Eocene successions. The Sembar Formation of Early Cretaceous age appears to be the source of gas. In the Kirthar, oil and gas have been discovered in Cretaceous and gas has been discovered in paleocene and Eocene rocks. Potential source rocks are identified in Kirthar and Ghazij formations of Eocene age in the western part. However, in the easter oil- and gas-producing Badin platform area, Union Texas has recognized the Sembar Formation of Early Cretaceous age as the only source of Cretaceous oil and gas. The Balochistan basin is part of an Early Tertiary arc-trench system. The basin is inadequately explored, and there is no oil or gas discovery so far. However, potential source rocks have been identified in Eocene, Oligocene, Miocene, and Pliocene successions based on geochemical analysis of surface samples. Mud volcanoes are present.« less

The Potential of Indonesian Heterobranchs Found around Bunaken Island for the Production of Bioactive Compounds

PubMed Central

Fisch, Katja M.; Hertzer, Cora; Böhringer, Nils; Wuisan, Zerlina G.; Schillo, Dorothee; Bara, Robert; Kaligis, Fontje; Wägele, Heike; König, Gabriele M.; Schäberle, Till F.

2017-01-01

The species diversity of marine heterobranch sea slugs found on field trips around Bunaken Island (North Sulawesi, Indonesia) and adjacent islands of the Bunaken National Marine Park forms the basis of this review. In a survey performed in 2015, 80 species from 23 families were collected, including 17 new species. Only three of these have been investigated previously in studies from Indonesia. Combining species diversity with a former study from 2003 reveals in total 140 species from this locality. The diversity of bioactive compounds known and yet to be discovered from these organisms is summarized and related to the producer if known or suspected (might it be down the food chain, de novo synthesised from the slug or an associated bacterium). Additionally, the collection of microorganisms for the discovery of natural products of pharmacological interest from this hotspot of biodiversity that is presented here contains more than 50 species that have never been investigated before in regard to bioactive secondary metabolites. This highlights the great potential of the sea slugs and the associated microorganisms for the discovery of natural products of pharmacological interest from this hotspot of biodiversity. PMID:29215579

Recent advancements in carbon nanofiber and carbon nanotube applications in drug delivery and tissue engineering.

PubMed

Stout, David A

2015-01-01

Since the discovery and synthesis of carbon nanotubes (CNTs) and carbon nanofibers (CNFs) over a decade ago, researchers have envisioned and discovered new potential applications for these materials. CNTs and CNFs have rapidly become a platform technology for a variety of uses, including biomedical applications due to their mechanical, electrical, thermal, optical and structural properties. CNTs and CNFs are also advantageous due to their ability to be produced in many different shapes and sizes. Since their discovery, of the many imaginable applications, CNTs and CNFs have gained a significant amount of attention and therapeutic potential in tissue engineering and drug delivery applications. In recent years, CNTs and CNFs have made significant contributions in designing new strategies for, delivery of pharmaceuticals, genes and molecular probes into cells, stem cell therapies and assisting in tissue regeneration. Furthermore, it is widely expressed that these materials will significantly contribute to the next generation of health care technologies in treating diseases and contributing to tissue growth. Hence, this review seeks to explore the recent advancements, current status and limitations of CNTs and CNFs for drug delivery and tissue engineering applications.

Reserve growth in oil fields of the North Sea

USGS Publications Warehouse

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

2005-01-01

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

Perspectives on NMR in drug discovery: a technique comes of age

PubMed Central

Pellecchia, Maurizio; Bertini, Ivano; Cowburn, David; Dalvit, Claudio; Giralt, Ernest; Jahnke, Wolfgang; James, Thomas L.; Homans, Steve W.; Kessler, Horst; Luchinat, Claudio; Meyer, Bernd; Oschkinat, Hartmut; Peng, Jeff; Schwalbe, Harald; Siegal, Gregg

2009-01-01

In the past decade, the potential of harnessing the ability of nuclear magnetic resonance (NMR) spectroscopy to monitor intermolecular interactions as a tool for drug discovery has been increasingly appreciated in academia and industry. In this Perspective, we highlight some of the major applications of NMR in drug discovery, focusing on hit and lead generation, and provide a critical analysis of its current and potential utility. PMID:19172689

Changing the Scale and Efficiency of Chemical Warfare Countermeasure Discovery Using the Zebrafish

PubMed Central

Peterson, Randall T.; MacRae, Calum A.

2013-01-01

As the scope of potential chemical warfare agents grows rapidly and as the diversity of potential threat scenarios expands with non-state actors, so a need for innovative approaches to countermeasure development has emerged. In the last few years, the utility of the zebrafish as a model organism that is amenable to high-throughput screening has become apparent and this system has been applied to the unbiased discovery of chemical warfare countermeasures. This review summarizes the in vivo screening approach that has been pioneered in the countermeasure discovery arena, and highlights the successes to date as well as the potential challenges in moving the field forward. Importantly, the establishment of a zebrafish platform for countermeasure discovery would offer a rapid response system for the development of antidotes to the continuous stream of new potential chemical warfare agents. PMID:24273586

Paths to the discovery of antivenom serotherapy in France.

PubMed

Bochner, Rosany

2016-01-01

The current study presents a descriptive chronological survey of the articles published by Césaire Auguste Phisalix and Albert Calmette on snake poison, with the aim of shedding a light on the areas of research and reasoning followed by these scientists, leading up to their simultaneous discovery of antivenom serotherapy in 1894. The path taken by Phisalix is revealed in 15 articles that demonstrate the motivation of a naturalist and the way he confronted the puzzle of immunity against snake venom. In the case of Calmette, two articles preceded the discovery; microbiology was his theoretical base and the Pasteurian spirit of solving health problems his driving force. These two researchers followed distinct paths, mobilized by different motivations, but produced one single result. It is incontestable that the discovery of antivenom serotherapy was the work of two groups of researchers who deserve equal recognition, but who, in fact, did not receive it. Following the discovery both Calmette and Phisalix returned to their previous motivations. Calmette put the discovery into practice and began to produce antivenom serum in Lille. He came to be generally considered as the sole discoverer of antivenom serotherapy and was the recipient of a number of prestigious prizes. Phisalix, on the other hand, received little recognition and returned to his original interests, devoting himself to research on natural immunity. In Brazil, the discovery of antivenom serum therapy had a profound impact on the work of Vital Brazil Mineiro da Campanha, a researcher known worldwide for his scientific discoveries and for the evidence of the specificity of antivenom serums.

Using Molecular Networking for Microbial Secondary Metabolite Bioprospecting.

PubMed

Purves, Kevin; Macintyre, Lynsey; Brennan, Debra; Hreggviðsson, Guðmundur Ó; Kuttner, Eva; Ásgeirsdóttir, Margrét E; Young, Louise C; Green, David H; Edrada-Ebel, Ruangelie; Duncan, Katherine R

2016-01-08

The oceans represent an understudied resource for the isolation of bacteria with the potential to produce novel secondary metabolites. In particular, actinomyces are well known to produce chemically diverse metabolites with a wide range of biological activities. This study characterised spore-forming bacteria from both Scottish and Antarctic sediments to assess the influence of isolation location on secondary metabolite production. Due to the selective isolation method used, all 85 isolates belonged to the phyla Firmicutes and Actinobacteria, with the majority of isolates belonging to the genera Bacillus and Streptomyces. Based on morphology, thirty-eight isolates were chosen for chemical investigation. Molecular networking based on chemical profiles (HR-MS/MS) of fermentation extracts was used to compare complex metabolite extracts. The results revealed 40% and 42% of parent ions were produced by Antarctic and Scottish isolated bacteria, respectively, and only 8% of networked metabolites were shared between these locations, implying a high degree of biogeographic influence upon secondary metabolite production. The resulting molecular network contained over 3500 parent ions with a mass range of m/z 149-2558 illustrating the wealth of metabolites produced. Furthermore, seven fermentation extracts showed bioactivity against epithelial colon adenocarcinoma cells, demonstrating the potential for the discovery of novel bioactive compounds from these understudied locations.

Using Molecular Networking for Microbial Secondary Metabolite Bioprospecting

PubMed Central

Purves, Kevin; Macintyre, Lynsey; Brennan, Debra; Hreggviðsson, Guðmundur Ó.; Kuttner, Eva; Ásgeirsdóttir, Margrét E.; Young, Louise C.; Green, David H.; Edrada-Ebel, Ruangelie; Duncan, Katherine R.

2016-01-01

The oceans represent an understudied resource for the isolation of bacteria with the potential to produce novel secondary metabolites. In particular, actinomyces are well known to produce chemically diverse metabolites with a wide range of biological activities. This study characterised spore-forming bacteria from both Scottish and Antarctic sediments to assess the influence of isolation location on secondary metabolite production. Due to the selective isolation method used, all 85 isolates belonged to the phyla Firmicutes and Actinobacteria, with the majority of isolates belonging to the genera Bacillus and Streptomyces. Based on morphology, thirty-eight isolates were chosen for chemical investigation. Molecular networking based on chemical profiles (HR-MS/MS) of fermentation extracts was used to compare complex metabolite extracts. The results revealed 40% and 42% of parent ions were produced by Antarctic and Scottish isolated bacteria, respectively, and only 8% of networked metabolites were shared between these locations, implying a high degree of biogeographic influence upon secondary metabolite production. The resulting molecular network contained over 3500 parent ions with a mass range of m/z 149–2558 illustrating the wealth of metabolites produced. Furthermore, seven fermentation extracts showed bioactivity against epithelial colon adenocarcinoma cells, demonstrating the potential for the discovery of novel bioactive compounds from these understudied locations. PMID:26761036

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, KSC employee Chris Moore repairs tile on the forward area of the orbiter Discovery. The vehicle has undergone Orbiter Major Modifications in the past year, which includes tile check and repair. The tiles are part of the Orbiter Thermal Protection System, thermal shields to protect against temperatures as high as 3,000° Fahrenheit, which are produced during descent for landing. Discovery is scheduled to fly on mission STS-121 to the International Space Station.

NASA Image and Video Library

2003-12-09

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, KSC employee Chris Moore repairs tile on the forward area of the orbiter Discovery. The vehicle has undergone Orbiter Major Modifications in the past year, which includes tile check and repair. The tiles are part of the Orbiter Thermal Protection System, thermal shields to protect against temperatures as high as 3,000° Fahrenheit, which are produced during descent for landing. Discovery is scheduled to fly on mission STS-121 to the International Space Station.

Synthetic biology of antimicrobial discovery

PubMed Central

Zakeri, Bijan; Lu, Timothy K.

2012-01-01

Antibiotic discovery has a storied history. From the discovery of penicillin by Sir Alexander Fleming to the relentless quest for antibiotics by Selman Waksman, the stories have become like folklore, used to inspire future generations of scientists. However, recent discovery pipelines have run dry at a time when multidrug resistant pathogens are on the rise. Nature has proven to be a valuable reservoir of antimicrobial agents, which are primarily produced by modularized biochemical pathways. Such modularization is well suited to remodeling by an interdisciplinary approach that spans science and engineering. Herein, we discuss the biological engineering of small molecules, peptides, and non-traditional antimicrobials and provide an overview of the growing applicability of synthetic biology to antimicrobials discovery. PMID:23654251

Synthetic biology of antimicrobial discovery.

PubMed

Zakeri, Bijan; Lu, Timothy K

2013-07-19

Antibiotic discovery has a storied history. From the discovery of penicillin by Sir Alexander Fleming to the relentless quest for antibiotics by Selman Waksman, the stories have become like folklore used to inspire future generations of scientists. However, recent discovery pipelines have run dry at a time when multidrug-resistant pathogens are on the rise. Nature has proven to be a valuable reservoir of antimicrobial agents, which are primarily produced by modularized biochemical pathways. Such modularization is well suited to remodeling by an interdisciplinary approach that spans science and engineering. Herein, we discuss the biological engineering of small molecules, peptides, and non-traditional antimicrobials and provide an overview of the growing applicability of synthetic biology to antimicrobials discovery.

Metabolomics-based chemotaxonomy of root endophytic fungi for natural products discovery.

PubMed

Maciá-Vicente, Jose G; Shi, Yan-Ni; Cheikh-Ali, Zakaria; Grün, Peter; Glynou, Kyriaki; Kia, Sevda Haghi; Piepenbring, Meike; Bode, Helge B

2018-03-01

Fungi are prolific producers of natural products routinely screened for biotechnological applications, and those living endophytically within plants attract particular attention because of their purported chemical diversity. However, the harnessing of their biosynthetic potential is hampered by a large and often cryptic phylogenetic and ecological diversity, coupled with a lack of large-scale natural products' dereplication studies. To guide efforts to discover new chemistries among root-endophytic fungi, we analyzed the natural products produced by 822 strains using an untargeted UPLC-ESI-MS/MS-based approach and linked the patterns of chemical features to fungal lineages. We detected 17 809 compounds of which 7951 were classified in 1992 molecular families, whereas the remaining were considered unique chemistries. Our approach allowed to annotate 1191 compounds with different degrees of accuracy, many of which had known fungal origins. Approximately 61% of the compounds were specific of a fungal order, and differences were observed across lineages in the diversity and characteristics of their chemistries. Chemical profiles also showed variable chemosystematic values across lineages, ranging from relative homogeneity to high heterogeneity among related fungi. Our results provide an extensive resource to dereplicate fungal natural products and may assist future discovery programs by providing a guide for the selection of target fungi. © 2018 Society for Applied Microbiology and John Wiley & Sons Ltd.

Fatal methane and cyanide poisoning as a result of handling industrial fish: a case report and review of the literature

PubMed Central

Cherian, M; Richmond, I

2000-01-01

The potential health hazards of handling industrial fish are well documented. Wet fish in storage consume oxygen and produce poisonous gases as they spoil. In addition to oxygen depletion, various noxious agents have been demonstrated in association with spoilage including carbon dioxide, sulphur dioxide, and ammonia. A fatal case of methane and cyanide poisoning among a group of deep sea trawler men is described. Subsequent independent investigation as a result of this case led to the discovery of cyanides as a further potential noxious agent. This is thus the first case in which cyanide poisoning has been recognised as a potentially fatal complication of handling spoiled fish. The previous literature is reviewed and the implications of the current case are discussed. Key Words: industrial fish • methane • cyanide PMID:11064677

Research & market strategy: how choice of drug discovery approach can affect market position.

PubMed

Sams-Dodd, Frank

2007-04-01

In principal, drug discovery approaches can be grouped into target- and function-based, with the respective aims of developing either a target-selective drug or a drug that produces a specific biological effect irrespective of its mode of action. Most analyses of drug discovery approaches focus on productivity, whereas the strategic implications of the choice of drug discovery approach on market position and ability to maintain market exclusivity are rarely considered. However, a comparison of approaches from the perspective of market position indicates that the functional approach is superior for the development of novel, innovative treatments.

Genetic Approach for the Fast Discovery of Phenazine Producing Bacteria

PubMed Central

Schneemann, Imke; Wiese, Jutta; Kunz, Anna Lena; Imhoff, Johannes F.

2011-01-01

A fast and efficient approach was established to identify bacteria possessing the potential to biosynthesize phenazines, which are of special interest regarding their antimicrobial activities. Sequences of phzE genes, which are part of the phenazine biosynthetic pathway, were used to design one universal primer system and to analyze the ability of bacteria to produce phenazine. Diverse bacteria from different marine habitats and belonging to six major phylogenetic lines were investigated. Bacteria exhibiting phzE gene fragments affiliated to Firmicutes, Alpha- and Gammaproteobacteria, and Actinobacteria. Thus, these are the first primers for amplifying gene fragments from Firmicutes and Alphaproteobacteria. The genetic potential for phenazine production was shown for four type strains belonging to the genera Streptomyces and Pseudomonas as well as for 13 environmental isolates from marine habitats. For the first time, the genetic ability of phenazine biosynthesis was verified by analyzing the metabolite pattern of all PCR-positive strains via HPLC-UV/MS. Phenazine production was demonstrated for the type strains known to produce endophenazines, 2-hydroxy-phenazine, phenazine-1-carboxylic acid, phenazine-1,6-dicarboxylic acid, and chlororaphin as well as for members of marine Actinobacteria. Interestingly, a number of unidentified phenazines possibly represent new phenazine structures. PMID:21673888

Oral challenges with four apple cultivars result in significant differences in oral allergy symptoms.

PubMed

Nybom, Hilde; Cervin-Hoberg, Charlotte; Andersson, Morgan

2013-01-01

We analyzed the hypoallergenic potential of a recently bred apple selection with unusually low content of Mal d 1, using an oral challenge model with three additional apple cultivars for comparison. Sixty-six birch pollen-allergic individuals with a history of oral allergy syndrome after apple intake were subjected to a double-blind oral provocation with two apple cultivars (B:0654 and 'Discovery'). Thirteen also tested two other apple cultivars ('Ingrid Marie' and 'Gloster'). Three doses were given consecutively, 30 min apart: 10 g without peel, and 10 and 50 g with peel. A final assessment was conducted 30 min after the last intake. Oral symptoms were graded from 0 to 5. Total oral symptom score (TOS) included all scores for each cultivar at all time points. B:0654 induced significantly higher TOS than 'Discovery' when tested by 66 individuals, in spite of its lower Mal d 1 content. TOS values were higher in females and increased with increasing age of the individuals when challenged with 'Discovery'. Among the 13 individuals who tested all four cultivars, B:0654 produced a higher score after the second dose compared to 'Ingrid Marie'. This was also the case after the third dose compared to 'Ingrid Marie' and 'Gloster', and again 30 min after the last intake compared to each of the other three cultivars, as well as a higher TOS compared to each of the other three cultivars (all p < 0.01). Our test was safe and well tolerated, and produced significant differences among the apple cultivars. Contrary to expectations, B:0654 was less well tolerated than the other three cultivars. Copyright © 2013 S. Karger AG, Basel.

Heartwood-specific transcriptome and metabolite signatures of tropical sandalwood (Santalum album) reveal the final step of (Z)-santalol fragrance biosynthesis.

PubMed

Celedon, Jose M; Chiang, Angela; Yuen, Macaire M S; Diaz-Chavez, Maria L; Madilao, Lufiani L; Finnegan, Patrick M; Barbour, Elizabeth L; Bohlmann, Jörg

2016-05-01

Tropical sandalwood (Santalum album) produces one of the world's most highly prized fragrances, which is extracted from mature heartwood. However, in some places such as southern India, natural populations of this slow-growing tree are threatened by over-exploitation. Sandalwood oil contains four major and fragrance-defining sesquiterpenols: (Z)-α-santalol, (Z)-β-santalol, (Z)-epi-β-santalol and (Z)-α-exo-bergamotol. The first committed step in their biosynthesis is catalyzed by a multi-product santalene/bergamotene synthase. Sandalwood cytochromes P450 of the CYP76F sub-family were recently shown to hydroxylate santalenes and bergamotene; however, these enzymes produced mostly (E)-santalols and (E)-α-exo-bergamotol. We hypothesized that different santalene/bergamotene hydroxylases evolved in S. album to stereo-selectively produce (E)- or (Z)-sesquiterpenols, and that genes encoding (Z)-specific P450s contribute to sandalwood oil formation if co-expressed in the heartwood with upstream genes of sesquiterpene biosynthesis. This hypothesis was validated by the discovery of a heartwood-specific transcriptome signature for sesquiterpenoid biosynthesis, including highly expressed SaCYP736A167 transcripts. We characterized SaCYP736A167 as a multi-substrate P450, which stereo-selectively produces (Z)-α-santalol, (Z)-β-santalol, (Z)-epi-β-santalol and (Z)-α-exo-bergamotol, matching authentic sandalwood oil. This work completes the discovery of the biosynthetic enzymes of key components of sandalwood fragrance, and highlights the evolutionary diversification of stereo-selective P450s in sesquiterpenoid biosynthesis. Bioengineering of microbial systems using SaCYP736A167, combined with santalene/bergamotene synthase, has potential for development of alternative industrial production systems for sandalwood oil fragrances. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

Diff-seq: A high throughput sequencing-based mismatch detection assay for DNA variant enrichment and discovery

PubMed Central

Karas, Vlad O; Sinnott-Armstrong, Nicholas A; Varghese, Vici; Shafer, Robert W; Greenleaf, William J; Sherlock, Gavin

2018-01-01

Abstract Much of the within species genetic variation is in the form of single nucleotide polymorphisms (SNPs), typically detected by whole genome sequencing (WGS) or microarray-based technologies. However, WGS produces mostly uninformative reads that perfectly match the reference, while microarrays require genome-specific reagents. We have developed Diff-seq, a sequencing-based mismatch detection assay for SNP discovery without the requirement for specialized nucleic-acid reagents. Diff-seq leverages the Surveyor endonuclease to cleave mismatched DNA molecules that are generated after cross-annealing of a complex pool of DNA fragments. Sequencing libraries enriched for Surveyor-cleaved molecules result in increased coverage at the variant sites. Diff-seq detected all mismatches present in an initial test substrate, with specific enrichment dependent on the identity and context of the variation. Application to viral sequences resulted in increased observation of variant alleles in a biologically relevant context. Diff-Seq has the potential to increase the sensitivity and efficiency of high-throughput sequencing in the detection of variation. PMID:29361139

Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies.

PubMed

Hu, Essa; Chen, Ning; Kunz, Roxanne K; Hwang, Dah-Ren; Michelsen, Klaus; Davis, Carl; Ma, Ji; Shi, Jianxia; Lester-Zeiner, Dianna; Hungate, Randall; Treanor, James; Chen, Hang; Allen, Jennifer R

2016-07-14

We report the discovery of PDE10A PET tracer AMG 580 developed to support proof of concept studies with PDE10A inhibitors in the clinic. To find a tracer with higher binding potential (BPND) in NHP than our previously reported tracer 1, we implemented a surface plasmon resonance assay to measure the binding off-rate to identify candidates with slower washout rate in vivo. Five candidates (2-6) from two structurally distinct scaffolds were identified that possessed both the in vitro characteristics that would favor central penetration and the structural features necessary for PET isotope radiolabeling. Two cinnolines (2, 3) and one keto-benzimidazole (5) exhibited PDE10A target specificity and brain uptake comparable to or better than 1 in the in vivo LC-MS/MS kinetics distribution study in SD rats. In NHP PET imaging study, [(18)F]-5 produced a significantly improved BPND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies.

Induced Pluripotent Stem Cells in Huntington's Disease Research: Progress and Opportunity.

PubMed

Tousley, Adelaide; Kegel-Gleason, Kimberly B

2016-06-28

Induced pluripotent stem cells (iPSCs) derived from controls and patients can act as a starting point for in vitro differentiation into human brain cells for discovery of novel targets and treatments for human disease without the same ethical limitations posed by embryonic stem cells. Numerous groups have successfully produced and characterized Huntington's disease (HD) iPSCs with different CAG repeat lengths, including cells from patients with one or two HD alleles. HD iPSCs and the neural cell types derived from them recapitulate some disease phenotypes found in both human patients and animal models. Although these discoveries are encouraging, the use of iPSCs for cutting edge and reproducible research has been limited due to some of the inherent problems with cell lines and the technological differences in the way laboratories use them. The goal of this review is to summarize the current state of the HD iPSC field, and to highlight some of the issues that need to be addressed to maximize their potential as research tools.

Targeting mammalian organelles with internalizing phage (iPhage) libraries

PubMed Central

Rangel, Roberto; Dobroff, Andrey S.; Guzman-Rojas, Liliana; Salmeron, Carolina C.; Gelovani, Juri G.; Sidman, Richard L.; Pasqualini, Renata; Arap, Wadih

2015-01-01

Techniques largely used for protein interaction studies and discovery of intracellular receptors, such as affinity capture complex purification and yeast two-hybrid, may produce inaccurate datasets due to protein insolubility, transient or weak protein interactions, or irrelevant intracellular context. A versatile tool to overcome these limitations as well as to potentially create vaccines and engineer peptides and antibodies as targeted diagnostic and therapeutic agents, is the phage display technique. We have recently developed a new technology for screening internalizing phage (iPhage) vectors and libraries utilizing a ligand/receptor-independent mechanism to penetrate eukaryotic cells. iPhage particles provide a unique discovery platform for combinatorial intracellular targeting of organelle ligands along with their corresponding receptors and to fingerprint functional protein domains in living cells. Here we explain the design, cloning, construction, and production of iPhage-based vectors and libraries, along with basic ligand-receptor identification and validation methodologies for organelle receptors. An iPhage library screening can be performed in ~8 weeks. PMID:24030441

Pharming Pharmacopoeia: Living Apothecaries from the Sea

NASA Astrophysics Data System (ADS)

Baden, D. G.

2012-12-01

The quest for, and development of, new drugs to treat extant and emerging diseases is an interdisciplinary effort, often requiring isolation of pro-drugs from new organisms, environments, and species followed by activity measurement. Exploitation of cultivated microalgae from marine sources has produced some of the most potent natural biological agents known, with specific receptor-mediated activities in pulmonary medicine, toxicology, cancer chemotherapy, the cardiovascular system, central and peripheral nervous system, and in dermatology. Our recent discovery that one class of marine-derived molecule promotes trans-membrane transport, a second that enhances mucus secretion, and a third which is an inhibitor of inflammation--- all isolated from the same organism, highlights the increasingly broad potential for innovative exploitation of natural products that occur in marine microalgae. Approaches that include interdisciplinary teams, permanent innovation, and disruptive technologies all will be described in the context of discoveries made in the treatment of cystic fibrosis, in the improvement of drug efficacy, and in the development of multiple for translational sciences in the ocean and health arenas.

Time, Lives, and Videotape: Operationalizing Discovery in Scenes of Literacy Sponsorship

ERIC Educational Resources Information Center

Halbritter, Bump; Lindquist, Julie

2012-01-01

We present an approach to operationalizing discovery in literacy research by describing a diagnostic, abductive methodology. This methodology treats products of videotaped interviews and participant-authored footage as narrative data produced in scenes of literacy sponsorship. In describing the operations of our diagnostic approach, we foreground…

"Ripples" in an Aluminum Pool?

ERIC Educational Resources Information Center

Rohr, James; Wang, Si-Yin; Nesterenko, Vitali F.

2018-01-01

Our motivation for this article is for students to realize that opportunities for discovery are all around them. Discoveries that can still puzzle present day researchers. Here we explore an observation by a middle school student concerning the production of what appears to be water-like "ripples" produced in aluminum foil when placed…

Use of plant roots for phytoremediation and molecular farming

PubMed Central

Gleba, Doloressa; Borisjuk, Nikolai V.; Borisjuk, Ludmyla G.; Kneer, Ralf; Poulev, Alexander; Skarzhinskaya, Marina; Dushenkov, Slavik; Logendra, Sithes; Gleba, Yuri Y.; Raskin, Ilya

1999-01-01

Alternative agriculture, which expands the uses of plants well beyond food and fiber, is beginning to change plant biology. Two plant-based biotechnologies were recently developed that take advantage of the ability of plant roots to absorb or secrete various substances. They are (i) phytoextraction, the use of plants to remove pollutants from the environment and (ii) rhizosecretion, a subset of molecular farming, designed to produce and secrete valuable natural products and recombinant proteins from roots. Here we discuss recent advances in these technologies and assess their potential in soil remediation, drug discovery, and molecular farming. PMID:10339526

Design of the ARES Mars Airplane and Mission Architecture

NASA Technical Reports Server (NTRS)

Braun, Robert D.; Wright, Henry S.; Croom, Mark A.; Levine, Joel S.; Spencer, David A.

2006-01-01

Significant technology advances have enabled planetary aircraft to be considered as viable science platforms. Such systems fill a unique planetary science measurement gap, that of regional-scale, near-surface observation, while providing a fresh perspective for potential discovery. Recent efforts have produced mature mission and flight system concepts, ready for flight project implementation. This paper summarizes the development of a Mars airplane mission architecture that balances science, implementation risk and cost. Airplane mission performance, flight system design and technology maturation are described. The design, analysis and testing completed demonstrates the readiness of this science platform for use in a Mars flight project.

Engineering Human Neural Tissue by 3D Bioprinting.

PubMed

Gu, Qi; Tomaskovic-Crook, Eva; Wallace, Gordon G; Crook, Jeremy M

2018-01-01

Bioprinting provides an opportunity to produce three-dimensional (3D) tissues for biomedical research and translational drug discovery, toxicology, and tissue replacement. Here we describe a method for fabricating human neural tissue by 3D printing human neural stem cells with a bioink, and subsequent gelation of the bioink for cell encapsulation, support, and differentiation to functional neurons and supporting neuroglia. The bioink uniquely comprises the polysaccharides alginate, water-soluble carboxymethyl-chitosan, and agarose. Importantly, the method could be adapted to fabricate neural and nonneural tissues from other cell types, with the potential to be applied for both research and clinical product development.

Gamma-butyrolactone and furan signaling systems in Streptomyces.

PubMed

Sidda, John D; Corre, Christophe

2012-01-01

Streptomyces bacteria produce different classes of diffusible signaling molecules that trigger secondary metabolite production and/or morphological development within the cell population. The biosynthesis of gamma-butyrolactones (GBLs) and 2-alkyl-4-hydroxymethylfuran-3-carboxylic acids (AHFCAs) signaling molecules is related and involves an essential AfsA-like butenolide synthase. This chapter first describes the catalytic role of AfsA-like enzyme then provides details about methods for the discovery and characterization of potentially novel signaling molecules. In section 4, one approach for establishing the biological role of these signaling molecules is presented. Copyright © 2012 Elsevier Inc. All rights reserved.

Probing New Physics with Jets at the LHC

ScienceCinema

Harris, Robert

2017-12-09

The Large Hadron Collider at CERN has the potential to make a major discovery as early as 2008 from simple measurements of events with two high energy jets. This talk will present the jet trigger and analysis plans of the CMS collaboration, which were produced at the LHC Physics Center at Fermilab. Plans to search the two jet channel for generic signals of new particles and forces will be discussed. I will present the anticipated sensitivity of the CMS experiment to a variety of models of new physics, including quark compositeness, technicolor, superstrings, extra dimensions and grand unification.

Chemical screening method for the rapid identification of microbial sources of marine invertebrate-associated metabolites.

PubMed

Berrue, Fabrice; Withers, Sydnor T; Haltli, Brad; Withers, Jo; Kerr, Russell G

2011-03-21

Marine invertebrates have proven to be a rich source of secondary metabolites. The growing recognition that marine microorganisms associated with invertebrate hosts are involved in the biosynthesis of secondary metabolites offers new alternatives for the discovery and development of marine natural products. However, the discovery of microorganisms producing secondary metabolites previously attributed to an invertebrate host poses a significant challenge. This study describes an efficient chemical screening method utilizing a 96-well plate-based bacterial cultivation strategy to identify and isolate microbial producers of marine invertebrate-associated metabolites.

Arrayed antibody library technology for therapeutic biologic discovery.

PubMed

Bentley, Cornelia A; Bazirgan, Omar A; Graziano, James J; Holmes, Evan M; Smider, Vaughn V

2013-03-15

Traditional immunization and display antibody discovery methods rely on competitive selection amongst a pool of antibodies to identify a lead. While this approach has led to many successful therapeutic antibodies, targets have been limited to proteins which are easily purified. In addition, selection driven discovery has produced a narrow range of antibody functionalities focused on high affinity antagonism. We review the current progress in developing arrayed protein libraries for screening-based, rather than selection-based, discovery. These single molecule per microtiter well libraries have been screened in multiplex formats against both purified antigens and directly against targets expressed on the cell surface. This facilitates the discovery of antibodies against therapeutically interesting targets (GPCRs, ion channels, and other multispanning membrane proteins) and epitopes that have been considered poorly accessible to conventional discovery methods. Copyright © 2013. Published by Elsevier Inc.

North Dakota`s Dickinson Lodgepole play - an update

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

LeFever, J.A.

1996-06-01

North Dakota`s Dickinson Lodgepole play began in February 1993 with the drilling and completion of Conoco`s No.74 Dickinson State well. The serendipitous discovery was found while drilling an in-field wildcat. Production is from a 294-ft-thick {open_quotes}Waulsortian-like{close_quotes} carbonate buildup in the Lodgepole Formation (Mississippian). Conoco estimated the ultimate recovery from this feature to be 7.86 million barrels of oil and 3.7 billion cubic feet of gas at the time of unitization. The field is currently under pressure maintenance by waterflood. The activity associated with the {open_quotes}mound{close_quotes} was primarily a land acquisition and a seismic play until the second quarter of 1995.more » Activity in the play accelerated with the discovery of Duncan - No.1-11 Knopik that tested 2707 BOPD from a new buildup (now Eland Field). This discovery not only increased interest but also increased the number of companies involved in the play. Currently, five fields are producing from carbonate buildups. Cumulative production through July, 1995 is 1.5 MBO, 835 MMCFG, and 15,990 BW. There is a high potential for this play to expand from the Dickinson area around the perimeter of the Williston Basin.« less

Current perspectives in drug discovery against tuberculosis from natural products.

PubMed

Nguta, Joseph Mwanzia; Appiah-Opong, Regina; Nyarko, Alexander K; Yeboah-Manu, Dorothy; Addo, Phyllis G A

2015-09-01

Currently, one third of the world's population is latently infected with Mycobacterium tuberculosis (MTB), while 8.9-9.9 million new and relapse cases of tuberculosis (TB) are reported yearly. The renewed research interests in natural products in the hope of discovering new and novel antitubercular leads have been driven partly by the increased incidence of multidrug-resistant strains of MTB and the adverse effects associated with the first- and second-line antitubercular drugs. Natural products have been, and will continue to be a rich source of new drugs against many diseases. The depth and breadth of therapeutic agents that have their origins in the secondary metabolites produced by living organisms cannot be compared with any other source of therapeutic agents. Discovery of new chemical molecules against active and latent TB from natural products requires an interdisciplinary approach, which is a major challenge facing scientists in this field. In order to overcome this challenge, cutting edge techniques in mycobacteriology and innovative natural product chemistry tools need to be developed and used in tandem. The present review provides a cross-linkage to the most recent literature in both fields and their potential to impact the early phase of drug discovery against TB if seamlessly combined. Copyright © 2015 Asian African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.

RHSEG and Subdue: Background and Preliminary Approach for Combining these Technologies for Enhanced Image Data Analysis, Mining and Knowledge Discovery

NASA Technical Reports Server (NTRS)

Tilton, James C.; Cook, Diane J.

2008-01-01

Under a project recently selected for funding by NASA's Science Mission Directorate under the Applied Information Systems Research (AISR) program, Tilton and Cook will design and implement the integration of the Subdue graph based knowledge discovery system, developed at the University of Texas Arlington and Washington State University, with image segmentation hierarchies produced by the RHSEG software, developed at NASA GSFC, and perform pilot demonstration studies of data analysis, mining and knowledge discovery on NASA data. Subdue represents a method for discovering substructures in structural databases. Subdue is devised for general-purpose automated discovery, concept learning, and hierarchical clustering, with or without domain knowledge. Subdue was developed by Cook and her colleague, Lawrence B. Holder. For Subdue to be effective in finding patterns in imagery data, the data must be abstracted up from the pixel domain. An appropriate abstraction of imagery data is a segmentation hierarchy: a set of several segmentations of the same image at different levels of detail in which the segmentations at coarser levels of detail can be produced from simple merges of regions at finer levels of detail. The RHSEG program, a recursive approximation to a Hierarchical Segmentation approach (HSEG), can produce segmentation hierarchies quickly and effectively for a wide variety of images. RHSEG and HSEG were developed at NASA GSFC by Tilton. In this presentation we provide background on the RHSEG and Subdue technologies and present a preliminary analysis on how RHSEG and Subdue may be combined to enhance image data analysis, mining and knowledge discovery.

Proposal and Evaluation of BLE Discovery Process Based on New Features of Bluetooth 5.0.

PubMed

Hernández-Solana, Ángela; Perez-Diaz-de-Cerio, David; Valdovinos, Antonio; Valenzuela, Jose Luis

2017-08-30

The device discovery process is one of the most crucial aspects in real deployments of sensor networks. Recently, several works have analyzed the topic of Bluetooth Low Energy (BLE) device discovery through analytical or simulation models limited to version 4.x. Non-connectable and non-scannable undirected advertising has been shown to be a reliable alternative for discovering a high number of devices in a relatively short time period. However, new features of Bluetooth 5.0 allow us to define a variant on the device discovery process, based on BLE scannable undirected advertising events, which results in higher discovering capacities and also lower power consumption. In order to characterize this new device discovery process, we experimentally model the real device behavior of BLE scannable undirected advertising events. Non-detection packet probability, discovery probability, and discovery latency for a varying number of devices and parameters are compared by simulations and experimental measurements. We demonstrate that our proposal outperforms previous works, diminishing the discovery time and increasing the potential user device density. A mathematical model is also developed in order to easily obtain a measure of the potential capacity in high density scenarios.

Proposal and Evaluation of BLE Discovery Process Based on New Features of Bluetooth 5.0

PubMed Central

2017-01-01

The device discovery process is one of the most crucial aspects in real deployments of sensor networks. Recently, several works have analyzed the topic of Bluetooth Low Energy (BLE) device discovery through analytical or simulation models limited to version 4.x. Non-connectable and non-scannable undirected advertising has been shown to be a reliable alternative for discovering a high number of devices in a relatively short time period. However, new features of Bluetooth 5.0 allow us to define a variant on the device discovery process, based on BLE scannable undirected advertising events, which results in higher discovering capacities and also lower power consumption. In order to characterize this new device discovery process, we experimentally model the real device behavior of BLE scannable undirected advertising events. Non-detection packet probability, discovery probability, and discovery latency for a varying number of devices and parameters are compared by simulations and experimental measurements. We demonstrate that our proposal outperforms previous works, diminishing the discovery time and increasing the potential user device density. A mathematical model is also developed in order to easily obtain a measure of the potential capacity in high density scenarios. PMID:28867786

Simultaneous Proteomic Discovery and Targeted Monitoring using Liquid Chromatography, Ion Mobility Spectrometry, and Mass Spectrometry*

PubMed Central

Burnum-Johnson, Kristin E.; Nie, Song; Casey, Cameron P.; Monroe, Matthew E.; Orton, Daniel J.; Ibrahim, Yehia M.; Gritsenko, Marina A.; Clauss, Therese R. W.; Shukla, Anil K.; Moore, Ronald J.; Purvine, Samuel O.; Shi, Tujin; Qian, Weijun; Liu, Tao; Baker, Erin S.; Smith, Richard D.

2016-01-01

Current proteomic approaches include both broad discovery measurements and quantitative targeted analyses. In many cases, discovery measurements are initially used to identify potentially important proteins (e.g. candidate biomarkers) and then targeted studies are employed to quantify a limited number of selected proteins. Both approaches, however, suffer from limitations. Discovery measurements aim to sample the whole proteome but have lower sensitivity, accuracy, and quantitation precision than targeted approaches, whereas targeted measurements are significantly more sensitive but only sample a limited portion of the proteome. Herein, we describe a new approach that performs both discovery and targeted monitoring (DTM) in a single analysis by combining liquid chromatography, ion mobility spectrometry and mass spectrometry (LC-IMS-MS). In DTM, heavy labeled target peptides are spiked into tryptic digests and both the labeled and unlabeled peptides are detected using LC-IMS-MS instrumentation. Compared with the broad LC-MS discovery measurements, DTM yields greater peptide/protein coverage and detects lower abundance species. DTM also achieved detection limits similar to selected reaction monitoring (SRM) indicating its potential for combined high quality discovery and targeted analyses, which is a significant step toward the convergence of discovery and targeted approaches. PMID:27670688

Mineral resource potential map of the Savannah Roadless Area, Liberty County, Florida

USGS Publications Warehouse

Patterson, Sam H.; Schmidt, Walter; Crandall, Thomas M.

1982-01-01

The Savannah Roadless Area is underlain by sedimentary rocks having low potential for oil and gas and minerals. The low potential for oil or gas notwithstanding, the possibilities for discovery cannot be ruled out because the area and nearby lands have not been thoroughly explored. No minerals have been mined within the Savannah Roadless Area, and the only production nearby has been the digging of clayey sand used in stabilizing U.S. Forest Service roads. Fuller's earth, quartz sand and gravel, clayey sand, and common clay presently are produced elsewhere in the region, and limestone and peat have been produced in the past. No clay suitable for structural clay products or fuller's earth is present in the roadless area; however, a bed of quartz sand and gravel of excellent quality was penetrated at a depth interval of 37-50 ft by one drill hole. Although this bed is coarser grained-and therefore is more suitable for many uses-than the sand deposits worked elsewhere in the Big Bend region, its mineral resource potential is reduced by the thickness of overburden above it and by its distance from markets in population centers. The Apalachicola National Forest has been explored for phosphate and reconnoitered for heavy minerals, but no valuable deposits of either have been found.

42 CFR 426.417 - Contractor's statement regarding new evidence.

Code of Federal Regulations, 2010 CFR

2010-10-01

... evidence submitted with an amended complaint; (3) New evidence produced during discovery; (4) New evidence produced when the ALJ consults with scientific and clinical experts; and (5) New evidence presented during...

42 CFR 426.417 - Contractor's statement regarding new evidence.

Code of Federal Regulations, 2012 CFR

2012-10-01

... complaint; (2) New evidence submitted with an amended complaint; (3) New evidence produced during discovery; (4) New evidence produced when the ALJ consults with scientific and clinical experts; and (5) New...

42 CFR 426.417 - Contractor's statement regarding new evidence.

Code of Federal Regulations, 2013 CFR

2013-10-01

... complaint; (2) New evidence submitted with an amended complaint; (3) New evidence produced during discovery; (4) New evidence produced when the ALJ consults with scientific and clinical experts; and (5) New...

42 CFR 426.417 - Contractor's statement regarding new evidence.

Code of Federal Regulations, 2014 CFR

2014-10-01

... complaint; (2) New evidence submitted with an amended complaint; (3) New evidence produced during discovery; (4) New evidence produced when the ALJ consults with scientific and clinical experts; and (5) New...

42 CFR 426.417 - Contractor's statement regarding new evidence.

Code of Federal Regulations, 2011 CFR

2011-10-01

... evidence submitted with an amended complaint; (3) New evidence produced during discovery; (4) New evidence produced when the ALJ consults with scientific and clinical experts; and (5) New evidence presented during...

Discovery of mosquito attractants and attraction-inhibitors invited talk on attractants and repellents

USDA-ARS?s Scientific Manuscript database

The United States Department of Agriculture (USDA) has developed repellents and insecticides for the U.S. military since 1942. A small component of this research program has aimed at the discovery of attractants that can be used to produce potent lures for haematophagous arthropods, with a primary f...

Endocannabinoid signaling in neurotoxicity and neuroprotection.

PubMed

Pope, C; Mechoulam, R; Parsons, L

2010-09-01

The cannabis plant and products produced from it, such as marijuana and hashish, have been used for centuries for their psychoactive properties. The mechanism for how Delta(9)-tetrahydrocannabinol (THC), the active constituent of cannabis, elicits these neurological effects remained elusive until relatively recently, when specific G-protein coupled receptors were discovered that appeared to mediate cellular actions of THC. Shortly after discovery of these specific receptors, endogenous ligands (endocannabinoids) were identified. Since that time, an extensive number of papers have been published on the endocannabinoid signaling system, a widespread neuromodulatory mechanism that influences neurotransmission throughout the nervous system. This paper summarizes presentations given at the 12th International Neurotoxicology Association meeting that described the potential role of endocannabinoids in the expression of neurotoxicity. Dr. Raphael Mechoulam first gave an overview of the discovery of exogenous and endogenous cannabinoids and their potential for neuroprotection in a variety of conditions. Dr. Larry Parsons then described studies suggesting that endocannabinoid signaling may play a selective role in drug reinforcement. Dr. Carey Pope presented information on the role that endocannabinoid signaling may have in the expression of cholinergic toxicity following anticholinesterase exposures. Together, these presentations highlighted the diverse types of neurological insults that may be modulated by endocannabinoids and drugs/toxicants which might influence endocannabinoid signaling pathways. Copyright © 2009 Elsevier Inc. All rights reserved.

ENDOCANNABINOID SIGNALING IN NEUROTOXICITY AND NEUROPROTECTION

PubMed Central

Pope, C.; Mechoulam, R.; Parsons, L.

2010-01-01

The cannabis plant and products produced from it, such as marijuana and hashish, have been used for centuries for their psychoactive properties. The mechanism for how Δ9 -tetrahydrocannabinol (THC), the active constituent of cannabis, elicits these neurological effects remained elusive until relatively recently, when specific G-protein coupled receptors were discovered that appeared to mediate cellular actions of THC. Shortly after discovery of these specific receptors, endogenous ligands (endocannabinoids) were identified. Since that time, an extensive number of papers have been published on the endocannabinoid signaling system, a widespread neuromodulatory mechanism that influences neurotransmission throughout the nervous system. This paper summarizes presentations given at the 12th International Neurotoxicology Association meeting that described the potential role of endocannabinoids in the expression of neurotoxicity. Dr. Raphael Mechoulam first gave an overview of the discovery of exogenous and endogenous cannabinoids and their potential for neuroprotection in a variety of conditions. Dr. Larry Parsons then described studies suggesting that endocannabinoid signaling may play a selective role in drug reinforcement. Dr. Carey Pope presented information on the role that endocannabinoid signaling may have in the expression of cholinergic toxicity following anticholinesterase exposures. Together, these presentations highlighted the diverse types of neurological insults that may be modulated by endocannabinoids and drugs/toxicants which might influence endocannabinoid signaling pathways. PMID:19969019

Atmospheric neutrinos and discovery of neutrino oscillations

PubMed Central

Kajita, Takaaki

2010-01-01

Neutrino oscillation was discovered through studies of neutrinos produced by cosmic-ray interactions in the atmosphere. These neutrinos are called atmospheric neutrinos. They are produced as decay products in hadronic showers resulting from collisions of cosmic rays with nuclei in the atmosphere. Electron-neutrinos and muon-neutrinos are produced mainly by the decay chain of charged pions to muons to electrons. Atmospheric neutrino experiments observed zenith-angle and energy dependent deficit of muon-neutrino events. Neutrino oscillations between muon-neutrinos and tau-neutrinos explain these data well. Neutrino oscillations imply that neutrinos have small but non-zero masses. The small neutrino masses have profound implications to our understanding of elementary particle physics and the Universe. This article discusses the experimental discovery of neutrino oscillations. PMID:20431258

Efficient differentiation of mouse embryonic stem cells into insulin-producing cells.

PubMed

Liu, Szu-Hsiu; Lee, Lain-Tze

2012-01-01

Embryonic stem (ES) cells are a potential source of a variety of differentiated cells for cell therapy, drug discovery, and toxicology screening. Here, we present an efficacy strategy for the differentiation of mouse ES cells into insulin-producing cells (IPCs) by a two-step differentiation protocol comprising of (i) the formation of definitive endoderm in monolayer culture by activin A, and (ii) this monolayer endoderm being induced to differentiate into IPCs by nicotinamide, insulin, and laminin. Differentiated cells can be obtained within approximately 7 days. The differentiation IPCs combined application of RT-PCR, ELISA, and immunofluorescence to characterize phenotypic and functional properties. In our study, we demonstrated that IPCs produced pancreatic transcription factors, endocrine progenitor marker, definitive endoderm, pancreatic β-cell markers, and Langerhans α and δ cells. The IPCs released insulin in a manner that was dose dependent upon the amount of glucose added. These techniques may be able to be applied to human ES cells, which would have very important ramifications for treating human disease.

The Impact of Students' Exploration Strategies on Discovery Learning Using Computer-Based Simulations

ERIC Educational Resources Information Center

Dalgarno, Barney; Kennedy, Gregor; Bennett, Sue

2014-01-01

Discovery-based learning designs incorporating active exploration are common within instructional software. However, researchers have highlighted empirical evidence showing that "pure" discovery learning is of limited value and strategies which reduce complexity and provide guidance to learners are important if potential learning…

Knowledge Discovery from Databases: An Introductory Review.

ERIC Educational Resources Information Center

Vickery, Brian

1997-01-01

Introduces new procedures being used to extract knowledge from databases and discusses rationales for developing knowledge discovery methods. Methods are described for such techniques as classification, clustering, and the detection of deviations from pre-established norms. Examines potential uses of knowledge discovery in the information field.…

Surfactants tailored by the class Actinobacteria

PubMed Central

Kügler, Johannes H.; Le Roes-Hill, Marilize; Syldatk, Christoph; Hausmann, Rudolf

2015-01-01

Globally the change towards the establishment of a bio-based economy has resulted in an increased need for bio-based applications. This, in turn, has served as a driving force for the discovery and application of novel biosurfactants. The class Actinobacteria represents a vast group of microorganisms with the ability to produce a diverse range of secondary metabolites, including surfactants. Understanding the extensive nature of the biosurfactants produced by actinobacterial strains can assist in finding novel biosurfactants with new potential applications. This review therefore presents a comprehensive overview of the knowledge available on actinobacterial surfactants, the chemical structures that have been completely or partly elucidated, as well as the identity of the biosurfactant-producing strains. Producer strains of not yet elucidated compounds are discussed, as well as the original habitats of all the producer strains, which seems to indicate that biosurfactant production is environmentally driven. Methodology applied in the isolation, purification and structural elucidation of the different types of surface active compounds, as well as surfactant activity tests, are also discussed. Overall, actinobacterial surfactants can be summarized to include the dominantly occurring trehalose-comprising surfactants, other non-trehalose containing glycolipids, lipopeptides and the more rare actinobacterial surfactants. The lack of structural information on a large proportion of actinobacterial surfactants should be considered as a driving force to further explore the abundance and diversity of these compounds. This would allow for a better understanding of actinobacterial surface active compounds and their potential for biotechnological application. PMID:25852670

Mitigating risk in academic preclinical drug discovery.

PubMed

Dahlin, Jayme L; Inglese, James; Walters, Michael A

2015-04-01

The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology.

Discovery of novel drugs for promising targets.

PubMed

Martell, Robert E; Brooks, David G; Wang, Yan; Wilcoxen, Keith

2013-09-01

Once a promising drug target is identified, the steps to actually discover and optimize a drug are diverse and challenging. The goal of this study was to provide a road map to navigate drug discovery. Review general steps for drug discovery and provide illustrating references. A number of approaches are available to enhance and accelerate target identification and validation. Consideration of a variety of potential mechanisms of action of potential drugs can guide discovery efforts. The hit to lead stage may involve techniques such as high-throughput screening, fragment-based screening, and structure-based design, with informatics playing an ever-increasing role. Biologically relevant screening models are discussed, including cell lines, 3-dimensional culture, and in vivo screening. The process of enabling human studies for an investigational drug is also discussed. Drug discovery is a complex process that has significantly evolved in recent years. © 2013 Elsevier HS Journals, Inc. All rights reserved.

Discovery of a widely distributed toxin biosynthetic gene cluster

PubMed Central

Lee, Shaun W.; Mitchell, Douglas A.; Markley, Andrew L.; Hensler, Mary E.; Gonzalez, David; Wohlrab, Aaron; Dorrestein, Pieter C.; Nizet, Victor; Dixon, Jack E.

2008-01-01

Bacteriocins represent a large family of ribosomally produced peptide antibiotics. Here we describe the discovery of a widely conserved biosynthetic gene cluster for the synthesis of thiazole and oxazole heterocycles on ribosomally produced peptides. These clusters encode a toxin precursor and all necessary proteins for toxin maturation and export. Using the toxin precursor peptide and heterocycle-forming synthetase proteins from the human pathogen Streptococcus pyogenes, we demonstrate the in vitro reconstitution of streptolysin S activity. We provide evidence that the synthetase enzymes, as predicted from our bioinformatics analysis, introduce heterocycles onto precursor peptides, thereby providing molecular insight into the chemical structure of streptolysin S. Furthermore, our studies reveal that the synthetase exhibits relaxed substrate specificity and modifies toxin precursors from both related and distant species. Given our findings, it is likely that the discovery of similar peptidic toxins will rapidly expand to existing and emerging genomes. PMID:18375757

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

Bogomilov, M.; Matev, R.; Tsenov, R.

The properties of the neutrino provide a unique window on physics beyond that described by the standard model. The study of subleading effects in neutrino oscillations, and the race to discover CP-invariance violation in the lepton sector, has begun with the recent discovery that theta(13) > 0. The measured value of theta(13) is large, emphasizing the need for a facility at which the systematic uncertainties can be reduced to the percent level. The neutrino factory, in which intense neutrino beams are produced from the decay of muons, has been shown to outperform all realistic alternatives and to be capable ofmore » making measurements of the requisite precision. Its unique discovery potential arises from the fact that only at the neutrino factory is it practical to produce high-energy electron (anti) neutrino beams of the required intensity. This paper presents the conceptual design of the neutrino factory accelerator facility developed by the European Commission Framework Programme 7 EURO nu. Design Study consortium. EURO nu coordinated the European contributions to the International Design Study for the Neutrino Factory (the IDS-NF) collaboration. The EURO nu baseline accelerator facility will provide 10(21) muon decays per year from 12.6 GeV stored muon beams serving a single neutrino detector situated at a source-detector distance of between 1 500 km and 2 500 km. A suite of near detectors will allow definitive neutrino-scattering experiments to be performed.« less

Neutrino factory

DOE PAGES

Bogomilov, M.; Matev, R.; Tsenov, R.; ...

2014-12-08

The properties of the neutrino provide a unique window on physics beyond that described by the standard model. The study of subleading effects in neutrino oscillations, and the race to discover CP-invariance violation in the lepton sector, has begun with the recent discovery that theta(13) > 0. The measured value of theta(13) is large, emphasizing the need for a facility at which the systematic uncertainties can be reduced to the percent level. The neutrino factory, in which intense neutrino beams are produced from the decay of muons, has been shown to outperform all realistic alternatives and to be capable ofmore » making measurements of the requisite precision. Its unique discovery potential arises from the fact that only at the neutrino factory is it practical to produce high-energy electron (anti) neutrino beams of the required intensity. This paper presents the conceptual design of the neutrino factory accelerator facility developed by the European Commission Framework Programme 7 EURO nu. Design Study consortium. EURO nu coordinated the European contributions to the International Design Study for the Neutrino Factory (the IDS-NF) collaboration. The EURO nu baseline accelerator facility will provide 10(21) muon decays per year from 12.6 GeV stored muon beams serving a single neutrino detector situated at a source-detector distance of between 1 500 km and 2 500 km. A suite of near detectors will allow definitive neutrino-scattering experiments to be performed.« less

Simultaneous Proteomic Discovery and Targeted Monitoring using Liquid Chromatography, Ion Mobility Spectrometry, and Mass Spectrometry.

PubMed

Burnum-Johnson, Kristin E; Nie, Song; Casey, Cameron P; Monroe, Matthew E; Orton, Daniel J; Ibrahim, Yehia M; Gritsenko, Marina A; Clauss, Therese R W; Shukla, Anil K; Moore, Ronald J; Purvine, Samuel O; Shi, Tujin; Qian, Weijun; Liu, Tao; Baker, Erin S; Smith, Richard D

2016-12-01

Current proteomic approaches include both broad discovery measurements and quantitative targeted analyses. In many cases, discovery measurements are initially used to identify potentially important proteins (e.g. candidate biomarkers) and then targeted studies are employed to quantify a limited number of selected proteins. Both approaches, however, suffer from limitations. Discovery measurements aim to sample the whole proteome but have lower sensitivity, accuracy, and quantitation precision than targeted approaches, whereas targeted measurements are significantly more sensitive but only sample a limited portion of the proteome. Herein, we describe a new approach that performs both discovery and targeted monitoring (DTM) in a single analysis by combining liquid chromatography, ion mobility spectrometry and mass spectrometry (LC-IMS-MS). In DTM, heavy labeled target peptides are spiked into tryptic digests and both the labeled and unlabeled peptides are detected using LC-IMS-MS instrumentation. Compared with the broad LC-MS discovery measurements, DTM yields greater peptide/protein coverage and detects lower abundance species. DTM also achieved detection limits similar to selected reaction monitoring (SRM) indicating its potential for combined high quality discovery and targeted analyses, which is a significant step toward the convergence of discovery and targeted approaches. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Bacterial symbionts and natural products

PubMed Central

Crawford, Jason M.; Clardy, Jon

2011-01-01

The study of bacterial symbionts of eukaryotic hosts has become a powerful discovery engine for chemistry. This highlight looks at four case studies that exemplify the range of chemistry and biology involved in these symbioses: a bacterial symbiont of a fungus and a marine invertebrate that produce compounds with significant anticancer activity, and bacterial symbionts of insects and nematodes that produce compounds that regulate multilateral symbioses. In the last ten years, a series of shocking revelations – the molecular equivalents of a reality TV show’s uncovering the true parents of a well known individual or a deeply hidden family secret – altered the study of genetically encoded small molecules, natural products for short. These revelations all involved natural products produced by bacterial symbionts, and while details differed, two main plot lines emerged: parentage, in which the real producers of well known natural products with medical potential were not the organisms from which they were originally discovered, and hidden relationships, in which bacterially produced small molecules turned out to be the unsuspected regulators of complex interactions. For chemists, these studies led to new molecules, new biosynthetic pathways, and an understanding of the biological functions these molecules fulfill. PMID:21594283

Evaluation of solar electric propulsion technologies for discovery class missions

NASA Technical Reports Server (NTRS)

Oh, David Y.

2005-01-01

A detailed study examines the potential benefits that advanced electric propulsion (EP) technologies offer to the cost-capped missions in NASA's Discovery program. The study looks at potential cost and performance benefits provided by three EP technologies that are currently in development: NASA's Evolutionary Xenon Thruster (NEXT), an Enhanced NSTAR system, and a Low Power Hall effect thruster. These systems are analyzed on three straw man Discovery class missions and their performance is compared to a state of the art system using the NSTAR ion thruster. An electric propulsion subsystem cost model is used to conduct a cost-benefit analysis for each option. The results show that each proposed technology offers a different degree of performance and/or cost benefit for Discovery class missions.

Potential for pharmacological manipulation of human embryonic stem cells

PubMed Central

Atkinson, Stuart P; Lako, Majlinda; Armstrong, Lyle

2013-01-01

The therapeutic potential of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) is vast, allowing disease modelling, drug discovery and testing and perhaps most importantly regenerative therapies. However, problems abound; techniques for cultivating self-renewing hESCs tend to give a heterogeneous population of self-renewing and partially differentiated cells and general include animal-derived products that can be cost-prohibitive for large-scale production, and effective lineage-specific differentiation protocols also still remain relatively undefined and are inefficient at producing large amounts of cells for therapeutic use. Furthermore, the mechanisms and signalling pathways that mediate pluripotency and differentiation are still to be fully appreciated. However, over the recent years, the development/discovery of a range of effective small molecule inhibitors/activators has had a huge impact in hESC biology. Large-scale screening techniques, coupled with greater knowledge of the pathways involved, have generated pharmacological agents that can boost hESC pluripotency/self-renewal and survival and has greatly increased the efficiency of various differentiation protocols, while also aiding the delineation of several important signalling pathways. Within this review, we hope to describe the current uses of small molecule inhibitors/activators in hESC biology and their potential uses in the future. LINKED ARTICLES This article is part of a themed section on Regenerative Medicine and Pharmacology: A Look to the Future. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-2 PMID:22515554

In Vitro Toxicity Screening Technique for Volatile Substances ...

EPA Pesticide Factsheets

In 2007 the National Research Council envisioned the need for inexpensive, high throughput, cell based toxicity testing methods relevant to human health. High Throughput Screening (HTS) in vitro screening approaches have addressed these problems by using robotics. However the challenge is that many of these chemicals are volatile and not amenable to HTS robotic liquid handling applications. We assembled an in vitro cell culture apparatus capable of screening volatile chemicals for toxicity with potential for miniaturization for high throughput. BEAS-2B lung cells were grown in an enclosed culture apparatus under air-liquid interface (ALI) conditions, and exposed to an array of xenobiotics in 5% CO2. Use of ALI conditions allows direct contact of cells with a gas xenobiotic, as well as release of endogenous gaseous molecules without interference by medium on the apical surface. To identify potential xenobiotic-induced perturbations in cell homeostasis, we monitored for alterations of endogenously-produced gaseous molecules in air directly above the cells, termed “headspace”. Alterations in specific endogenously-produced gaseous molecules (e.g., signaling molecules nitric oxide (NO) and carbon monoxide (CO) in headspace is indicative of xenobiotic-induced perturbations of specific cellular processes. Additionally, endogenously produced volatile organic compounds (VOCs) may be monitored in a nonspecific, discovery manner to determine whether cell processes are

Mitigating risk in academic preclinical drug discovery

PubMed Central

Dahlin, Jayme L.; Inglese, James; Walters, Michael A.

2018-01-01

The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology. PMID:25829283

Central ridge of Newfoundland: Little explored, potential large

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

Silva, N.R. De

The Central ridge on the northeastern Grand Banks off Newfoundland represents a large area with known hydrocarbon accumulations and the potential for giant fields. It covers some 17,000 sq km with water less than 400 m deep. The first major hydrocarbon discovery on the Newfoundland Grand Banks is giant Hibernia field in the Jeanne d'Arc basin. Hibernia field, discovered in 1979, has reserves of 666 million bbl and is due onstream in 1997. Since Hibernia, 14 other discoveries have been made on the Grand Banks, with three on the Central ridge. Oil was first discovered on Central Ridge in 1980more » with the Mobil et al. South Tempest G-88 well. In 1982 gas was discovered with the Mobil et al. North Dana I-43 well 30 km northeast of the earlier discovery. In 1983 gas and condensate were discovered with the Husky-Bow Valley et al. Trave E-87 well 20 km south of the South Tempest well. These discoveries are held under significant discovery licenses and an additional 2,400 sq km are held under exploration licenses. The paper discusses the history of the basin, the reservoir source traps, and the basin potential.« less

30 CFR 285.802 - What must I do if I discover a potential archaeological resource while conducting my approved...

Code of Federal Regulations, 2010 CFR

2010-07-01

... seafloor-disturbing activities within the area of the discovery; (2) Notify MMS of the discovery within 72 hours; and (3) Keep the location of the discovery confidential and not take any action that may... for carrying out preservation responsibilities under the OCS Lands Act. ...

Recent advances in inkjet dispensing technologies: applications in drug discovery.

PubMed

Zhu, Xiangcheng; Zheng, Qiang; Yang, Hu; Cai, Jin; Huang, Lei; Duan, Yanwen; Xu, Zhinan; Cen, Peilin

2012-09-01

Inkjet dispensing technology is a promising fabrication methodology widely applied in drug discovery. The automated programmable characteristics and high-throughput efficiency makes this approach potentially very useful in miniaturizing the design patterns for assays and drug screening. Various custom-made inkjet dispensing systems as well as specialized bio-ink and substrates have been developed and applied to fulfill the increasing demands of basic drug discovery studies. The incorporation of other modern technologies has further exploited the potential of inkjet dispensing technology in drug discovery and development. This paper reviews and discusses the recent developments and practical applications of inkjet dispensing technology in several areas of drug discovery and development including fundamental assays of cells and proteins, microarrays, biosensors, tissue engineering, basic biological and pharmaceutical studies. Progression in a number of areas of research including biomaterials, inkjet mechanical systems and modern analytical techniques as well as the exploration and accumulation of profound biological knowledge has enabled different inkjet dispensing technologies to be developed and adapted for high-throughput pattern fabrication and miniaturization. This in turn presents a great opportunity to propel inkjet dispensing technology into drug discovery.

Biosurfactants, bioemulsifiers and exopolysaccharides from marine microorganisms.

PubMed

Satpute, Surekha K; Banat, Ibrahim M; Dhakephalkar, Prashant K; Banpurkar, Arun G; Chopade, Balu A

2010-01-01

Marine biosphere offers wealthy flora and fauna, which represents a vast natural resource of imperative functional commercial grade products. Among the various bioactive compounds, biosurfactant (BS)/bioemulsifiers (BE) are attracting major interest and attention due to their structural and functional diversity. The versatile properties of surface active molecules find numerous applications in various industries. Marine microorganisms such as Acinetobacter, Arthrobacter, Pseudomonas, Halomonas, Myroides, Corynebacteria, Bacillus, Alteromonas sp. have been studied for production of BS/BE and exopolysaccharides (EPS). Due to the enormity of marine biosphere, most of the marine microbial world remains unexplored. The discovery of potent BS/BE producing marine microorganism would enhance the use of environmental biodegradable surface active molecule and hopefully reduce total dependence or number of new application oriented towards the chemical synthetic surfactant industry. Our present review gives comprehensive information on BS/BE which has been reported to be produced by marine microorganisms and their possible potential future applications.

Antibiotics and specialized metabolites from the human microbiota.

PubMed

Mousa, Walaa K; Athar, Bilal; Merwin, Nishanth J; Magarvey, Nathan A

2017-11-15

Covering: 2000 to 2017Decades of research on human microbiota have revealed much of their taxonomic diversity and established their direct link to health and disease. However, the breadth of bioactive natural products secreted by our microbial partners remains unknown. Of particular interest are antibiotics produced by our microbiota to ward off invasive pathogens. Members of the human microbiota exclusively produce evolved small molecules with selective antimicrobial activity against human pathogens. Herein, we expand upon the current knowledge concerning antibiotics derived from human microbiota and their distribution across body sites. We analyze, using our in-house chem-bioinformatic tools and natural products database, the encoded antibiotic potential of the human microbiome. This compilation of information may create a foundation for the continued exploration of this intriguing resource of chemical diversity and expose challenges and future perspectives to accelerate the discovery rate of small molecules from the human microbiota.

Review of high-throughput techniques for detecting solid phase Transformation from material libraries produced by combinatorial methods

NASA Technical Reports Server (NTRS)

Lee, Jonathan A.

2005-01-01

High-throughput measurement techniques are reviewed for solid phase transformation from materials produced by combinatorial methods, which are highly efficient concepts to fabricate large variety of material libraries with different compositional gradients on a single wafer. Combinatorial methods hold high potential for reducing the time and costs associated with the development of new materials, as compared to time-consuming and labor-intensive conventional methods that test large batches of material, one- composition at a time. These high-throughput techniques can be automated to rapidly capture and analyze data, using the entire material library on a single wafer, thereby accelerating the pace of materials discovery and knowledge generation for solid phase transformations. The review covers experimental techniques that are applicable to inorganic materials such as shape memory alloys, graded materials, metal hydrides, ferric materials, semiconductors and industrial alloys.

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

Xu, Jingke; Stanford, Chris; Westerdale, Shawn

Here, one major background in direct searches for weakly interacting massive particles (WIMPs) comes from the deposition of radon progeny on detector surfaces. A dangerous surface background is the 206Pb nuclear recoils produced by 210Po decays. In this paper, we report the first characterization of this background in liquid argon. The scintillation signal of low energy Pb recoils is measured to be highly quenched in argon, and we estimate that the 103 keV 206Pb recoil background will produce a signal equal to that of a ~5 keV (30 keV) electron recoil ( 40Ar recoil). In addition, we demonstrate that thismore » dangerous 210Po surface background can be suppressed, using pulse shape discrimination methods, by a factor of ~100 or higher, which can make argon dark matter detectors near background-free and enhance their potential for discovery of medium- and high-mass WIMPs. Lastly, we also discuss the impact on other low background experiments.« less

Behind the Scenes of the Discovery Channel's Rosetta Mission Documentary Special

NASA Astrophysics Data System (ADS)

Ayres, S.

2016-03-01

On the evening of 12 November 2014, the Discovery Channel documentary Landing on a Comet: Rosetta Mission was broadcast around the world. This was the culmination of months of preparation and behind-the-scenes lming. Shelley Ayres, the producer, director and writer of the one-hour special recounts how this came about and re ects on her experience.

Closing the Loop: Automated Data-Driven Cognitive Model Discoveries Lead to Improved Instruction and Learning Gains

ERIC Educational Resources Information Center

Liu, Ran; Koedinger, Kenneth R.

2017-01-01

As the use of educational technology becomes more ubiquitous, an enormous amount of learning process data is being produced. Educational data mining seeks to analyze and model these data, with the ultimate goal of improving learning outcomes. The most firmly grounded and rigorous evaluation of an educational data mining discovery is whether it…

Skin Stem Cells: At the Frontier Between the Laboratory and Clinical Practice. Part 1: Epidermal Stem Cells.

PubMed

Pastushenko, I; Prieto-Torres, L; Gilaberte, Y; Blanpain, C

2015-11-01

Stem cells are characterized by their ability to self-renew and differentiate into the different cell lineages of their tissue of origin. The discovery of stem cells in adult tissues, together with the description of specific markers for their isolation, has opened up new lines of investigation, expanding the horizons of biomedical research and raising new hope in the treatment of many diseases. In this article, we review in detail the main characteristics of the stem cells that produce the specialized cells of the skin (epidermal, mesenchymal, and melanocyte stem cells) and their potential implications and applications in diseases affecting the skin. Part I deals with the principal characteristics and potential applications of epidermal stem cells in dermatology. Copyright © 2015 Elsevier España, S.L.U. and AEDV. All rights reserved.

Systematic in J-PARC/Hyper-K

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

Minamino, Akihiro

The Hyper-Kamiokande (Hyper-K) detector is a next generation underground water Chrenkov detector. The J-PARC to Hyper-K experiment has good potential for precision measurements of neutrino oscillation parameters and discovery reach for CP violation in the lepton sector. With a total exposure of 10 years to a neutrino beam produced by the 750 kW J-PARC proton synchrotron, it is expected that the CP phase δ can be determined to better than 18 degree for all possible values of δ if sin{sup 2} 2θ{sub 13} > 0.03 and the mass hierarchy is known. Control of systematic uncertainties is critical to make maximummore » use of the Hyper-K potential. Based on learning from T2K experience, a strategy to reduce systematic uncertainties in J-PARC/Hyper-K are developed.« less

The Origin of Gravitation

NASA Astrophysics Data System (ADS)

Zheng, Sheng Ming

2012-10-01

In the natural world, people have discovered four kinds of forces: electromagnetic force, gravitation, weak force, and strong force. Although the gravitation has been discovered more than three hundred years, its mechanism of origin is unclear until today. While investigating the origin of gravitation, I do some experiments discover the moving photons produce gravitation. This discovery shows the origin of gravitation. Meanwhile I do some experiments discover the light interference fringes are produced by the gravitation: my discovery demonstrate light is a particle, but is not a wave-particle duality. Furthermore, applications of this discovery to other moving particles show a similar effect. In a word: the micro particle moving produce gravitation and electromagnetic force. Then I do quantity experiment get a general formula: Reveal the essence of gravitational mass and the essence of electric charge; reveal the origin of gravitation and the essence of matter wave. Along this way, I unify the gravitation and electromagnetic force. Namely I find a natural law that from atomic world to star world play in moving track. See website: https://www.lap-publishing.com/catalog/details/store/gb/book/978-3-8473-2658-8/mechanism-of-interaction-in-moving-matter

Occidental conserves Libyan gas by reinjection into oil reservoir

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

Cozens, E.T.

1972-04-24

As a leading producer in the Libyan Arab Republic, Occidental Petroleum Corp. is vitally concerned with conservation of gas produced along with the oil. Important among the manifestations of this concern is the use of residue gas from a processing plant for injection into an oil-producing reservoir. The miscible drive created by the gas will increase ultimate recovery, and the processing plant recovers LP gas and condensate for sale. Following discovery of the 103-A in 1967, Occidental moved quickly to install production equipment and a 40-in. pipeline to Zueitina, 135 miles distant on the Mediterranean. By Feb. 1968, the firstmore » oil was loaded into tankers. Discovery of C and D fields in the 103 concession followed shortly. The three 103 fields plus an original discovery in the 102 concession increased Occidental's oil rate to more than 700,000 bpd by 1970. Facilities in the Intisar A and D fields each consist of a centralized separator system containing 3 stages of separation, plus degassing boots and surge tanks. The terminal at Zueitina includes 8,000,000 bbl of oil storage. The gas processing, the products pipeline, and other aspects of the industrial plant are discussed in detail.« less

Lysobacter species: a potential source of novel antibiotics.

PubMed

Panthee, Suresh; Hamamoto, Hiroshi; Paudel, Atmika; Sekimizu, Kazuhisa

2016-11-01

Infectious diseases threaten global health due to the ability of microbes to acquire resistance against clinically used antibiotics. Continuous discovery of antibiotics with a novel mode of action is thus required. Actinomycetes and fungi are currently the major sources of antibiotics, but the decreasing rate of discovery of novel antibiotics suggests that the focus should be changed to previously untapped groups of microbes. Lysobacter species have a genome size of ~6 Mb with a relatively high G + C content of 61-70 % and are characterized by their ability to produce peptides that damage the cell walls or membranes of other microbes. Genome sequence analysis revealed that each Lysobacter species has gene clusters for the production of 12-16 secondary metabolites, most of which are peptides, thus making them 'peptide production specialists'. Given that the number of antibiotics isolated is much lower than the number of gene clusters harbored, further intensive studies of Lysobacter are likely to unearth novel antibiotics with profound biomedical applications. In this review, we summarize the structural diversity, activity and biosynthesis of lysobacterial antibiotics and highlight the importance of Lysobacter species for antibiotic production.

Microbial Biotransformation to Obtain New Antifungals

PubMed Central

Bianchini, Luiz F.; Arruda, Maria F. C.; Vieira, Sergio R.; Campelo, Patrícia M. S.; Grégio, Ana M. T.; Rosa, Edvaldo A. R.

2015-01-01

Antifungal drugs belong to few chemical groups and such low diversity limits the therapeutic choices. The urgent need of innovative options has pushed researchers to search new bioactive molecules. Literature regarding the last 15 years reveals that different research groups have used different approaches to achieve such goal. However, the discovery of molecules with different mechanisms of action still demands considerable time and efforts. This review was conceived to present how Pharmaceutical Biotechnology might contribute to the discovery of molecules with antifungal properties by microbial biotransformation procedures. Authors present some aspects of (1) microbial biotransformation of herbal medicines and food; (2) possibility of major and minor molecular amendments in existing molecules by biocatalysis; (3) methodological improvements in processes involving whole cells and immobilized enzymes; (4) potential of endophytic fungi to produce antimicrobials by bioconversions; and (5) in silico research driving to the improvement of molecules. All these issues belong to a new conception of transformation procedures, so-called “green chemistry,” which aims the highest possible efficiency with reduced production of waste and the smallest environmental impact. PMID:26733974

First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass

PubMed Central

Wang, Guangliang; Rajpurohit, Surendra K; Delaspre, Fabien; Walker, Steven L; White, David T; Ceasrine, Alexis; Kuruvilla, Rejji; Li, Ruo-jing; Shim, Joong S; Liu, Jun O; Parsons, Michael J; Mumm, Jeff S

2015-01-01

Whole-organism chemical screening can circumvent bottlenecks that impede drug discovery. However, in vivo screens have not attained throughput capacities possible with in vitro assays. We therefore developed a method enabling in vivo high-throughput screening (HTS) in zebrafish, termed automated reporter quantification in vivo (ARQiv). In this study, ARQiv was combined with robotics to fully actualize whole-organism HTS (ARQiv-HTS). In a primary screen, this platform quantified cell-specific fluorescent reporters in >500,000 transgenic zebrafish larvae to identify FDA-approved (Federal Drug Administration) drugs that increased the number of insulin-producing β cells in the pancreas. 24 drugs were confirmed as inducers of endocrine differentiation and/or stimulators of β-cell proliferation. Further, we discovered novel roles for NF-κB signaling in regulating endocrine differentiation and for serotonergic signaling in selectively stimulating β-cell proliferation. These studies demonstrate the power of ARQiv-HTS for drug discovery and provide unique insights into signaling pathways controlling β-cell mass, potential therapeutic targets for treating diabetes. DOI: http://dx.doi.org/10.7554/eLife.08261.001 PMID:26218223

Managing the innovation supply chain to maximize personalized medicine.

PubMed

Waldman, S A; Terzic, A

2014-02-01

Personalized medicine epitomizes an evolving model of care tailored to the individual patient. This emerging paradigm harnesses radical technological advances to define each patient's molecular characteristics and decipher his or her unique pathophysiological processes. Translated into individualized algorithms, personalized medicine aims to predict, prevent, and cure disease without producing therapeutic adverse events. Although the transformative power of personalized medicine is generally recognized by physicians, patients, and payers, the complexity of translating discoveries into new modalities that transform health care is less appreciated. We often consider the flow of innovation and technology along a continuum of discovery, development, regulation, and application bridging the bench with the bedside. However, this process also can be viewed through a complementary prism, as a necessary supply chain of services and providers, each making essential contributions to the development of the final product to maximize value to consumers. Considering personalized medicine in this context of supply chain management highlights essential points of vulnerability and/or scalability that can ultimately constrain translation of the biological revolution or potentiate it into individualized diagnostics and therapeutics for optimized value creation and delivery.

Uncovering the repertoire of fungal secondary metabolites: From Fleming's laboratory to the International Space Station.

PubMed

Boruta, Tomasz

2018-01-01

Fungi produce a variety of secondary metabolites (SMs), low-molecular weight compounds associated with many potentially useful biologic activities. The examples of biotechnologically relevant fungal metabolites include penicillin, a β-lactam antibiotic, and lovastatin, a cholesterol-lowering drug. The discovery of pharmaceutical lead compounds within the microbial metabolic pools relies on the selection and biochemical characterization of promising strains. Not all SMs are produced under standard cultivation conditions, hence the uncovering of chemical potential of investigated strains often requires the use of induction strategies to awake the associated biosynthetic genes. Triggering the secondary metabolic pathways can be achieved through the variation of cultivation conditions and growth media composition. The alternative strategy is to use genetic engineering to activate the respective genomic segments, e.g. by the manipulation of regulators or chromatin-modifying enzymes. Recently, whole-genome sequencing of several fungi isolated from the Chernobyl accident area was reported by Singh et al. (Genome Announc 2017; 5:e01602-16). These strains were selected for exposure to microgravity at the International Space Station. Biochemical characterization of fungi cultivated under extreme conditions is likely to provide valuable insights into the adaptation mechanism associated with metabolism and, possibly, a catalog of novel molecules of potential pharmaceutical importance.

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

PubMed

Arbesman, Samuel; Laughlin, Gregory

2010-10-04

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

The Progress of Physics

NASA Astrophysics Data System (ADS)

Schuster, Arthur

2015-10-01

Introduction; 1. Scope of lectures. State of physics in 1875. Science of energy. Theory of gases. Elastic solid theory of light. Maxwell's theory of electricity. Training of students. Maxwell's view. Accurate measurement and discovery of Argon. German methods. Kirchhoff's laboratory. Wilhelm Weber's laboratory. The two laboratories of Berlin. Laboratory instruction at Manchester. Position of physics in mathematical tripos at Cambridge. Todhunter's views. The Cavendish laboratory. Spectrum analysis. The radiometer. Theory of vortex atom; 2. Action at a distance. Elastic solid of theory of light. Maxwell's theory of electrical action. Electro-magnetic theory. Verification of electromagnetic theory by Hertz. Electro-magnetic waves. Wireless telegraphy. First suggestion of molecular structure of electricity. Early experiments in the electric discharge through gases. Kathode rays. Works of Goldstein and Crookes. Hittorf's investigations. Own work on the discharge through gases. Ionization of gases. Magnetic deflexion of kathode rays. J. J. Thomson's experiments. Measurement of atomic charge; 3. Roentgen's discovery. Theories of Roentgen rays. Ionizing power of Roentgen rays. Conduction of electricity through ionized gases. Discovery of radio-activity. Discovery of radium. Magnetic deflexion of rays emitted by radio-active bodies. Discovery of emanations. Theory of radio-active change. Decay of the atom. Connexion between helium and the a ray. Helium produced by radium. Strutt's researches on helium accumulated in rocks. Electric inertia. Constitution of atom. J. J. Thomson's theory of Roentgen radiation. The Michelson-Morley experiment. Principle of relativity. The Zeeman effect. Other consequences of electron theory. Contrast between old and modern school of physics; 4. Observational sciences. Judgment affected by scale. Terrestrial magnetism. Existence of potential. Separation of internal and external causes. Diurnal variation. Magnetic storms. Their causes. Solar influence. Theories of secular variation. Atmospheric electricity. Negative charge of Earth. Ionization of air. Origin of atmospheric electricity. Electric charge of rain. Ebert's theory. Cause of thunderstorms. The age of the Earth. Rigidity of Earth. Displacement of axis. Gravitation. Identity of molecules of the same kind; Index.

Simulated JWST/NIRISS Transit Spectroscopy of Anticipated TESS Planets Compared to Select Discoveries from Space-Based and Ground-Based Surveys

NASA Astrophysics Data System (ADS)

Louie, Dana; Deming, Drake; Albert, Loic; Bouma, Luke; Bean, Jacob; Lopez-Morales, Mercedes

2018-01-01

The Transiting Exoplanet Survey Satellite (TESS) will embark in 2018 on a 2-year wide-field survey mission of most of the celestial sky, discovering over a thousand super-Earth and sub-Neptune-sized exoplanets potentially suitable for follow-up observations using the James Webb Space Telescope (JWST). Bouma et al. (2017) and Sullivan et al. (2015) used Monte Carlo simulations to predict the properties of the planetary systems that TESS is likely to detect, basing their simulations upon Kepler-derived planet occurrence rates and photometric performance models for the TESS cameras. We employed a JWST Near InfraRed Imager and Slitless Spectrograph (NIRISS) simulation tool to estimate the signal-to-noise (S/N) that JWST/NIRISS will attain in transmission spectroscopy of these anticipated TESS discoveries, and we then compared the S/N for anticipated TESS discoveries to our estimates of S/N for 18 known exoplanets. We analyzed the sensitivity of our results to planetary composition, cloud cover, and presence of an observational noise floor. We find that only a few anticipated TESS discoveries in the terrestrial planet regime will result in better JWST/NIRISS S/N than currently known exoplanets, such as the TRAPPIST-1 planets, GJ1132b, or LHS1140b. However, we emphasize that this outcome is based upon Kepler-derived occurrence rates, and that co-planar compact systems (e.g. TRAPPIST-1) were not included in predicting the anticipated TESS planet yield. Furthermore, our results show that several hundred anticipated TESS discoveries in the super-Earth and sub-Neptune regime will produce S/N higher than currently known exoplanets such as K2-3b or K2-3c. We apply our results to estimate the scope of a JWST follow-up observation program devoted to mapping the transition region between high molecular weight and primordial planetary atmospheres.

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.

Evolution of the radiation processing industry

NASA Astrophysics Data System (ADS)

Cleland, Marshall R.

2013-04-01

Early investigations of the effects of treating materials with ionizing radiations began in 1894 with the irradiation of gases at atmospheric pressure using cathode rays from a Crookes gas-discharge tube, in 1895 with the discovery of X-rays emitted from a Crookes tube, and in 1896 with the discovery of radioactivity in uranium. In 1897, small electrically charged particles were detected and identified in the gas discharges inside Crookes tubes. These particles were then named electrons. During the next three decades, it was found that these novel forms of energy could produce ions to initiate chemical reactions in some gases and liquids. By 1921, it had also been shown that insects, parasites and bacteria could be killed by treatment with ionizing radiation. In 1925, a high-vacuum tube with a thermionic cathode and a thin metallic anode was developed to produce electron beams in air by using accelerating potentials up to 250 kilovolts. That unique apparatus was the precursor of the many types of electron accelerators that have been developed since then for a variety of industrial applications. In 1929, the vulcanization of natural rubber without using any chemical additives was achieved by irradiation with electrons from a 250 kilovolt accelerator. In 1939, several liquid monomers were polymerized by treatment with gamma rays from radioactive nuclides. These early results were not exploited before the end of World War II because intense sources of ionizing radiation were not available then. Shortly after that war, there was increased interest in developing the peaceful uses of atomic energy, which included the chemical and biological effects of radiation exposures. Many uses that have been developed since then are described briefly in this paper. These industrial applications are now producing billions of US dollars in revenue every year.

Evolution of the radiation processing industry

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

Cleland, Marshall R.

2013-04-19

Early investigations of the effects of treating materials with ionizing radiations began in 1894 with the irradiation of gases at atmospheric pressure using cathode rays from a Crookes gas-discharge tube, in 1895 with the discovery of X-rays emitted from a Crookes tube, and in 1896 with the discovery of radioactivity in uranium. In 1897, small electrically charged particles were detected and identified in the gas discharges inside Crookes tubes. These particles were then named electrons. During the next three decades, it was found that these novel forms of energy could produce ions to initiate chemical reactions in some gases andmore » liquids. By 1921, it had also been shown that insects, parasites and bacteria could be killed by treatment with ionizing radiation. In 1925, a high-vacuum tube with a thermionic cathode and a thin metallic anode was developed to produce electron beams in air by using accelerating potentials up to 250 kilovolts. That unique apparatus was the precursor of the many types of electron accelerators that have been developed since then for a variety of industrial applications. In 1929, the vulcanization of natural rubber without using any chemical additives was achieved by irradiation with electrons from a 250 kilovolt accelerator. In 1939, several liquid monomers were polymerized by treatment with gamma rays from radioactive nuclides. These early results were not exploited before the end of World War II because intense sources of ionizing radiation were not available then. Shortly after that war, there was increased interest in developing the peaceful uses of atomic energy, which included the chemical and biological effects of radiation exposures. Many uses that have been developed since then are described briefly in this paper. These industrial applications are now producing billions of US dollars in revenue every year.« less

Working Group Proposed to Preserve Archival Records

NASA Astrophysics Data System (ADS)

Bartlett, Jennifer L.

2013-01-01

The AAS and AIP co-hosted a Workshop in April 2012 with NSF support (AST-1110231) that recommends establishing a Working Group on Time Domain Astronomy (WGTDA) to encourage and advise on preserving historical observations in a form meaningful for future scientific analysis. Participants specifically considered archival observations that could describe how astronomical objects change over time. Modern techniques and increased storage capacity enable extracting additional information from older media. Despite the photographic plate focus, other formats also concerned participants. To prioritize preservation efforts, participants recommended considering the information density, the amount of previously published data, their format and associated materials, their current condition, and their expected deterioration rate. Because the best digitization still produces an observation of an observation, the originals should be retained. For accessibility, participants recommended that observations and their metadata be available digitally and on-line. Standardized systems for classifying, organizing, and listing holdings should enable discovery of historical observations through the Virtual Astronomical Observatory. Participants recommended pilot projects that produce scientific results, demonstrate the dependence of some advances on heritage data, and open new avenues of exploration. Surveying a broad region of the sky with a long time-base and high cadence should reveal new phenomena and improve statistics for rare events. Adequate financial support is essential. While their capacity to produce new science is the primary motivation for preserving astronomical records, their potential for historical research and citizen science allows targeting cultural institutions and other private sources. A committee was elected to prepare the WGTDA proposal. The WGTDA executive committee should be composed of ~10 members representing modern surveys, heritage materials, data management, data standardization and integration, follow-up of time-domain discoveries, and virtual observatories. The Working Group on the Preservation of Astronomical Heritage Web page includes a full report.

Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T-Type Calcium Channel Blocker, ABT-639

PubMed Central

2015-01-01

The discovery of a novel peripherally acting and selective Cav3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits 1 and 2, which have poor metabolic stability, were optimized to obtain 4, which has improved stability and oral bioavailability. Modification of 4 to further improve ADME properties led to the discovery of ABT-639. Following oral administration, ABT-639 produces robust antinociceptive activity in experimental pain models at doses that do not significantly alter psychomotor or hemodynamic function in the rat. PMID:26101566

Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T-Type Calcium Channel Blocker, ABT-639.

PubMed

Zhang, Qingwei; Xia, Zhiren; Joshi, Shailen; Scott, Victoria E; Jarvis, Michael F

2015-06-11

The discovery of a novel peripherally acting and selective Cav3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits 1 and 2, which have poor metabolic stability, were optimized to obtain 4, which has improved stability and oral bioavailability. Modification of 4 to further improve ADME properties led to the discovery of ABT-639. Following oral administration, ABT-639 produces robust antinociceptive activity in experimental pain models at doses that do not significantly alter psychomotor or hemodynamic function in the rat.

Microfluidics for Drug Discovery and Development: From Target Selection to Product Lifecycle Management

PubMed Central

Kang, Lifeng; Chung, Bong Geun; Langer, Robert; Khademhosseini, Ali

2009-01-01

Microfluidic technologies’ ability to miniaturize assays and increase experimental throughput have generated significant interest in the drug discovery and development domain. These characteristics make microfluidic systems a potentially valuable tool for many drug discovery and development applications. Here, we review the recent advances of microfluidic devices for drug discovery and development and highlight their applications in different stages of the process, including target selection, lead identification, preclinical tests, clinical trials, chemical synthesis, formulations studies, and product management. PMID:18190858

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

PubMed Central

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

2017-01-01

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

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

PubMed

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

2014-01-01

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

Three novel proteins co-localise with polyhydroxybutyrate (PHB) granules in Rhodospirillum rubrum S1.

PubMed

Narancic, Tanja; Scollica, Elisa; Cagney, Gerard; O'Connor, Kevin E

2018-04-01

Polyhydroxybutyrate (PHB), a biodegradable polymer accumulated by bacteria is deposited intracellularly in the form of inclusion bodies often called granules. The granules are supramolecular complexes harbouring a varied number of proteins on their surface, which have specific but incompletely characterised functions. By comparison with other organisms that produce biodegradable polymers, only two phasins have been described to date for Rhodosprillum rubrum, raising the possibility that more await discovery. Using a comparative proteomics strategy to compare the granules of wild-type R. rubrum with a PHB-negative mutant housing artificial PHB granules, we identified four potential PHB granules' associated proteins. These were: Q2RSI4, an uncharacterised protein; Q2RWU9, annotated as an extracellular solute-binding protein; Q2RQL4, annotated as basic membrane lipoprotein; and Q2RQ51, annotated as glucose-6-phosphate isomerase. In silico analysis revealed that Q2RSI4 harbours a Phasin_2 family domain and shares low identity with a single-strand DNA-binding protein from Sphaerochaeta coccoides. Fluorescence microscopy found that three proteins Q2RSI4, Q2EWU9 and Q2RQL4 co-localised with PHB granules. This work adds three potential new granule associated proteins to the repertoire of factors involved in bacterial storage granule formation, and confirms that proteomics screens are an effective strategy for discovery of novel granule associated proteins.

Comparative genomics uncovers the prolific and distinctive metabolic potential of the cyanobacterial genus Moorea

PubMed Central

Leao, Tiago; Castelão, Guilherme; Monroe, Emily A.; Podell, Sheila; Glukhov, Evgenia; Allen, Eric E.; Gerwick, William H.; Gerwick, Lena

2017-01-01

Cyanobacteria are major sources of oxygen, nitrogen, and carbon in nature. In addition to the importance of their primary metabolism, some cyanobacteria are prolific producers of unique and bioactive secondary metabolites. Chemical investigations of the cyanobacterial genus Moorea have resulted in the isolation of over 190 compounds in the last two decades. However, preliminary genomic analysis has suggested that genome-guided approaches can enable the discovery of novel compounds from even well-studied Moorea strains, highlighting the importance of obtaining complete genomes. We report a complete genome of a filamentous tropical marine cyanobacterium, Moorea producens PAL, which reveals that about one-fifth of its genome is devoted to production of secondary metabolites, an impressive four times the cyanobacterial average. Moreover, possession of the complete PAL genome has allowed improvement to the assembly of three other Moorea draft genomes. Comparative genomics revealed that they are remarkably similar to one another, despite their differences in geography, morphology, and secondary metabolite profiles. Gene cluster networking highlights that this genus is distinctive among cyanobacteria, not only in the number of secondary metabolite pathways but also in the content of many pathways, which are potentially distinct from all other bacterial gene clusters to date. These findings portend that future genome-guided secondary metabolite discovery and isolation efforts should be highly productive. PMID:28265051

Discovery of novel enzymes with industrial potential from a cold and alkaline environment by a combination of functional metagenomics and culturing

PubMed Central

2014-01-01

Background The use of cold-active enzymes has many advantages, including reduced energy consumption and easy inactivation. The ikaite columns of SW Greenland are permanently cold (4-6°C) and alkaline (above pH 10), and the microorganisms living there and their enzymes are adapted to these conditions. Since only a small fraction of the total microbial diversity can be cultured in the laboratory, a combined approach involving functional screening of a strain collection and a metagenomic library was undertaken for discovery of novel enzymes from the ikaite columns. Results A strain collection with 322 cultured isolates was screened for enzymatic activities identifying a large number of enzyme producers, with a high re-discovery rate to previously characterized strains. A functional expression library established in Escherichia coli identified a number of novel cold-active enzymes. Both α-amylases and β-galactosidases were characterized in more detail with respect to temperature and pH profiles and one of the β-galactosidases, BGalI17E2, was able to hydrolyze lactose at 5°C. A metagenome sequence of the expression library indicated that the majority of enzymatic activities were not detected by functional expression. Phylogenetic analysis showed that different bacterial communities were targeted with the culture dependent and independent approaches and revealed the bias of multiple displacement amplification (MDA) of DNA isolated from complex microbial communities. Conclusions Many cold- and/or alkaline-active enzymes of industrial relevance were identified in the culture based approach and the majority of the enzyme-producing isolates were closely related to previously characterized strains. The function-based metagenomic approach, on the other hand, identified several enzymes (β-galactosidases, α-amylases and a phosphatase) with low homology to known sequences that were easily expressed in the production host E. coli. The β-galactosidase BGalI17E2 was able to hydrolyze lactose at low temperature, suggesting a possibly use in the dairy industry for this enzyme. The two different approaches complemented each other by targeting different microbial communities, highlighting the usefulness of combining methods for bioprospecting. Finally, we document here that ikaite columns constitute an important source of cold- and/or alkaline-active enzymes with industrial application potential. PMID:24886068

Discovery of novel enzymes with industrial potential from a cold and alkaline environment by a combination of functional metagenomics and culturing.

PubMed

Vester, Jan Kjølhede; Glaring, Mikkel Andreas; Stougaard, Peter

2014-05-20

The use of cold-active enzymes has many advantages, including reduced energy consumption and easy inactivation. The ikaite columns of SW Greenland are permanently cold (4-6°C) and alkaline (above pH 10), and the microorganisms living there and their enzymes are adapted to these conditions. Since only a small fraction of the total microbial diversity can be cultured in the laboratory, a combined approach involving functional screening of a strain collection and a metagenomic library was undertaken for discovery of novel enzymes from the ikaite columns. A strain collection with 322 cultured isolates was screened for enzymatic activities identifying a large number of enzyme producers, with a high re-discovery rate to previously characterized strains. A functional expression library established in Escherichia coli identified a number of novel cold-active enzymes. Both α-amylases and β-galactosidases were characterized in more detail with respect to temperature and pH profiles and one of the β-galactosidases, BGalI17E2, was able to hydrolyze lactose at 5°C. A metagenome sequence of the expression library indicated that the majority of enzymatic activities were not detected by functional expression. Phylogenetic analysis showed that different bacterial communities were targeted with the culture dependent and independent approaches and revealed the bias of multiple displacement amplification (MDA) of DNA isolated from complex microbial communities. Many cold- and/or alkaline-active enzymes of industrial relevance were identified in the culture based approach and the majority of the enzyme-producing isolates were closely related to previously characterized strains. The function-based metagenomic approach, on the other hand, identified several enzymes (β-galactosidases, α-amylases and a phosphatase) with low homology to known sequences that were easily expressed in the production host E. coli. The β-galactosidase BGalI17E2 was able to hydrolyze lactose at low temperature, suggesting a possibly use in the dairy industry for this enzyme. The two different approaches complemented each other by targeting different microbial communities, highlighting the usefulness of combining methods for bioprospecting. Finally, we document here that ikaite columns constitute an important source of cold- and/or alkaline-active enzymes with industrial application potential.

Optimal False Discovery Rate Control for Dependent Data

PubMed Central

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

2013-01-01

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

Scientific Discoveries: What Is Required for Lasting Impact.

PubMed

Lømo, Terje

2016-01-01

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

Computational phenotype discovery using unsupervised feature learning over noisy, sparse, and irregular clinical data.

PubMed

Lasko, Thomas A; Denny, Joshua C; Levy, Mia A

2013-01-01

Inferring precise phenotypic patterns from population-scale clinical data is a core computational task in the development of precision, personalized medicine. The traditional approach uses supervised learning, in which an expert designates which patterns to look for (by specifying the learning task and the class labels), and where to look for them (by specifying the input variables). While appropriate for individual tasks, this approach scales poorly and misses the patterns that we don't think to look for. Unsupervised feature learning overcomes these limitations by identifying patterns (or features) that collectively form a compact and expressive representation of the source data, with no need for expert input or labeled examples. Its rising popularity is driven by new deep learning methods, which have produced high-profile successes on difficult standardized problems of object recognition in images. Here we introduce its use for phenotype discovery in clinical data. This use is challenging because the largest source of clinical data - Electronic Medical Records - typically contains noisy, sparse, and irregularly timed observations, rendering them poor substrates for deep learning methods. Our approach couples dirty clinical data to deep learning architecture via longitudinal probability densities inferred using Gaussian process regression. From episodic, longitudinal sequences of serum uric acid measurements in 4368 individuals we produced continuous phenotypic features that suggest multiple population subtypes, and that accurately distinguished (0.97 AUC) the uric-acid signatures of gout vs. acute leukemia despite not being optimized for the task. The unsupervised features were as accurate as gold-standard features engineered by an expert with complete knowledge of the domain, the classification task, and the class labels. Our findings demonstrate the potential for achieving computational phenotype discovery at population scale. We expect such data-driven phenotypes to expose unknown disease variants and subtypes and to provide rich targets for genetic association studies.

Computational Phenotype Discovery Using Unsupervised Feature Learning over Noisy, Sparse, and Irregular Clinical Data

PubMed Central

Lasko, Thomas A.; Denny, Joshua C.; Levy, Mia A.

2013-01-01

Inferring precise phenotypic patterns from population-scale clinical data is a core computational task in the development of precision, personalized medicine. The traditional approach uses supervised learning, in which an expert designates which patterns to look for (by specifying the learning task and the class labels), and where to look for them (by specifying the input variables). While appropriate for individual tasks, this approach scales poorly and misses the patterns that we don’t think to look for. Unsupervised feature learning overcomes these limitations by identifying patterns (or features) that collectively form a compact and expressive representation of the source data, with no need for expert input or labeled examples. Its rising popularity is driven by new deep learning methods, which have produced high-profile successes on difficult standardized problems of object recognition in images. Here we introduce its use for phenotype discovery in clinical data. This use is challenging because the largest source of clinical data – Electronic Medical Records – typically contains noisy, sparse, and irregularly timed observations, rendering them poor substrates for deep learning methods. Our approach couples dirty clinical data to deep learning architecture via longitudinal probability densities inferred using Gaussian process regression. From episodic, longitudinal sequences of serum uric acid measurements in 4368 individuals we produced continuous phenotypic features that suggest multiple population subtypes, and that accurately distinguished (0.97 AUC) the uric-acid signatures of gout vs. acute leukemia despite not being optimized for the task. The unsupervised features were as accurate as gold-standard features engineered by an expert with complete knowledge of the domain, the classification task, and the class labels. Our findings demonstrate the potential for achieving computational phenotype discovery at population scale. We expect such data-driven phenotypes to expose unknown disease variants and subtypes and to provide rich targets for genetic association studies. PMID:23826094

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.

Harnessing the potential of natural products in drug discovery from a cheminformatics vantage point.

PubMed

Rodrigues, Tiago

2017-11-15

Natural products (NPs) present a privileged source of inspiration for chemical probe and drug design. Despite the biological pre-validation of the underlying molecular architectures and their relevance in drug discovery, the poor accessibility to NPs, complexity of the synthetic routes and scarce knowledge of their macromolecular counterparts in phenotypic screens still hinder their broader exploration. Cheminformatics algorithms now provide a powerful means of circumventing the abovementioned challenges and unlocking the full potential of NPs in a drug discovery context. Herein, I discuss recent advances in the computer-assisted design of NP mimics and how artificial intelligence may accelerate future NP-inspired molecular medicine.

Chemicals that produce anosmia in mosquitoes

USDA-ARS?s Scientific Manuscript database

The United States Department of Agriculture (USDA) has developed repellents and insecticides for the U.S. military since 1942. A small component of this research program has been focused on the discovery of attractants that can be used to produce potent lures for haematophagous arthropods, especial...

Potential therapeutic targets and the role of technology in developing novel cannabinoid drugs from cyanobacteria.

PubMed

Vijayakumar, S; Manogar, P; Prabhu, S

2016-10-01

Cyanobacteria find several applications in pharmacology as potential candidates for drug design. The need for new compounds that can be used as drugs has always been on the rise in therapeutics. Cyanobacteria have been identified as promising targets of research in the quest for new pharmaceutical compounds as they can produce secondary metabolites with novel chemical structures. Cyanobacteria is now recognized as a vital source of bioactive molecules like Curacin A, Largazole and Apratoxin which have succeeded in reaching Phase II and Phase III into clinical trials. The discovery of several new clinical cannabinoid drugs in the past decade from diverse marine life should translate into a number of new drugs for cannabinoid in the years to come. Conventional cannabinoid drugs have high toxicity and as a result, they affect the efficacy of chemotherapy and patients' life very much. The present review focuses on how potential, safe and affordable drugs used for cannabinoid treatment could be developed from cyanobacteria. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

DNA-conjugated gold nanoparticles based colorimetric assay to assess helicase activity: a novel route to screen potential helicase inhibitors

NASA Astrophysics Data System (ADS)

Deka, Jashmini; Mojumdar, Aditya; Parisse, Pietro; Onesti, Silvia; Casalis, Loredana

2017-03-01

Helicase are essential enzymes which are widespread in all life-forms. Due to their central role in nucleic acid metabolism, they are emerging as important targets for anti-viral, antibacterial and anti-cancer drugs. The development of easy, cheap, fast and robust biochemical assays to measure helicase activity, overcoming the limitations of the current methods, is a pre-requisite for the discovery of helicase inhibitors through high-throughput screenings. We have developed a method which exploits the optical properties of DNA-conjugated gold nanoparticles (AuNP) and meets the required criteria. The method was tested with the catalytic domain of the human RecQ4 helicase and compared with a conventional FRET-based assay. The AuNP-based assay produced similar results but is simpler, more robust and cheaper than FRET. Therefore, our nanotechnology-based platform shows the potential to provide a useful alternative to the existing conventional methods for following helicase activity and to screen small-molecule libraries as potential helicase inhibitors.

The path to producing pharmaceuticals from natural products uncovered by academia-from the perspective of a science coordinator.

PubMed

Fujie, Akihiko

2017-01-01

To actualize the invention of all-Japanese medicines, the Department of Innovative Drug Discovery and Development (iD3) in the Japan Agency for Medical Research and Development (AMED) serves as the headquarters for the Drug Discovery Support Network. iD3 assists with creating research strategies for the seeds of medicines discovered by academia and provides technological support, intellectual property management, and aid for applying the seeds through industry-led efforts. In this review, from the perspective of a science coordinator, I will describe the current activities of the drug discovery support network and iD3 as well as the challenges and future developments of pharmaceutical research and development using the natural product drug discovery method.

RAS - Screens & Assays - Drug Discovery

Cancer.gov

The RAS Drug Discovery group aims to develop assays that will reveal aspects of RAS biology upon which cancer cells depend. Successful assay formats are made available for high-throughput screening programs to yield potentially effective drug compounds.

Isolation, structure elucidation and anticancer activity from Brevibacillus brevis EGS 9 that combats Multi Drug Resistant actinobacteria.

PubMed

Arumugam, T; Senthil Kumar, P; Hemavathy, R V; Swetha, V; Karishma Sri, R

2018-02-01

Actinobacteria is the most widely distributed organism in the mangrove environment and produce a large amount of secondary metabolites. A new environmental actinobacterial stain exhibited strong antimicrobial activity against vancomycin and methicillin resistant actinobacteria. The active producer strain was found to be as Brevibacillus brevis EGS9, which was confirmed by its morphological, biochemical characteristics and 16S rRNA gene sequencing. It was deposited in NCBI GeneBank database and received with an accession number of KX388147. Brevibacillus brevis EGS9 was cultivated by submerged fermentation to produce antimicrobial compounds. The anti-proliferative agent was extracted from Brevibacillus brevis EGS9 with ethyl acetate. The bioactive metabolites of mangrove actinobacteria was identified by Liquid chromatography with mass spectrometry analysis. The result of the present investigation revealed that actinobacteria isolated from mangroves are potent source of anticancer activity. The strain of Brevibacillus brevis EGS9 exhibited a potential in vitro anticancer activity. The present research concluded that the actinobacteria isolated from mangrove soil sediment are valuable in discovery of novel species. Copyright © 2017. Published by Elsevier Ltd.

Quantifying the Ease of Scientific Discovery

PubMed Central

Arbesman, Samuel

2012-01-01

It has long been known that scientific output proceeds on an exponential increase, or more properly, a logistic growth curve. The interplay between effort and discovery is clear, and the nature of the functional form has been thought to be due to many changes in the scientific process over time. Here I show a quantitative method for examining the ease of scientific progress, another necessary component in understanding scientific discovery. Using examples from three different scientific disciplines – mammalian species, chemical elements, and minor planets – I find the ease of discovery to conform to an exponential decay. In addition, I show how the pace of scientific discovery can be best understood as the outcome of both scientific output and ease of discovery. A quantitative study of the ease of scientific discovery in the aggregate, such as done here, has the potential to provide a great deal of insight into both the nature of future discoveries and the technical processes behind discoveries in science. PMID:22328796

Quantifying the Ease of Scientific Discovery.

PubMed

Arbesman, Samuel

2011-02-01

It has long been known that scientific output proceeds on an exponential increase, or more properly, a logistic growth curve. The interplay between effort and discovery is clear, and the nature of the functional form has been thought to be due to many changes in the scientific process over time. Here I show a quantitative method for examining the ease of scientific progress, another necessary component in understanding scientific discovery. Using examples from three different scientific disciplines - mammalian species, chemical elements, and minor planets - I find the ease of discovery to conform to an exponential decay. In addition, I show how the pace of scientific discovery can be best understood as the outcome of both scientific output and ease of discovery. A quantitative study of the ease of scientific discovery in the aggregate, such as done here, has the potential to provide a great deal of insight into both the nature of future discoveries and the technical processes behind discoveries in science.

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

USGS Publications Warehouse

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

1980-01-01

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

Constraining Modified Theories of Gravity with Gravitational-Wave Stochastic Backgrounds

NASA Astrophysics Data System (ADS)

Maselli, Andrea; Marassi, Stefania; Ferrari, Valeria; Kokkotas, Kostas; Schneider, Raffaella

2016-08-01

The direct discovery of gravitational waves has finally opened a new observational window on our Universe, suggesting that the population of coalescing binary black holes is larger than previously expected. These sources produce an unresolved background of gravitational waves, potentially observable by ground-based interferometers. In this Letter we investigate how modified theories of gravity, modeled using the parametrized post-Einsteinian formalism, affect the expected signal, and analyze the detectability of the resulting stochastic background by current and future ground-based interferometers. We find the constraints that Advanced LIGO would be able to set on modified theories, showing that they may significantly improve the current bounds obtained from astrophysical observations of binary pulsars.

Reclassification of the Specialized Metabolite Producer Pseudomonas mesoacidophila ATCC 31433 as a Member of the Burkholderia cepacia Complex.

PubMed

Loveridge, E Joel; Jones, Cerith; Bull, Matthew J; Moody, Suzy C; Kahl, Małgorzata W; Khan, Zainab; Neilson, Louis; Tomeva, Marina; Adams, Sarah E; Wood, Andrew C; Rodriguez-Martin, Daniel; Pinel, Ingrid; Parkhill, Julian; Mahenthiralingam, Eshwar; Crosby, John

2017-07-01

Pseudomonas mesoacidophila ATCC 31433 is a Gram-negative bacterium, first isolated from Japanese soil samples, that produces the monobactam isosulfazecin and the β-lactam-potentiating bulgecins. To characterize the biosynthetic potential of P. mesoacidophila ATCC 31433, its complete genome was determined using single-molecule real-time DNA sequence analysis. The 7.8-Mb genome comprised four replicons, three chromosomal (each encoding rRNA) and one plasmid. Phylogenetic analysis demonstrated that P. mesoacidophila ATCC 31433 was misclassified at the time of its deposition and is a member of the Burkholderia cepacia complex, most closely related to Burkholderia ubonensis The sequenced genome shows considerable additional biosynthetic potential; known gene clusters for malleilactone, ornibactin, isosulfazecin, alkylhydroxyquinoline, and pyrrolnitrin biosynthesis and several uncharacterized biosynthetic gene clusters for polyketides, nonribosomal peptides, and other metabolites were identified. Furthermore, P. mesoacidophila ATCC 31433 harbors many genes associated with environmental resilience and antibiotic resistance and was resistant to a range of antibiotics and metal ions. In summary, this bioactive strain should be designated B. cepacia complex strain ATCC 31433, pending further detailed taxonomic characterization. IMPORTANCE This work reports the complete genome sequence of Pseudomonas mesoacidophila ATCC 31433, a known producer of bioactive compounds. Large numbers of both known and novel biosynthetic gene clusters were identified, indicating that P. mesoacidophila ATCC 31433 is an untapped resource for discovery of novel bioactive compounds. Phylogenetic analysis demonstrated that P. mesoacidophila ATCC 31433 is in fact a member of the Burkholderia cepacia complex, most closely related to the species Burkholderia ubonensis Further investigation of the classification and biosynthetic potential of P. mesoacidophila ATCC 31433 is warranted. Copyright © 2017 Loveridge et al.

Toward Systems Metabolic Engineering of Streptomycetes for Secondary Metabolites Production.

PubMed

Robertsen, Helene Lunde; Weber, Tilmann; Kim, Hyun Uk; Lee, Sang Yup

2018-01-01

Streptomycetes are known for their inherent ability to produce pharmaceutically relevant secondary metabolites. Discovery of medically useful, yet novel compounds has become a great challenge due to frequent rediscovery of known compounds and a consequent decline in the number of relevant clinical trials in the last decades. A paradigm shift took place when the first whole genome sequences of streptomycetes became available, from which silent or "cryptic" biosynthetic gene clusters (BGCs) were discovered. Cryptic BGCs reveal a so far untapped potential of the microorganisms for the production of novel compounds, which has spurred new efforts in understanding the complex regulation between primary and secondary metabolism. This new trend has been accompanied with development of new computational resources (genome and compound mining tools), generation of various high-quality omics data, establishment of molecular tools, and other strain engineering strategies. They all come together to enable systems metabolic engineering of streptomycetes, allowing more systematic and efficient strain development. In this review, the authors present recent progresses within systems metabolic engineering of streptomycetes for uncovering their hidden potential to produce novel compounds and for the improved production of secondary metabolites. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Genetically attenuated Trypanosoma cruzi parasites as a potential vaccination tool

PubMed Central

Brandan, Cecilia Pérez; Basombrío, Miguel Ángel

2012-01-01

Chagas disease is the clinical manifestation of the infection produced by the parasite Trypanosoma cruzi. Currently there is no vaccine to prevent this disease and the protection attained with vaccines containing non-replicating parasites is limited. Genetically attenuated trypanosomatid parasites can be obtained by deletion of selected genes. Gene deletion takes advantage of the fact that this parasite can undergo homologous recombination between endogenous and foreign DNA sequences artificially introduced in the cells. This approach facilitated the discovery of several unknown gene functions, as well as allowing us to speculate about the potential for genetically attenuated live organisms as experimental immunogens. Vaccination with live attenuated parasites has been used effectively in mice to reduce parasitemia and histological damage, and in dogs, to prevent vector-delivered infection in the field. However, the use of live parasites as immunogens is controversial due to the risk of reversion to a virulent phenotype. Herein, we present our results from experiments on genetic manipulation of two T. cruzi strains to produce parasites with impaired replication and infectivity, and using the mutation of the dhfr-ts gene as a safety device against reversion to virulence. PMID:22705838

Gene discovery in EST sequences from the wheat leaf rust fungus Puccinia triticina sexual spores, asexual spores and haustoria, compared to other rust and corn smut fungi

PubMed Central

2011-01-01

Background Rust fungi are biotrophic basidiomycete plant pathogens that cause major diseases on plants and trees world-wide, affecting agriculture and forestry. Their biotrophic nature precludes many established molecular genetic manipulations and lines of research. The generation of genomic resources for these microbes is leading to novel insights into biology such as interactions with the hosts and guiding directions for breakthrough research in plant pathology. Results To support gene discovery and gene model verification in the genome of the wheat leaf rust fungus, Puccinia triticina (Pt), we have generated Expressed Sequence Tags (ESTs) by sampling several life cycle stages. We focused on several spore stages and isolated haustorial structures from infected wheat, generating 17,684 ESTs. We produced sequences from both the sexual (pycniospores, aeciospores and teliospores) and asexual (germinated urediniospores) stages of the life cycle. From pycniospores and aeciospores, produced by infecting the alternate host, meadow rue (Thalictrum speciosissimum), 4,869 and 1,292 reads were generated, respectively. We generated 3,703 ESTs from teliospores produced on the senescent primary wheat host. Finally, we generated 6,817 reads from haustoria isolated from infected wheat as well as 1,003 sequences from germinated urediniospores. Along with 25,558 previously generated ESTs, we compiled a database of 13,328 non-redundant sequences (4,506 singlets and 8,822 contigs). Fungal genes were predicted using the EST version of the self-training GeneMarkS algorithm. To refine the EST database, we compared EST sequences by BLASTN to a set of 454 pyrosequencing-generated contigs and Sanger BAC-end sequences derived both from the Pt genome, and to ESTs and genome reads from wheat. A collection of 6,308 fungal genes was identified and compared to sequences of the cereal rusts, Puccinia graminis f. sp. tritici (Pgt) and stripe rust, P. striiformis f. sp. tritici (Pst), and poplar leaf rust Melampsora species, and the corn smut fungus, Ustilago maydis (Um). While extensive homologies were found, many genes appeared novel and species-specific; over 40% of genes did not match any known sequence in existing databases. Focusing on spore stages, direct comparison to Um identified potential functional homologs, possibly allowing heterologous functional analysis in that model fungus. Many potentially secreted protein genes were identified by similarity searches against genes and proteins of Pgt and Melampsora spp., revealing apparent orthologs. Conclusions The current set of Pt unigenes contributes to gene discovery in this major cereal pathogen and will be invaluable for gene model verification in the genome sequence. PMID:21435244

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

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

Epple, D.; Hansen, L.P.

1981-12-01

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

Reducing the Bottleneck in Discovery of Novel Antibiotics.

PubMed

Jones, Marcus B; Nierman, William C; Shan, Yue; Frank, Bryan C; Spoering, Amy; Ling, Losee; Peoples, Aaron; Zullo, Ashley; Lewis, Kim; Nelson, Karen E

2017-04-01

Most antibiotics were discovered by screening soil actinomycetes, but the efficiency of the discovery platform collapsed in the 1960s. By now, more than 3000 antibiotics have been described and most of the current discovery effort is focused on the rediscovery of known compounds, making the approach impractical. The last marketed broad-spectrum antibiotics discovered were daptomycin, linezolid, and fidaxomicin. The current state of the art in the development of new anti-infectives is a non-existent pipeline in the absence of a discovery platform. This is particularly troubling given the emergence of pan-resistant pathogens. The current practice in dealing with the problem of the background of known compounds is to use chemical dereplication of extracts to assess the relative novelty of a compound it contains. Dereplication typically requires scale-up, extraction, and often fractionation before an accurate mass and structure can be produced by MS analysis in combination with 2D NMR. Here, we describe a transcriptome analysis approach using RNA sequencing (RNASeq) to identify promising novel antimicrobial compounds from microbial extracts. Our pipeline permits identification of antimicrobial compounds that produce distinct transcription profiles using unfractionated cell extracts. This efficient pipeline will eliminate the requirement for purification and structure determination of compounds from extracts and will facilitate high-throughput screen of cell extracts for identification of novel compounds.

Simultaneous Proteomic Discovery and Targeted Monitoring using Liquid Chromatography, Ion Mobility Spectrometry, and Mass Spectrometry

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

Burnum-Johnson, Kristin E.; Nie, Song; Casey, Cameron P.

Current proteomics approaches are comprised of both broad discovery measurements as well as more quantitative targeted measurements. These two different measurement types are used to initially identify potentially important proteins (e.g., candidate biomarkers) and then enable improved quantification for a limited number of selected proteins. However, both approaches suffer from limitations, particularly the lower sensitivity, accuracy, and quantitation precision for discovery approaches compared to targeted approaches, and the limited proteome coverage provided by targeted approaches. Herein, we describe a new proteomics approach that allows both discovery and targeted monitoring (DTM) in a single analysis using liquid chromatography, ion mobility spectrometrymore » and mass spectrometry (LC-IMS-MS). In DTM, heavy labeled peptides for target ions are spiked into tryptic digests and both the labeled and unlabeled peptides are broadly detected using LC-IMS-MS instrumentation, allowing the benefits of discovery and targeted approaches. To understand the possible improvement of the DTM approach, it was compared to LC-MS broad measurements using an accurate mass and time tag database and selected reaction monitoring (SRM) targeted measurements. The DTM results yielded greater peptide/protein coverage and a significant improvement in the detection of lower abundance species compared to LC-MS discovery measurements. DTM was also observed to have similar detection limits as SRM for the targeted measurements indicating its potential for combining the discovery and targeted approaches.« less

Targeting Transient Receptor Potential Vanilloid 1 (TRPV1) Channel Softly: The Discovery of Passerini Adducts as a Topical Treatment for Inflammatory Skin Disorders.

PubMed

Serafini, Marta; Griglio, Alessia; Aprile, Silvio; Seiti, Fabio; Travelli, Cristina; Pattarino, Franco; Grosa, Giorgio; Sorba, Giovanni; Genazzani, Armando A; Gonzalez-Rodriguez, Sara; Butron, Laura; Devesa, Isabel; Fernandez-Carvajal, Asia; Pirali, Tracey; Ferrer-Montiel, Antonio

2018-05-24

Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and the development of new capsaicinoids is a promising pharmacological approach in the management of skin disorders related to inflammation and pruritus. Here we report the synthesis and the evaluation of capsaicin soft drugs that undergo deactivation by the hydrolyzing activity of skin esterases. The implanting of an ester group in the lipophilic moiety of capsaicinoids by the Passerini multicomponent reaction affords both agonists and antagonists that retain transient receptor potential vanilloid 1 channel (TRPV1) modulating activity and, at the same time, are susceptible to hydrolysis. The most promising antagonist identified shows in vivo anti-nociceptive activity on pruritus and hyperalgesia without producing hyperthermia, thus validating it as novel treatment for dermatological conditions that implicate TRPV1 channel dysfunction.

Novel bacteriocins from lactic acid bacteria (LAB): various structures and applications

PubMed Central

2014-01-01

Bacteriocins are heat-stable ribosomally synthesized antimicrobial peptides produced by various bacteria, including food-grade lactic acid bacteria (LAB). These antimicrobial peptides have huge potential as both food preservatives, and as next-generation antibiotics targeting the multiple-drug resistant pathogens. The increasing number of reports of new bacteriocins with unique properties indicates that there is still a lot to learn about this family of peptide antibiotics. In this review, we highlight our system of fast tracking the discovery of novel bacteriocins, belonging to different classes, and isolated from various sources. This system employs molecular mass analysis of supernatant from the candidate strain, coupled with a statistical analysis of their antimicrobial spectra that can even discriminate novel variants of known bacteriocins. This review also discusses current updates regarding the structural characterization, mode of antimicrobial action, and biosynthetic mechanisms of various novel bacteriocins. Future perspectives and potential applications of these novel bacteriocins are also discussed. PMID:25186038

Novel bacteriocins from lactic acid bacteria (LAB): various structures and applications.

PubMed

Perez, Rodney H; Zendo, Takeshi; Sonomoto, Kenji

2014-08-29

Bacteriocins are heat-stable ribosomally synthesized antimicrobial peptides produced by various bacteria, including food-grade lactic acid bacteria (LAB). These antimicrobial peptides have huge potential as both food preservatives, and as next-generation antibiotics targeting the multiple-drug resistant pathogens. The increasing number of reports of new bacteriocins with unique properties indicates that there is still a lot to learn about this family of peptide antibiotics. In this review, we highlight our system of fast tracking the discovery of novel bacteriocins, belonging to different classes, and isolated from various sources. This system employs molecular mass analysis of supernatant from the candidate strain, coupled with a statistical analysis of their antimicrobial spectra that can even discriminate novel variants of known bacteriocins. This review also discusses current updates regarding the structural characterization, mode of antimicrobial action, and biosynthetic mechanisms of various novel bacteriocins. Future perspectives and potential applications of these novel bacteriocins are also discussed.

Barriers to HIV Cure.

PubMed

Stein, J; Storcksdieck Genannt Bonsmann, M; Streeck, H

2016-10-01

Since the beginning of the epidemic, more than 70 million people have been infected with human immunodeficiency virus (HIV) and about 38 million have died from acquired immune deficiency syndrome (AIDS)-related illnesses. While the discovery of highly active antiretroviral therapy (HAART) in the mid 90's has saved millions of lives, a complete eradication of HIV is still not possible as HIV can persist for decades in a small reservoir of latently infected cells. Once reactivated, these latently infected cells can actively produce viral particles. Recent studies suggest that several sanctuaries exist within infected individuals where HIV can remain undetected by the immune system. These cellular, anatomical and microanatomical viral reservoirs represent a major obstacle for the eradication of HIV. Here we review recent findings on potential sanctuaries of HIV and address potential avenues to overcome these immunological barriers. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

PubMed

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

2011-12-01

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

A review of lysergic acid diethylamide (LSD) in the treatment of addictions: historical perspectives and future prospects.

PubMed

Liester, Mitchell B

2014-01-01

Lysergic acid diethylamide (LSD) is a semisynthetic compound with strong psychoactive properties. Chemically related to serotonin, LSD was initially hypothesized to produce a psychosislike state. Later, LSD was reported to have benefits in the treatment of addictions. However, widespread indiscriminate use and reports of adverse affects resulted in the classification of LSD as an illicit drug with no accepted medical use. This article reviews LSD's storied history from its discovery, to its use as a research tool, followed by its widespread association with the counterculture movement of the 1960s, and finally to its rebirth as a medicine with potential benefits in the treatment of addictions. LSD's pharmacology, phenomenology, effects at neurotransmitter receptors, and effects on patterns of gene expression are reviewed. Based upon a review of the literature, it is concluded that further research into LSD's potential as a treatment for addictions is warranted.

The discovery of long-term potentiation.

PubMed

Lømo, Terje

2003-04-29

This paper describes circumstances around the discovery of long-term potentiation (LTP). In 1966, I had just begun independent work for the degree of Dr medicinae (PhD) in Per Andersen's laboratory in Oslo after an eighteen-month apprenticeship with him. Studying the effects of activating the perforant path to dentate granule cells in the hippocampus of anaesthetized rabbits, I observed that brief trains of stimuli resulted in increased efficiency of transmission at the perforant path-granule cell synapses that could last for hours. In 1968, Tim Bliss came to Per Andersen's laboratory to learn about the hippocampus and field potential recording for studies of possible memory mechanisms. The two of us then followed up my preliminary results from 1966 and did the experiments that resulted in a paper that is now properly considered to be the basic reference for the discovery of LTP.

Bead-based screening in chemical biology and drug discovery.

PubMed

Komnatnyy, Vitaly V; Nielsen, Thomas E; Qvortrup, Katrine

2018-06-11

High-throughput screening is an important component of the drug discovery process. The screening of libraries containing hundreds of thousands of compounds requires assays amenable to miniaturisation and automization. Combinatorial chemistry holds a unique promise to deliver structurally diverse libraries for early drug discovery. Among the various library forms, the one-bead-one-compound (OBOC) library, where each bead carries many copies of a single compound, holds the greatest potential for the rapid identification of novel hits against emerging drug targets. However, this potential has not yet been fully realized due to a number of technical obstacles. In this feature article, we review the progress that has been made in bead-based library screening and its application to the discovery of bioactive compounds. We identify the key challenges of this approach and highlight key steps needed for making a greater impact in the field.

Marine actinomycetes: an ongoing source of novel bioactive metabolites.

PubMed

Subramani, Ramesh; Aalbersberg, William

2012-12-20

Actinomycetes are virtually unlimited sources of novel compounds with many therapeutic applications and hold a prominent position due to their diversity and proven ability to produce novel bioactive compounds. There are more than 22,000 known microbial secondary metabolites, 70% of which are produced by actinomycetes, 20% from fungi, 7% from Bacillus spp. and 1-2% by other bacteria. Among the actinomycetes, streptomycetes group are considered economically important because out of the approximately more than 10,000 known antibiotics, 50-55% are produced by this genus. The ecological role of actinomycetes in the marine ecosystem is largely neglected and various assumptions meant there was little incentive to isolate marine strains for search and discovery of new drugs. The search for and discovery of rare and new actinomycetes is of significant interest to drug discovery due to a growing need for the development of new and potent therapeutic agents. Modern molecular technologies are adding strength to the target-directed search for detection and isolation of bioactive actinomycetes, and continued development of improved cultivation methods and molecular technologies for accessing the marine environment promises to provide access to this significant new source of chemical diversity with novel/rare actinomycetes including new species of previously reported actinomycetes. Copyright © 2012 Elsevier GmbH. All rights reserved.

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

PubMed Central

Arbesman, Samuel; Laughlin, Gregory

2010-01-01

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

Risk Assessment Using Cytochrome P450 Time-Dependent Inhibition Assays at Single Time and Concentration in the Early Stage of Drug Discovery.

PubMed

Kosaka, Mai; Kosugi, Yohei; Hirabayashi, Hideki

2017-09-01

In this article, we proposed a risk assessment strategy for CYP3A time-dependent inhibition (TDI) during drug discovery based on a thorough retrospective study of 13 reference drugs, some of which are known to have in vitro TDI potential but have unknown clinical relevance. First, the traditional parameter k inact /K I , recommended by regulatory authorities for necessity decision making in clinical drug-drug interaction (DDI) studies, was investigated as a predictive index for clinical TDI liability. The cutoff value of 1.1 for k inact /K I , established by the Food and Drug Administration, tended to produce false-positive prediction results for clinical DDI occurrence. The value of 1.25 recommended in the European Medicines Evaluation Agency draft guideline yielded better predictions with only 1 false negative for diltiazem. Second, to enable earlier risk assessment, remaining activity, defined as the residual CYP3A activity in vitro obtained in the screening conditions, was investigated as an alternative index. As a result, the ratios of unbound C max or area under the curve to remaining activity precisely predicted clinical DDI occurrence. In conclusion, we demonstrated the predictive power of k inact /K I and remaining activity values for clinical DDIs. These findings provide insights that enable TDI risk assessment, even during drug discovery. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Discovery of a novel amino acid racemase through exploration of natural variation in Arabidopsis thaliana

PubMed Central

Strauch, Renee C.; Svedin, Elisabeth; Dilkes, Brian; Chapple, Clint; Li, Xu

2015-01-01

Plants produce diverse low-molecular-weight compounds via specialized metabolism. Discovery of the pathways underlying production of these metabolites is an important challenge for harnessing the huge chemical diversity and catalytic potential in the plant kingdom for human uses, but this effort is often encumbered by the necessity to initially identify compounds of interest or purify a catalyst involved in their synthesis. As an alternative approach, we have performed untargeted metabolite profiling and genome-wide association analysis on 440 natural accessions of Arabidopsis thaliana. This approach allowed us to establish genetic linkages between metabolites and genes. Investigation of one of the metabolite–gene associations led to the identification of N-malonyl-d-allo-isoleucine, and the discovery of a novel amino acid racemase involved in its biosynthesis. This finding provides, to our knowledge, the first functional characterization of a eukaryotic member of a large and widely conserved phenazine biosynthesis protein PhzF-like protein family. Unlike most of known eukaryotic amino acid racemases, the newly discovered enzyme does not require pyridoxal 5′-phosphate for its activity. This study thus identifies a new d-amino acid racemase gene family and advances our knowledge of plant d-amino acid metabolism that is currently largely unexplored. It also demonstrates that exploitation of natural metabolic variation by integrating metabolomics with genome-wide association is a powerful approach for functional genomics study of specialized metabolism. PMID:26324904

Discovery of a novel amino acid racemase through exploration of natural variation in Arabidopsis thaliana

DOE PAGES

Strauch, Renee C.; Svedin, Elisabeth; Dilkes, Brian; ...

2015-08-31

Plants produce diverse low-molecular-weight compounds via specialized metabolism. Discovery of the pathways underlying production of these metabolites is an important challenge for harnessing the huge chemical diversity and catalytic potential in the plant kingdom for human uses, but this effort is often encumbered by the necessity to initially identify compounds of interest or purify a catalyst involved in their synthesis. Here, as an alternative approach, we have performed untargeted metabolite profiling and genome-wide association analysis on 440 natural accessions of Arabidopsis thaliana. This approach allowed us to establish genetic linkages between metabolites and genes. Investigation of one of the metabolite-genemore » associations led to the identification of N-malonyl-D-allo-isoleucine, and the discovery of a novel amino acid racemase involved in its biosynthesis. This finding provides, to our knowledge, the first functional characterization of a eukaryotic member of a large and widely conserved phenazine biosynthesis protein PhzF-like protein family. Unlike most of known eukaryotic amino acid racemases, the newly discovered enzyme does not require pyridoxal 5'-phosphate for its activity. In conclusion, this study thus identifies a new d-amino acid racemase gene family and advances our knowledge of plant d-amino acid metabolism that is currently largely unexplored. As a result, it also demonstrates that exploitation of natural metabolic variation by integrating metabolomics with genome-wide association is a powerful approach for functional genomics study of specialized metabolism.« less

Discovery of a novel amino acid racemase through exploration of natural variation in Arabidopsis thaliana

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

Strauch, Renee C.; Svedin, Elisabeth; Dilkes, Brian

Plants produce diverse low-molecular-weight compounds via specialized metabolism. Discovery of the pathways underlying production of these metabolites is an important challenge for harnessing the huge chemical diversity and catalytic potential in the plant kingdom for human uses, but this effort is often encumbered by the necessity to initially identify compounds of interest or purify a catalyst involved in their synthesis. Here, as an alternative approach, we have performed untargeted metabolite profiling and genome-wide association analysis on 440 natural accessions of Arabidopsis thaliana. This approach allowed us to establish genetic linkages between metabolites and genes. Investigation of one of the metabolite-genemore » associations led to the identification of N-malonyl-D-allo-isoleucine, and the discovery of a novel amino acid racemase involved in its biosynthesis. This finding provides, to our knowledge, the first functional characterization of a eukaryotic member of a large and widely conserved phenazine biosynthesis protein PhzF-like protein family. Unlike most of known eukaryotic amino acid racemases, the newly discovered enzyme does not require pyridoxal 5'-phosphate for its activity. In conclusion, this study thus identifies a new d-amino acid racemase gene family and advances our knowledge of plant d-amino acid metabolism that is currently largely unexplored. As a result, it also demonstrates that exploitation of natural metabolic variation by integrating metabolomics with genome-wide association is a powerful approach for functional genomics study of specialized metabolism.« less

Discovery of secondary metabolites from Bacillus spp. biocontrol strains using genome mining and mass spectroscopy

USDA-ARS?s Scientific Manuscript database

Genome sequencing, data mining and mass spectrometry were used to identify secondary metabolites produced by several Bacillus spp. biocontrol strains. These biocontrol strains have shown promise in managing Fusarium head blight in wheat. Draft genomes were produced and screened in silico using genom...

Current Status of Genotyping and Discovery Work at USMARC

USDA-ARS?s Scientific Manuscript database

The Illumina BovineSNP50 DNA chip has substantially changed the genetic and genomic research program at USMARC. It has enhanced our commitment to produce genetic tools that can be exported to beef cattle producers to further their selection goals in hard-to-measure traits such as feed efficiency, co...

Cyclopiazonic Acid Biosynthesis of Aspergillus flavus and Aspergillus oryzae

USDA-ARS?s Scientific Manuscript database

Cyclopiazonic acid (CPA) is an indole-tetramic acid neurotoxin produced by some of the same strains of A. flavus that produce aflatoxins and by some Aspergillus oryzae strains. Despite its discovery 40 years ago, few reviews of its toxicity and biosynthesis have been reported. This review examines w...

Ketamine and phencyclidine: the good, the bad and the unexpected

PubMed Central

Lodge, D; Mercier, M S

2015-01-01

The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The findings of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms. PMID:26075331

The Impact of Chemical Probes in Drug Discovery: A Pharmaceutical Industry Perspective.

PubMed

Garbaccio, Robert M; Parmee, Emma R

2016-01-21

Chemical probes represent an important component of both academic and pharmaceutical drug discovery research. As a complement to prior reviews that have defined this scientific field, we aim to provide an industry perspective on the value of having high-quality chemical probes throughout the course of preclinical research. By studying examples from the internal Merck pipeline, we recognize that these probes require significant collaborative investment to realize their potential impact in clarifying the tractability and translation of a given therapeutic target. This perspective concludes with recommendations for chemical probe discovery aimed toward maximizing their potential to identify targets that result in the successful delivery of novel therapeutics. Copyright © 2016 Elsevier Ltd. All rights reserved.

Metagenomics and novel gene discovery

PubMed Central

Culligan, Eamonn P; Sleator, Roy D; Marchesi, Julian R; Hill, Colin

2014-01-01

Metagenomics provides a means of assessing the total genetic pool of all the microbes in a particular environment, in a culture-independent manner. It has revealed unprecedented diversity in microbial community composition, which is further reflected in the encoded functional diversity of the genomes, a large proportion of which consists of novel genes. Herein, we review both sequence-based and functional metagenomic methods to uncover novel genes and outline some of the associated problems of each type of approach, as well as potential solutions. Furthermore, we discuss the potential for metagenomic biotherapeutic discovery, with a particular focus on the human gut microbiome and finally, we outline how the discovery of novel genes may be used to create bioengineered probiotics. PMID:24317337

A systematic study of chemogenomics of carbohydrates.

PubMed

Gu, Jiangyong; Luo, Fang; Chen, Lirong; Yuan, Gu; Xu, Xiaojie

2014-03-04

Chemogenomics focuses on the interactions between biologically active molecules and protein targets for drug discovery. Carbohydrates are the most abundant compounds in natural products. Compared with other drugs, the carbohydrate drugs show weaker side effects. Searching for multi-target carbohydrate drugs can be regarded as a solution to improve therapeutic efficacy and safety. In this work, we collected 60 344 carbohydrates from the Universal Natural Products Database (UNPD) and explored the chemical space of carbohydrates by principal component analysis. We found that there is a large quantity of potential lead compounds among carbohydrates. Then we explored the potential of carbohydrates in drug discovery by using a network-based multi-target computational approach. All carbohydrates were docked to 2389 target proteins. The most potential carbohydrates for drug discovery and their indications were predicted based on a docking score-weighted prediction model. We also explored the interactions between carbohydrates and target proteins to find the pathological networks, potential drug candidates and new indications.

Advancements in Aptamer Discovery Technologies.

PubMed

Gotrik, Michael R; Feagin, Trevor A; Csordas, Andrew T; Nakamoto, Margaret A; Soh, H Tom

2016-09-20

Affinity reagents that specifically bind to their target molecules are invaluable tools in nearly every field of modern biomedicine. Nucleic acid-based aptamers offer many advantages in this domain, because they are chemically synthesized, stable, and economical. Despite these compelling features, aptamers are currently not widely used in comparison to antibodies. This is primarily because conventional aptamer-discovery techniques such as SELEX are time-consuming and labor-intensive and often fail to produce aptamers with comparable binding performance to antibodies. This Account describes a body of work from our laboratory in developing advanced methods for consistently producing high-performance aptamers with higher efficiency, fewer resources, and, most importantly, a greater probability of success. We describe our efforts in systematically transforming each major step of the aptamer discovery process: selection, analysis, and characterization. To improve selection, we have developed microfluidic devices (M-SELEX) that enable discovery of high-affinity aptamers after a minimal number of selection rounds by precisely controlling the target concentration and washing stringency. In terms of improving aptamer pool analysis, our group was the first to use high-throughput sequencing (HTS) for the discovery of new aptamers. We showed that tracking the enrichment trajectory of individual aptamer sequences enables the identification of high-performing aptamers without requiring full convergence of the selected aptamer pool. HTS is now widely used for aptamer discovery, and open-source software has become available to facilitate analysis. To improve binding characterization, we used HTS data to design custom aptamer arrays to measure the affinity and specificity of up to ∼10(4) DNA aptamers in parallel as a means to rapidly discover high-quality aptamers. Most recently, our efforts have culminated in the invention of the "particle display" (PD) screening system, which transforms solution-phase aptamers into "aptamer particles" that can be individually screened at high-throughput via fluorescence-activated cell sorting. Using PD, we have shown the feasibility of rapidly generating aptamers with exceptional affinities, even for proteins that have previously proven intractable to aptamer discovery. We are confident that these advanced aptamer-discovery methods will accelerate the discovery of aptamer reagents with excellent affinities and specificities, perhaps even exceeding those of the best monoclonal antibodies. Since aptamers are reproducible, renewable, stable, and can be distributed as sequence information, we anticipate that these affinity reagents will become even more valuable tools for both research and clinical applications.

Discovery of naked charm particles and lifetime differences among charm species using nuclear emulsion techniques innovated in Japan

PubMed Central

NIU, Kiyoshi

2008-01-01

This is a historical review of the discovery of naked charm particles and lifetime differences among charm species. These discoveries in the field of cosmic-ray physics were made by the innovation of nuclear emulsion techniques in Japan. A pair of naked charm particles was discovered in 1971 in a cosmic-ray interaction, three years prior to the discovery of the hidden charm particle, J/Ψ, in western countries. Lifetime differences between charged and neutral charm particles were pointed out in 1975, which were later re-confirmed by the collaborative Experiment E531 at Fermilab. Japanese physicists led by K.Niu made essential contributions to it with improved emulsion techniques, complemented by electronic detectors. This review also discusses the discovery of artificially produced naked charm particles by us in an accelerator experiment at Fermilab in 1975 and of multiple-pair productions of charm particles in a single interaction in 1987 by the collaborative Experiment WA75 at CERN. PMID:18941283

Radiation Detection Material Discovery Initiative at PNNL

NASA Astrophysics Data System (ADS)

Milbrath, Brian

2006-05-01

Today's security threats are being met with 30-year old radiation technology. Discovery of new radiation detection materials is currently a slow and Edisonian process. With heightened concerns over nuclear proliferation, terrorism and unconventional warfare, an alternative strategy for identification and development of potential radiation detection materials must be adopted. Through the Radiation Detection Materials Discovery Initiative, PNNL focuses on the science-based discovery of next generation materials for radiation detection by addressing three ``grand challenges'': fundamental understanding of radiation detection, identification of new materials, and accelerating the discovery process. The new initiative has eight projects addressing these challenges, which will be described, including early work, paths forward and the opportunities for collaboration.

Nexus Between Protein–Ligand Affinity Rank-Ordering, Biophysical Approaches, and Drug Discovery

PubMed Central

2013-01-01

The confluence of computational and biophysical methods to accurately rank-order the binding affinities of small molecules and determine structures of macromolecular complexes is a potentially transformative advance in the work flow of drug discovery. This viewpoint explores the impact that advanced computational methods may have on the efficacy of small molecule drug discovery and optimization, particularly with respect to emerging fragment-based methods. PMID:24900579

Updates on Managing Type 2 Diabetes Mellitus with Natural Products: Towards Antidiabetic Drug Development.

PubMed

Alam, Fahmida; Islam, Md Asiful; Kamal, M A; Gan, Siew Hua

2016-08-13

Over the years, natural products have shown success as antidiabetics in vitro, in vivo and in clinical trials. Because natural product-derived drugs are more affordable and effective with fewer side-effects compared to conventional therapies, pharmaceutical research is increasingly leaning towards the discovery of new antidiabetic drugs from natural products targeting pathways or components associated with type 2 diabetes mellitus (T2DM) pathophysiology. However, the drug discovery process is very lengthy and costly with significant challenges. Therefore, various techniques are currently being developed for the preclinical research phase of drug discovery with the aim of drug development with less time and efforts from natural products. In this review, we have provided an update on natural products including fruits, vegetables, spices, nuts, beverages and mushrooms with potential antidiabetic activities from in vivo, in vitro and clinical studies. Synergistic interactions between natural products and antidiabetic drugs; and potential antidiabetic active compounds from natural products are also documented to pave the way for combination treatment and new drug discovery, respectively. Additionally, a brief idea of the drug discovery process along with the challenges that arise during drug development from natural products and the methods to conquer those challenges are discussed to create a more convenient future drug discovery process.

High-field MRS in clinical drug development.

PubMed

Ross, Brian D

2013-07-01

Magnetic resonance spectroscopy (MRS) will continue to play an ever increasing role in drug discovery because MRS does readily define biomarkers for several hundreds of clinically distinct diseases. Published evidence based medicine (EBM) surveys, which generally conclude the opposite, are seriously flawed and do a disservice to the field of drug discovery. This article presents MRS and how it has guided several hundreds of practical human 'drug discovery' endeavors since its development. Specifically, the author looks at the process of 'reverse-translation' and its influence in the expansion of the number of preclinical drug discoveries from in vivo MRS. The author also provides a structured approach of eight criteria, including EBM acceptance, which could potentially re-open the field of MRS for productive exploration of existing and repurposed drugs and cost-effective drug-discovery. MRS-guided drug discovery is poised for future expansion. The cost of clinical trials has escalated and the use of biomarkers has become increasingly useful in improving patient selection for drug trials. Clinical MRS has uncovered a treasure-trove of novel biomarkers and clinical MRS itself has become better standardized and more widely available on 'routine' clinical MRI scanners. When combined with available new MRI sequences, MRS can provide a 'one stop shop' with multiple potential outcome measures for the disease and the drug in question.

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.

West Chalkey, Cameron Parish, Louisiana - A case for continued exploration in mature producing provinces

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

Klefstad, G.E.

A potential giant gas field has been discovered in the very mature exploration province of south Louisiana by Transco Exploration Partners (TXP) and Exxon Company USA. The West Chalkley prospect is located in Cameron Parish, Louisiana, and is productive in the upper Oligocene Miogypsinoides (Miogyp) sandstones. The discovery is in the same producing trend as the prolific South Lake Arthur field, where the Miogyp sandstones have gas reserves on the order of 1.0 tcf The prospect was generated by a combination of trend analysis, subsurface well control, and reflection seismic data. The feature appears to be a faulted anticline separatemore » from the nearest production in the area, Chalkley field, which is located about 1 mi cast and discovered in 1938. Both TXP and Exxon, working independently, recognized the potential prospect and pursued leasing activities in the area. TXP initiated discussions with the landowner in February 1988 and acquired a 960 ac lease in June. Exxon leased approximately 2,100 ac surrounding the TXP lease about one month later. TXP subsequently sold the prospect to Exxon on October 12, 1988. The Exxon 1 Sweet Lake Land and Oil Company was spudded on March 16, 1989, and reached total depth of 15,600 ft on July 4, 1989. Log analysis indicated nearly 500 net ft of gas pay in the 805-ft gross productive interval. Testing through perforations near the base of the pay zone yielded flow rates as high as 21.28 MMCFGPD and 338 BOPD. The discovery well is expected to be on production by early 1990 at rates approaching 50 MMCFGPD. Two delineation wells are currently drilling and a deeper pool wildcat is planned to spud around mid-1990 to determine the areal extent and ultimate size of this important new find.« less

Identification of Novel Perfluoroalkyl Ether Carboxylic Acids (PFECAs) and Sulfonic Acids (PFESAs) in Natural Waters Using Accurate Mass Time-of-Flight Mass Spectrometry (TOFMS).

PubMed

Strynar, Mark; Dagnino, Sonia; McMahen, Rebecca; Liang, Shuang; Lindstrom, Andrew; Andersen, Erik; McMillan, Larry; Thurman, Michael; Ferrer, Imma; Ball, Carol

2015-10-06

Recent scientific scrutiny and concerns over exposure, toxicity, and risk have led to international regulatory efforts resulting in the reduction or elimination of certain perfluorinated compounds from various products and waste streams. Some manufacturers have started producing shorter chain per- and polyfluorinated compounds to try to reduce the potential for bioaccumulation in humans and wildlife. Some of these new compounds contain central ether oxygens or other minor modifications of traditional perfluorinated structures. At present, there has been very limited information published on these "replacement chemistries" in the peer-reviewed literature. In this study we used a time-of-flight mass spectrometry detector (LC-ESI-TOFMS) to identify fluorinated compounds in natural waters collected from locations with historical perfluorinated compound contamination. Our workflow for discovery of chemicals included sequential sampling of surface water for identification of potential sources, nontargeted TOFMS analysis, molecular feature extraction (MFE) of samples, and evaluation of features unique to the sample with source inputs. Specifically, compounds were tentatively identified by (1) accurate mass determination of parent and/or related adducts and fragments from in-source collision-induced dissociation (CID), (2) in-depth evaluation of in-source adducts formed during analysis, and (3) confirmation with authentic standards when available. We observed groups of compounds in homologous series that differed by multiples of CF2 (m/z 49.9968) or CF2O (m/z 65.9917). Compounds in each series were chromatographically separated and had comparable fragments and adducts produced during analysis. We detected 12 novel perfluoroalkyl ether carboxylic and sulfonic acids in surface water in North Carolina, USA using this approach. A key piece of evidence was the discovery of accurate mass in-source n-mer formation (H(+) and Na(+)) differing by m/z 21.9819, corresponding to the mass difference between the protonated and sodiated dimers.

"Ripples" in an Aluminum Pool?

NASA Astrophysics Data System (ADS)

Rohr, James; Wang, Si-Yin; Nesterenko, Vitali F.

2018-05-01

Our motivation for this article is for students to realize that opportunities for discovery are all around them. Discoveries that can still puzzle present day researchers. Here we explore an observation by a middle school student concerning the production of what appears to be water-like "ripples" produced in aluminum foil when placed between two colliding spheres. We both applaud and explore the student's reasoning that the ripples were formed in a melted aluminum pool.

Reaching out in new Ways: Bridging the gap Between Science and Media Through the National Oceanic and Atmospheric Administration's Office of Ocean Exploration

NASA Astrophysics Data System (ADS)

Gorell, F. R.; Martinez, C.

2006-12-01

NOAA's Office of Ocean Exploration (OE) was created in response to the recommendations of the President's Panel on Ocean Exploration in 2000. With the establishment of OE, NOAA developed a great opportunity to reach out to teachers, students, and the general public to share the excitement of discovery. As exciting expeditions are the core of our NOAA program, outreach efforts are focused around these cruises. Through various initiatives, OE works with the science community to share the excitement of ocean science and discovery with a wide variety of audiences. Initiatives include media events held during port calls, media conference calls arranged with scientists at sea, journalists' participation in expeditions, and select interviews with scientist-explorers. NOAA OE is now poised to initiate a major ongoing satellite-based education and public outreach program from its new dedicated research vessel, the Okeanos Explorer that will become operational in 2008. Through telepresence technology designed by the Institute for Exploration (IFE) in Mystic, CT, expeditions can be managed `virtually' by scientists working from Science Command Centers on land, live education broadcasts can be produced in real-time, and media events can be held through shore-based consoles connected to scientists at sea. Three pilot programs were successfully completed in the past few years demonstrating the potential for this new technology to allow for unlimited access to data, including video, from expeditions, sharing in real-time the excitement of discovery through multiple virtual pathways. News media provide a powerful means to inform and educate the public. In some cases, scientists may believe that interaction with media representatives poses risks unmatched by rewards. While it is important to serve the public's right to know, scientist-explorers on NOAA-sponsored ocean expeditions have a recognized interest in protecting certain data, including images, for a number of legitimate reasons including the potential for further research to gain greater understanding, and the potential for publishing discoveries in scientific journals. At the same time, NOAA has an interest in informing the public in a timely manner about expedition findings, and seeks to do so via Web site coverage, news releases, embarked media, and news conferences ashore and at sea. These sometimes competing interests require advance planning, understandings and agreements, in a delicate balance of cooperation that serves the interests of all. This is especially true in light of the rapidly developing telepresence technology that allows for immediate transmission of information in real-time.

Scalable Production of Glioblastoma Tumor-initiating Cells in 3 Dimension Thermoreversible Hydrogels

NASA Astrophysics Data System (ADS)

Li, Qiang; Lin, Haishuang; Wang, Ou; Qiu, Xuefeng; Kidambi, Srivatsan; Deleyrolle, Loic P.; Reynolds, Brent A.; Lei, Yuguo

2016-08-01

There is growing interest in developing drugs that specifically target glioblastoma tumor-initiating cells (TICs). Current cell culture methods, however, cannot cost-effectively produce the large numbers of glioblastoma TICs required for drug discovery and development. In this paper we report a new method that encapsulates patient-derived primary glioblastoma TICs and grows them in 3 dimension thermoreversible hydrogels. Our method allows long-term culture (~50 days, 10 passages tested, accumulative ~>1010-fold expansion) with both high growth rate (~20-fold expansion/7 days) and high volumetric yield (~2.0 × 107 cells/ml) without the loss of stemness. The scalable method can be used to produce sufficient, affordable glioblastoma TICs for drug discovery.

Collection and Retention Procedures for Electronically Stored Information (ESI) Collected Using E-Discovery Tools

EPA Pesticide Factsheets

This procedure is designed to support the collection of potentially responsive information using automated E-Discovery tools that rely on keywords, key phrases, index queries, or other technological assistance to retrieve Electronically Stored Information

The discovery of long-term potentiation.

PubMed Central

Lømo, Terje

2003-01-01

This paper describes circumstances around the discovery of long-term potentiation (LTP). In 1966, I had just begun independent work for the degree of Dr medicinae (PhD) in Per Andersen's laboratory in Oslo after an eighteen-month apprenticeship with him. Studying the effects of activating the perforant path to dentate granule cells in the hippocampus of anaesthetized rabbits, I observed that brief trains of stimuli resulted in increased efficiency of transmission at the perforant path-granule cell synapses that could last for hours. In 1968, Tim Bliss came to Per Andersen's laboratory to learn about the hippocampus and field potential recording for studies of possible memory mechanisms. The two of us then followed up my preliminary results from 1966 and did the experiments that resulted in a paper that is now properly considered to be the basic reference for the discovery of LTP. PMID:12740104

Therapeutic Potential of Foldamers: From Chemical Biology Tools To Drug Candidates?

PubMed

Gopalakrishnan, Ranganath; Frolov, Andrey I; Knerr, Laurent; Drury, William J; Valeur, Eric

2016-11-10

Over the past decade, foldamers have progressively emerged as useful architectures to mimic secondary structures of proteins. Peptidic foldamers, consisting of various amino acid based backbones, have been the most studied from a therapeutic perspective, while polyaromatic foldamers have barely evolved from their nascency and remain perplexing for medicinal chemists due to their poor drug-like nature. Despite these limitations, this compound class may still offer opportunities to study challenging targets or provide chemical biology tools. The potential of foldamer drug candidates reaching the clinic is still a stretch. Nevertheless, advances in the field have demonstrated their potential for the discovery of next generation therapeutics. In this perspective, the current knowledge of foldamers is reviewed in a drug discovery context. Recent advances in the early phases of drug discovery including hit finding, target validation, and optimization and molecular modeling are discussed. In addition, challenges and focus areas are debated and gaps highlighted.

Improving Cardiac Action Potential Measurements: 2D and 3D Cell Culture.

PubMed

Daily, Neil J; Yin, Yue; Kemanli, Pinar; Ip, Brian; Wakatsuki, Tetsuro

2015-11-01

Progress in the development of assays for measuring cardiac action potential is crucial for the discovery of drugs for treating cardiac disease and assessing cardiotoxicity. Recently, high-throughput methods for assessing action potential using induced pluripotent stem cell (iPSC) derived cardiomyocytes in both two-dimensional monolayer cultures and three-dimensional tissues have been developed. We describe an improved method for assessing cardiac action potential using an ultra-fast cost-effective plate reader with commercially available dyes. Our methods improve dramatically the detection of the fluorescence signal from these dyes and make way for the development of more high-throughput methods for cardiac drug discovery and cardiotoxicity.

Van Allen Discovery Most Important

NASA Technical Reports Server (NTRS)

Jastrow, R.

1959-01-01

The first step toward the exploration of space occurred approximately 22 months ago as a part of the International Geophysical Year. In the short interval since October, 1957, the new tools of research, the satellite and the space rocket, have produced two unexpected results of fundamental scientific importance. First, instruments placed in the Explorer satellites by James A. Van Allen have revealed the existence of layers of energetic particles in the outer atmosphere. This discovery constitutes the most significant research achievement of the IGY satellite program. The layers may provide the explanation for the aurora and other geophysical phenomena, and they will also influence the design of vehicles for manned space flight, whose occupants must be shielded against their harmful biological effects. Second, the shape of the earth has been determined very accurately with the aid of data from the first Vanguard. As a result of this investigation, we have found that our planet tends toward the shape of a pear, with its stem at the North Pole. This discovery may produce major changes in our ideas on the interior structure of the earth.

Aerogel Development

NASA Technical Reports Server (NTRS)

Sahai, Rashmi K.

2005-01-01

Aerogel is one of the most promising materials of the future. It's unique properties, including high porosity, transparency, very high thermal tolerance, and environmental friendliness give it the potential of replacing many different products used in society today. However, the market for aerogel is still very limited because of the cost of producing the material and its fragility. The principle objective of my project has been to find new ways to apply aerogel in order to increase its practicality and appeal to different aspects of society. More specifically, I have focused on finding different chemicals that will coat aerogel and increase its durability. Because aerogel is so fragile and will crumble under the pressure of most coatings this has been no easy task. However, by experimenting with many different coatings and combinations of aerogel properties, I have made several significant discoveries. Aerogel (ideally, high density and hydrophobic) can be coated with several acrylic polymers, including artist's gel and nail polish. These materials provide a protective layering around the aerogel and keep it from breaking as easily. Because fragility is one of the main reasons applications of aerogel are limited, these discoveries will hopefully aid in finding future applications for this extraordinary material.

Aflatoxin control--how a regulatory agency managed risk from an unavoidable natural toxicant in food and feed.

PubMed

Park, D L; Stoloff, L

1989-04-01

The control by the Food and Drug Administration (FDA) of aflatoxin, a relatively recently discovered, unavoidable natural contaminant produced by specific molds that invade a number of basic food and feedstuffs, provides an example of the varying forces that affect risk assessment and management by a regulatory Agency. This is the story of how the FDA responded to the initial discovery of a potential carcinogenic hazard to humans in a domestic commodity, to the developing information concerning the nature of the hazard, to the economic and political pressures that are created by the impact of natural forces on regulatory controls, and to the restraints of laws within which the Agency must work. This story covers four periods: the years of discovery and action decisions on the basis of meager knowledge and the fear of cancer; the years of tinkering on paper with the regulatory process, the years of digestion of the accumulating knowledge, and the application of that knowledge to actions forced by natural events; and an audit of the current status of knowledge about the hazard from aflatoxin, and proposals for regulatory control based on that knowledge.

Earliest Porotic Hyperostosis on a 1.5-Million-Year-Old Hominin, Olduvai Gorge, Tanzania

PubMed Central

Domínguez-Rodrigo, Manuel; Pickering, Travis Rayne; Diez-Martín, Fernando; Mabulla, Audax; Musiba, Charles; Trancho, Gonzalo; Baquedano, Enrique; Bunn, Henry T.; Barboni, Doris; Santonja, Manuel; Uribelarrea, David; Ashley, Gail M.; Martínez-Ávila, María del Sol; Barba, Rebeca; Gidna, Agness; Yravedra, José; Arriaza, Carmen

2012-01-01

Meat-eating was an important factor affecting early hominin brain expansion, social organization and geographic movement. Stone tool butchery marks on ungulate fossils in several African archaeological assemblages demonstrate a significant level of carnivory by Pleistocene hominins, but the discovery at Olduvai Gorge of a child's pathological cranial fragments indicates that some hominins probably experienced scarcity of animal foods during various stages of their life histories. The child's parietal fragments, excavated from 1.5-million-year-old sediments, show porotic hyperostosis, a pathology associated with anemia. Nutritional deficiencies, including anemia, are most common at weaning, when children lose passive immunity received through their mothers' milk. Our results suggest, alternatively, that (1) the developmentally disruptive potential of weaning reached far beyond sedentary Holocene food-producing societies and into the early Pleistocene, or that (2) a hominin mother's meat-deficient diet negatively altered the nutritional content of her breast milk to the extent that her nursing child ultimately died from malnourishment. Either way, this discovery highlights that by at least 1.5 million years ago early human physiology was already adapted to a diet that included the regular consumption of meat. PMID:23056303

The Skeletal Muscle Satellite Cell

PubMed Central

2011-01-01

The skeletal muscle satellite cell was first described and named based on its anatomic location between the myofiber plasma and basement membranes. In 1961, two independent studies by Alexander Mauro and Bernard Katz provided the first electron microscopic descriptions of satellite cells in frog and rat muscles. These cells were soon detected in other vertebrates and acquired candidacy as the source of myogenic cells needed for myofiber growth and repair throughout life. Cultures of isolated myofibers and, subsequently, transplantation of single myofibers demonstrated that satellite cells were myogenic progenitors. More recently, satellite cells were redefined as myogenic stem cells given their ability to self-renew in addition to producing differentiated progeny. Identification of distinctively expressed molecular markers, in particular Pax7, has facilitated detection of satellite cells using light microscopy. Notwithstanding the remarkable progress made since the discovery of satellite cells, researchers have looked for alternative cells with myogenic capacity that can potentially be used for whole body cell-based therapy of skeletal muscle. Yet, new studies show that inducible ablation of satellite cells in adult muscle impairs myofiber regeneration. Thus, on the 50th anniversary since its discovery, the satellite cell’s indispensable role in muscle repair has been reaffirmed. PMID:22147605

IMG-ABC: new features for bacterial secondary metabolism analysis and targeted biosynthetic gene cluster discovery in thousands of microbial genomes

DOE PAGES

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

2016-11-29

Secondary metabolites produced by microbes have diverse biological functions, which makes them a great potential source of biotechnologically relevant compounds with antimicrobial, anti-cancer and other activities. The proteins needed to synthesize these natural products are often encoded by clusters of co-located genes called biosynthetic gene clusters (BCs). In order to advance the exploration of microbial secondary metabolism, we developed the largest publically available database of experimentally verified and predicted BCs, the Integrated Microbial Genomes Atlas of Biosynthetic gene Clusters (IMG-ABC) (https://img.jgi.doe.gov/abc/). Here, we describe an update of IMG-ABC, which includes ClusterScout, a tool for targeted identification of custom biosynthetic genemore » clusters across 40 000 isolate microbial genomes, and a new search capability to query more than 700 000 BCs from isolate genomes for clusters with similar Pfam composition. Additional features enable fast exploration and analysis of BCs through two new interactive visualization features, a BC function heatmap and a BC similarity network graph. These new tools and features add to the value of IMG-ABC's vast body of BC data, facilitating their in-depth analysis and accelerating secondary metabolite discovery.« less

Dichotomous roles of leptin and adiponectin as enforcers against lipotoxicity during feast and famine.

PubMed

Unger, Roger H; Scherer, Philipp E; Holland, William L

2013-10-01

Science is marked by the death of dogmas; the discovery that adipocytes are more than just lipid-storing cells but rather produce potent hormones is one such example that caught physiologists by surprise and reshaped our views of metabolism. While we once considered the adipocyte as a passive storage organ for efficient storage of long-term energy reserves in the form of triglyceride, we now appreciate the general idea (once a radical one) that adipocytes are sophisticated enough to have potent endocrine functions. Over the past two decades, the discoveries of these adipose-derived factors ("adipokines") and their mechanistic actions have left us marveling at and struggling to understand the role these factors serve in physiology and the pathophysiology of obesity and diabetes. These hormones may serve an integral role in protecting nonadipose tissues from lipid-induced damage during nutrient-deprived or replete states. As such, adipocytes deliver not only potentially cytotoxic free fatty acids but, along with these lipids, antilipotoxic adipokines such as leptin, adiponectin, and fibroblast growth factor 21 that potently eliminate excessive local accumulation of these lipids or their conversion to unfavorable sphingolipid intermediates.

Optimization of the genotyping-by-sequencing strategy for population genomic analysis in conifers.

PubMed

Pan, Jin; Wang, Baosheng; Pei, Zhi-Yong; Zhao, Wei; Gao, Jie; Mao, Jian-Feng; Wang, Xiao-Ru

2015-07-01

Flexibility and low cost make genotyping-by-sequencing (GBS) an ideal tool for population genomic studies of nonmodel species. However, to utilize the potential of the method fully, many parameters affecting library quality and single nucleotide polymorphism (SNP) discovery require optimization, especially for conifer genomes with a high repetitive DNA content. In this study, we explored strategies for effective GBS analysis in pine species. We constructed GBS libraries using HpaII, PstI and EcoRI-MseI digestions with different multiplexing levels and examined the effect of restriction enzymes on library complexity and the impact of sequencing depth and size selection of restriction fragments on sequence coverage bias. We tested and compared UNEAK, Stacks and GATK pipelines for the GBS data, and then developed a reference-free SNP calling strategy for haploid pine genomes. Our GBS procedure proved to be effective in SNP discovery, producing 7000-11 000 and 14 751 SNPs within and among three pine species, respectively, from a PstI library. This investigation provides guidance for the design and analysis of GBS experiments, particularly for organisms for which genomic information is lacking. © 2014 John Wiley & Sons Ltd.

IMG-ABC: new features for bacterial secondary metabolism analysis and targeted biosynthetic gene cluster discovery in thousands of microbial genomes

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

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

Secondary metabolites produced by microbes have diverse biological functions, which makes them a great potential source of biotechnologically relevant compounds with antimicrobial, anti-cancer and other activities. The proteins needed to synthesize these natural products are often encoded by clusters of co-located genes called biosynthetic gene clusters (BCs). In order to advance the exploration of microbial secondary metabolism, we developed the largest publically available database of experimentally verified and predicted BCs, the Integrated Microbial Genomes Atlas of Biosynthetic gene Clusters (IMG-ABC) (https://img.jgi.doe.gov/abc/). Here, we describe an update of IMG-ABC, which includes ClusterScout, a tool for targeted identification of custom biosynthetic genemore » clusters across 40 000 isolate microbial genomes, and a new search capability to query more than 700 000 BCs from isolate genomes for clusters with similar Pfam composition. Additional features enable fast exploration and analysis of BCs through two new interactive visualization features, a BC function heatmap and a BC similarity network graph. These new tools and features add to the value of IMG-ABC's vast body of BC data, facilitating their in-depth analysis and accelerating secondary metabolite discovery.« less

Advanced Visualization and Interactive Display Rapid Innovation and Discovery Evaluation Research (VISRIDER) Program Task 6: Point Cloud Visualization Techniques for Desktop and Web Platforms

DTIC Science & Technology

2017-04-01

ADVANCED VISUALIZATION AND INTERACTIVE DISPLAY RAPID INNOVATION AND DISCOVERY EVALUATION RESEARCH (VISRIDER) PROGRAM TASK 6: POINT CLOUD...To) OCT 2013 – SEP 2014 4. TITLE AND SUBTITLE ADVANCED VISUALIZATION AND INTERACTIVE DISPLAY RAPID INNOVATION AND DISCOVERY EVALUATION RESEARCH...various point cloud visualization techniques for viewing large scale LiDAR datasets. Evaluate their potential use for thick client desktop platforms

5 CFR 1201.72 - Explanation and scope of discovery.

Code of Federal Regulations, 2010 CFR

2010-01-01

... obtain relevant information, including the identification of potential witnesses, from another person or a party, that the other person or party has not otherwise provided. Relevant information includes information that appears reasonably calculated to lead to the discovery of admissible evidence. This...

Phenotypic mutant library: potential for gene discovery

USDA-ARS?s Scientific Manuscript database

The rapid development of high throughput and affordable Next- Generation Sequencing (NGS) techniques has renewed interest in gene discovery using forward genetics. The conventional forward genetic approach starts with isolation of mutants with a phenotype of interest, mapping the mutation within a s...

Potentials for win-win alliances among animal agriculture and forest products industries: application of the principles of industrial ecology and sustainable development.

PubMed

Cowling, Ellis B; Furiness, Carl S

2005-12-01

Commercial forests in many parts of the world are deficient in nitrogen and phosphorus. These nutrient-deficient forests often exist in close proximity to large animal feeding operations, meat processing and other food, textile, or other biomass-processing plants, and municipal waste treatment facilities. Many of these facilities produce large surpluses of nitrogen, phosphorus, and organic matter as gaseous ammonia, urea, uric acid, phosphorus compounds, bacterial sludges, and partially treated municipal wastewaters. These co-existing and substantial nutrient deficiencies and surpluses offer ready-made opportunities for discovery, demonstration, and commercial development of science-based, technology-facilitated, environmentally sound, economically viable, and socially acceptable "win-win alliances" among these major industries based on the principles of industrial ecology and sustainable development. The major challenge is to discover practical means to capture the surplus nutrients and put them to work in forest stands from which value-added products can be produced and sold at a profit.

First measurement of surface nuclear recoil background for argon dark matter searches

DOE PAGES

Xu, Jingke; Stanford, Chris; Westerdale, Shawn; ...

2017-09-19

Here, one major background in direct searches for weakly interacting massive particles (WIMPs) comes from the deposition of radon progeny on detector surfaces. A dangerous surface background is the 206Pb nuclear recoils produced by 210Po decays. In this paper, we report the first characterization of this background in liquid argon. The scintillation signal of low energy Pb recoils is measured to be highly quenched in argon, and we estimate that the 103 keV 206Pb recoil background will produce a signal equal to that of a ~5 keV (30 keV) electron recoil ( 40Ar recoil). In addition, we demonstrate that thismore » dangerous 210Po surface background can be suppressed, using pulse shape discrimination methods, by a factor of ~100 or higher, which can make argon dark matter detectors near background-free and enhance their potential for discovery of medium- and high-mass WIMPs. Lastly, we also discuss the impact on other low background experiments.« less

Novel anti-infective compounds from marine bacteria.

PubMed

Rahman, Hafizur; Austin, Brian; Mitchell, Wilfrid J; Morris, Peter C; Jamieson, Derek J; Adams, David R; Spragg, Andrew Mearns; Schweizer, Michael

2010-03-05

As a result of the continuous evolution of microbial pathogens towards antibiotic-resistance, there have been demands for the development of new and effective antimicrobial compounds. Since the 1960s, the scientific literature has accumulated many publications about novel pharmaceutical compounds produced by a diverse range of marine bacteria. Indeed, marine micro-organisms continue to be a productive and successful focus for natural products research, with many newly isolated compounds possessing potentially valuable pharmacological activities. In this regard, the marine environment will undoubtedly prove to be an increasingly important source of novel antimicrobial metabolites, and selective or targeted approaches are already enabling the recovery of a significant number of antibiotic-producing micro-organisms. The aim of this review is to consider advances made in the discovery of new secondary metabolites derived from marine bacteria, and in particular those effective against the so called "superbugs", including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE), which are largely responsible for the increase in numbers of hospital acquired, i.e., nosocomial, infections.

Cloned animal products in the human food chain: FDA should protect American consumers.

PubMed

Butler, Jennifer E F

2009-01-01

Animal cloning is "complex process that lets one exactly copy the genetic, or inherited, traits of an animal." In 1997, Dolly the sheep was the first animal cloned and since then "scientists have used animal cloning to breed dairy cows, beef cattle, poultry, hogs and other species of livestock." Cloned animals are highly attractive to livestock breeders because "cloning essentially produces an identical copy of an animal with superior traits." The main purpose of cloning livestock is "more focused on efficiency and economic benefits of the producer rather than the overall effect of cloning on an animal's physical and mental welfare." The focus of this article is threefold. First, the science behind animal cloning is explained and some potential uses and risks of this technology are explored. Second, FDA's historical evolution, current regulatory authority, and limitations of that authority, is described. Lastly, a new regulatory vision recognizes the realities of 21st century global markets and the dynamic evolution of scientific discovery and technology.

Bioprospecting for microbial products that affect ice crystal formation and growth.

PubMed

Christner, Brent C

2010-01-01

At low temperatures, some organisms produce proteins that affect ice nucleation, ice crystal structure, and/or the process of recrystallization. Based on their ice-interacting properties, these proteins provide an advantage to species that commonly experience the phase change from water to ice or rarely experience temperatures above the melting point. Substances that bind, inhibit or enhance, and control the size, shape, and growth of ice crystals could offer new possibilities for a number of agricultural, biomedical, and industrial applications. Since their discovery more than 40 years ago, ice nucleating and structuring proteins have been used in cryopreservation, frozen food preparation, transgenic crops, and even weather modification. Ice-interacting proteins have demonstrated commercial value in industrial applications; however, the full biotechnological potential of these products has yet to be fully realized. The Earth's cold biosphere contains an almost endless diversity of microorganisms to bioprospect for microbial compounds with novel ice-interacting properties. Microorganisms are the most appropriate biochemical factories to cost effectively produce ice nucleating and structuring proteins on large commercial scales.

Discovery and toxicity assessment of a novel type A trichothecene produced by US isolates of Fusarium graminearum

USDA-ARS?s Scientific Manuscript database

The filamentous fungus Fusarium graminearum shows a widespread occurrence across temperate regions of the world and can produce several mycotoxins on almost every cereal. A large-scale survey of F. graminearum (sensu stricto) on wheat in the northern United States was conducted to investigate the po...

Discovery of a dhurrin QTL in sorghum bicolor: colocalization of dhurrin biosynthesis and a novel stay-green QTL

USDA-ARS?s Scientific Manuscript database

Dhurrin [(S)-p-hydroxymandelonitrile-ß-D-glucopyranoside] is a cyanogenic glucoside produced by (Sorghum bicolor L. Moench) and is generally considered a natural defense compound capable of producing the toxin hydrogen cyanide (HCN) to deter animal herbivory. Recently, high levels of leaf dhurrin h...

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

Al Gore did Not Invent the Internet, Hans Christian Oersted did in 1820

NASA Astrophysics Data System (ADS)

Roberts, James; Anand, Aman; Dahiya, Jai

2009-04-01

In this talk it will be shown how the simple process of a current in a wire producing ``action at a distance'' in a compass can lead to development of the telegraph, telephone, wireless communication and finally to the internet. This discovery led to the invention of a motor and an electric generator. Such simple discoveries often have profound effects on what we are able to do. A discussion of how activities based on this discovery are being used in the Regional Collaborative for Excellence in Science Teaching UNT to engage students and teachers in science activities. Hand out materials will be provided to the audience on these activities.

Sequence- and Interactome-Based Prediction of Viral Protein Hotspots Targeting Host Proteins: A Case Study for HIV Nef

PubMed Central

Sarmady, Mahdi; Dampier, William; Tozeren, Aydin

2011-01-01

Virus proteins alter protein pathways of the host toward the synthesis of viral particles by breaking and making edges via binding to host proteins. In this study, we developed a computational approach to predict viral sequence hotspots for binding to host proteins based on sequences of viral and host proteins and literature-curated virus-host protein interactome data. We use a motif discovery algorithm repeatedly on collections of sequences of viral proteins and immediate binding partners of their host targets and choose only those motifs that are conserved on viral sequences and highly statistically enriched among binding partners of virus protein targeted host proteins. Our results match experimental data on binding sites of Nef to host proteins such as MAPK1, VAV1, LCK, HCK, HLA-A, CD4, FYN, and GNB2L1 with high statistical significance but is a poor predictor of Nef binding sites on highly flexible, hoop-like regions. Predicted hotspots recapture CD8 cell epitopes of HIV Nef highlighting their importance in modulating virus-host interactions. Host proteins potentially targeted or outcompeted by Nef appear crowding the T cell receptor, natural killer cell mediated cytotoxicity, and neurotrophin signaling pathways. Scanning of HIV Nef motifs on multiple alignments of hepatitis C protein NS5A produces results consistent with literature, indicating the potential value of the hotspot discovery in advancing our understanding of virus-host crosstalk. PMID:21738584

High-throughput platform for the discovery of elicitors of silent bacterial gene clusters.

PubMed

Seyedsayamdost, Mohammad R

2014-05-20

Over the past decade, bacterial genome sequences have revealed an immense reservoir of biosynthetic gene clusters, sets of contiguous genes that have the potential to produce drugs or drug-like molecules. However, the majority of these gene clusters appear to be inactive for unknown reasons prompting terms such as "cryptic" or "silent" to describe them. Because natural products have been a major source of therapeutic molecules, methods that rationally activate these silent clusters would have a profound impact on drug discovery. Herein, a new strategy is outlined for awakening silent gene clusters using small molecule elicitors. In this method, a genetic reporter construct affords a facile read-out for activation of the silent cluster of interest, while high-throughput screening of small molecule libraries provides potential inducers. This approach was applied to two cryptic gene clusters in the pathogenic model Burkholderia thailandensis. The results not only demonstrate a prominent activation of these two clusters, but also reveal that the majority of elicitors are themselves antibiotics, most in common clinical use. Antibiotics, which kill B. thailandensis at high concentrations, act as inducers of secondary metabolism at low concentrations. One of these antibiotics, trimethoprim, served as a global activator of secondary metabolism by inducing at least five biosynthetic pathways. Further application of this strategy promises to uncover the regulatory networks that activate silent gene clusters while at the same time providing access to the vast array of cryptic molecules found in bacteria.

Geology and hydrocarbon potential in the state of Qatar, Arabian Gulf

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

Alsharhan, A.S.; Nairn, A.E.M.

The state of Qatar is situated in the southern Arabian Gulf and covers an area of 12,000 km{sup 2}. It is formed by a large, broad anticline, which is part of the regional south-southwest-north-northeast-trending Qatar-South Fars arch. The arch separates the two Infracambrian salt basins. The Dukhan field was the first discovery, made in 1939, in the Upper Jurassic limestones. Since then, a series of discoveries have been made so that Qatar has become one of the leading OPEC oil states. Hydrocarbon accumulations are widely dispersed throughout the stratigraphic column from upper Paleozoic to Cretaceous producing strata. The most prolificmore » reservoirs are the Permian and Mesozoic shelf carbonate sequences. Minor clastic reservoirs occur in the Albian and Paleozoic sequences. Seals, mainly anhydrite and shale. occur both intraformationally and regionally. Several stratigraphic intervals contain source rocks or potential source rocks. The Silurian shales arc the most likely source of the hydrocarbon stored in the upper Paleozoic clastics and carbonates. The upper Oxfordian-middle Kimmeridgian rocks formed in the extensive starved basin during the Mesozoic period of sea level rise. Total organic carbon ranges between 1 and 6%, with the sulfur content approximately 9%. The source material consists of sapropelic liptodetrinite and algae. The geological background of the sedimentary facies through geologic time, stratigraphy, and structural evolution which control source, and the subsequent timing and migration of large-scale hydrocarbon generation are presented in detail.« less

Predictive teratology: teratogenic risk-hazard identification partnered in the discovery process.

PubMed

Augustine-Rauch, K A

2008-11-01

Unexpected teratogenicity is ranked as one of the most prevalent causes for toxicity-related attrition of drug candidates. Without proactive assessment, the liability tends to be identified relatively late in drug development, following significant investment in compound and engagement in pre clinical and clinical studies. When unexpected teratogenicity occurs in pre-clinical development, three principle questions arise: Can clinical trials that include women of child bearing populations be initiated? Will all compounds in this pharmacological class produce the same liability? Could this effect be related to the chemical structure resulting in undesirable off-target adverse effects? The first question is typically addressed at the time of the unexpected finding and involves considering the nature of the teratogenicity, whether or not maternal toxicity could have had a role in onset, human exposure margins and therapeutic indication. The latter two questions can be addressed proactively, earlier in the discovery process as drug target profiling and lead compound optimization is taking place. Such proactive approaches include thorough assessment of the literature for identification of potential liabilities and follow-up work that can be conducted on the level of target expression and functional characterization using molecular biology and developmental model systems. Developmental model systems can also be applied in the form of in vitro teratogenicity screens, and show potential for effective hazard identification or issue resolution on the level of characterizing teratogenic mechanism. This review discusses approaches that can be applied for proactive assessment of compounds for teratogenic liability.

Pharmacological Potential of Phylogenetically Diverse Actinobacteria Isolated from Deep-Sea Coral Ecosystems of the Submarine Avilés Canyon in the Cantabrian Sea.

PubMed

Sarmiento-Vizcaíno, Aida; González, Verónica; Braña, Alfredo F; Palacios, Juan J; Otero, Luis; Fernández, Jonathan; Molina, Axayacatl; Kulik, Andreas; Vázquez, Fernando; Acuña, José L; García, Luis A; Blanco, Gloria

2017-02-01

Marine Actinobacteria are emerging as an unexplored source for natural product discovery. Eighty-seven deep-sea coral reef invertebrates were collected during an oceanographic expedition at the submarine Avilés Canyon (Asturias, Spain) in a range of 1500 to 4700 m depth. From these, 18 cultivable bioactive Actinobacteria were isolated, mainly from corals, phylum Cnidaria, and some specimens of phyla Echinodermata, Porifera, Annelida, Arthropoda, Mollusca and Sipuncula. As determined by 16S rRNA sequencing and phylogenetic analyses, all isolates belong to the phylum Actinobacteria, mainly to the Streptomyces genus and also to Micromonospora, Pseudonocardia and Myceligenerans. Production of bioactive compounds of pharmacological interest was investigated by high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) techniques and subsequent database comparison. Results reveal that deep-sea isolated Actinobacteria display a wide repertoire of secondary metabolite production with a high chemical diversity. Most identified products (both diffusible and volatiles) are known by their contrasted antibiotic or antitumor activities. Bioassays with ethyl acetate extracts from isolates displayed strong antibiotic activities against a panel of important resistant clinical pathogens, including Gram-positive and Gram-negative bacteria, as well as fungi, all of them isolated at two main hospitals (HUCA and Cabueñes) from the same geographical region. The identity of the active extracts components of these producing Actinobacteria is currently being investigated, given its potential for the discovery of pharmaceuticals and other products of biotechnological interest.

NASA's Discovery Program: Moving Toward the Edge (of the Solar System)

NASA Technical Reports Server (NTRS)

Johnson, Les; Gilbert, Paul

2007-01-01

NASA's Planetary Science , Division sponsors a competitive program of small spacecraft missions with the goal of performing focused science investigations that complement NASA's larger planetary science explorations at relatively low cost. The goal of the Discovery program is to launch many smaller missions with fast development times to increase our understanding of the solar system by exploring the planets, dwarf planets, their moons, and small bodies such as comets and asteroids. Discovery missions are solicited from the broad planetary science community approximately every 2 years. Active missions within the Discovery program include several with direct scientific or engineering connections to potential future missions to the edge of the solar system and beyond. In addition to those in the Discovery program are the missions of the New Frontiers program. The first New Frontiers mission. is the New Horizons mission to Pluto, which will explore this 38-AU distant dwarf planet and potentially some Kuiper Belt objects beyond. The Discovery program's Dawn mission, when launched in mid-2007, will use ion drive as its primary propulsion system. Ion propulsion is one of only two technologies that appear feasible for early interstellar precursor missions with practical flight times. The Kepler mission will explore the structure and diversity of extrasolar planetary systems, with an emphasis on the detection of Earth-size planets around other stars. Kepler will survey nearby solar systems searching for planets that may fall within the habitable zone,' a region surrounding a star within which liquid water may exist on a planet's surface - an essential ingredient for life as we know it. With its open and competitive approach to mission selections, the Discovery program affords scientists the opportunity to propose missions to virtually any solar system destination. With its emphasis on science and proven openness to the use of new technologies such as ion propulsion, missions flown as part of the program will test out technologies needed for future very deep-space exploration and potentially take us to these difficult and distant destinations.

Blueprint for antimicrobial hit discovery targeting metabolic networks.

PubMed

Shen, Y; Liu, J; Estiu, G; Isin, B; Ahn, Y-Y; Lee, D-S; Barabási, A-L; Kapatral, V; Wiest, O; Oltvai, Z N

2010-01-19

Advances in genome analysis, network biology, and computational chemistry have the potential to revolutionize drug discovery by combining system-level identification of drug targets with the atomistic modeling of small molecules capable of modulating their activity. To demonstrate the effectiveness of such a discovery pipeline, we deduced common antibiotic targets in Escherichia coli and Staphylococcus aureus by identifying shared tissue-specific or uniformly essential metabolic reactions in their metabolic networks. We then predicted through virtual screening dozens of potential inhibitors for several enzymes of these reactions and showed experimentally that a subset of these inhibited both enzyme activities in vitro and bacterial cell viability. This blueprint is applicable for any sequenced organism with high-quality metabolic reconstruction and suggests a general strategy for strain-specific antiinfective therapy.

Accelerating the Rate of Astronomical Discovery

NASA Astrophysics Data System (ADS)

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

2010-05-01

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

Chemical Space of DNA-Encoded Libraries.

PubMed

Franzini, Raphael M; Randolph, Cassie

2016-07-28

In recent years, DNA-encoded chemical libraries (DECLs) have attracted considerable attention as a potential discovery tool in drug development. Screening encoded libraries may offer advantages over conventional hit discovery approaches and has the potential to complement such methods in pharmaceutical research. As a result of the increased application of encoded libraries in drug discovery, a growing number of hit compounds are emerging in scientific literature. In this review we evaluate reported encoded library-derived structures and identify general trends of these compounds in relation to library design parameters. We in particular emphasize the combinatorial nature of these libraries. Generally, the reported molecules demonstrate the ability of this technology to afford hits suitable for further lead development, and on the basis of them, we derive guidelines for DECL design.

The Production of 3D Tumor Spheroids for Cancer Drug Discovery

PubMed Central

Sant, Shilpa; Johnston, Paul A.

2017-01-01

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

Discovery sequence and the nature of low permeability gas accumulations

USGS Publications Warehouse

Attanasi, E.D.

2005-01-01

There is an ongoing discussion regarding the geologic nature of accumulations that host gas in low-permeability sandstone environments. This note examines the discovery sequence of the accumulations in low permeability sandstone plays that were classified as continuous-type by the U.S. Geological Survey for the 1995 National Oil and Gas Assessment. It compares the statistical character of historical discovery sequences of accumulations associated with continuous-type sandstone gas plays to those of conventional plays. The seven sandstone plays with sufficient data exhibit declining size with sequence order, on average, and in three of the seven the trend is statistically significant. Simulation experiments show that both a skewed endowment size distribution and a discovery process that mimics sampling proportional to size are necessary to generate a discovery sequence that consistently produces a statistically significant negative size order relationship. The empirical findings suggest that discovery sequence could be used to constrain assessed gas in untested areas. The plays examined represent 134 of the 265 trillion cubic feet of recoverable gas assessed in undeveloped areas of continuous-type gas plays in low permeability sandstone environments reported in the 1995 National Assessment. ?? 2005 International Association for Mathematical Geology.

Gut microbiota derived metabolites in cardiovascular health and disease.

PubMed

Wang, Zeneng; Zhao, Yongzhong

2018-05-03

Trillions of microbes inhabit the human gut, not only providing nutrients and energy to the host from the ingested food, but also producing metabolic bioactive signaling molecules to maintain health and elicit disease, such as cardiovascular disease (CVD). CVD is the leading cause of mortality worldwide. In this review, we presented gut microbiota derived metabolites involved in cardiovascular health and disease, including trimethylamine-N-oxide (TMAO), uremic toxins, short chain fatty acids (SCFAs), phytoestrogens, anthocyanins, bile acids and lipopolysaccharide. These gut microbiota derived metabolites play critical roles in maintaining a healthy cardiovascular function, and if dysregulated, potentially causally linked to CVD. A better understanding of the function and dynamics of gut microbiota derived metabolites holds great promise toward mechanistic predicative CVD biomarker discoveries and precise interventions.

Flavour physics and the Large Hadron Collider beauty experiment.

PubMed

Gibson, Valerie

2012-02-28

An exciting new era in flavour physics has just begun with the start of the Large Hadron Collider (LHC). The LHCb (where b stands for beauty) experiment, designed specifically to search for new phenomena in quantum loop processes and to provide a deeper understanding of matter-antimatter asymmetries at the most fundamental level, is producing many new and exciting results. It gives me great pleasure to describe a selected few of the results here-in particular, the search for rare B(0)(s)-->μ+ μ- decays and the measurement of the B(0)(s) charge-conjugation parity-violating phase, both of which offer high potential for the discovery of new physics at and beyond the LHC energy frontier in the very near future.

ZVI (Fe0) desalination: catalytic partial desalination of saline aquifers

NASA Astrophysics Data System (ADS)

Antia, David D. J.

2018-05-01

Globally, salinization affects between 100 and 1000 billion m3 a-1 of irrigation water. The discovery that zero valent iron (ZVI, Fe0) could be used to desalinate water (using intra-particle catalysis in a diffusion environment) raises the possibility that large-scale in situ desalination of aquifers could be undertaken to support agriculture. ZVI desalination removes NaCl by an adsorption-desorption process in a multi-stage cross-coupled catalytic process. This study considers the potential application of two ZVI desalination catalyst types for in situ aquifer desalination. The feasibility of using ZVI catalysts when placed in situ within an aquifer to produce 100 m3 d-1 of partially desalinated water from a saline aquifer is considered.

Fundamental Aspects on Conductive Textiles Implemented in Intelligent System

NASA Astrophysics Data System (ADS)

Manea, L. R.; Hristian, L.; Ene, D.; Amariei, N.; Popa, A.

2017-06-01

Conductive fibers, which are electrically conductive elements having the structure of a fiber, have a fairly long history and have been used for applications in electronic textiles as well as for aesthetics, anti-static and shielding purposes. Electrically conducting textile fibers, such as gold-coated threads, were produced in antiquity for aesthetic purposes, before the discovery of electricity, using various manufacturing methods. The textile intelligent systems, which comprise conducting textile structures (electroconducting wires or structures), present a dynamic behavior which favors the self regulation of the thermal insulation and vapor permeability with the purpose to maintain the thermo-physiological balance; the clothing assembly aims at monitoring the biologic potential, used only in critical situation (ex. accidents, falling down in a precipice etc.).

Circular RNAs: analysis, expression and potential functions

PubMed Central

Salzman, Julia

2016-01-01

Just a few years ago, it had been assumed that the dominant RNA isoforms produced from eukaryotic genes were variants of messenger RNA, functioning as intermediates in gene expression. In early 2012, however, a surprising discovery was made: circular RNA (circRNA) was shown to be a transcriptional product in thousands of human and mouse genes and in hundreds of cases constituted the dominant RNA isoform. Subsequent studies revealed that the expression of circRNAs is developmentally regulated, tissue and cell-type specific, and shared across the eukaryotic tree of life. These features suggest important functions for these molecules. Here, we describe major advances in the field of circRNA biology, focusing on the regulation of and functional roles played by these molecules. PMID:27246710

On the Faceting and Linking of PROV for Earth Science Data Systems

NASA Astrophysics Data System (ADS)

Hua, H.; Manipon, G.; Wilson, B. D.; Tan, D.; Starch, M.

2015-12-01

Faceted search has yielded powerful capabilities for discovery of information by applying multiple filters to explore information. This is often more effective when the information is decomposed into faceted components that can be sliced and diced during faceted navigation. We apply this approach to the representation of PROV for Earth Science (PROV-ES) to facilitate more atomic units of provenance for discovery. Traditional bundles of PROV are then decomposed to enable finer-grain discovery of provenance. Linkages across provenance components can then be explored across seemingly disparate bundles. We will show how mappings into this provenance approach can be used to explore more data life-cycle relationships from observation to data to findings. We will also show examples of how this approach can be used to improve the discovery, access, and transparency of NASA datasets and the science data systems that were used to capture, manage, and produce the provenance information.

Induced pluripotent stem cells for regenerative cardiovascular therapies and biomedical discovery.

PubMed

Nsair, Ali; MacLellan, W Robb

2011-04-30

The discovery of induced pluripotent stem cells (iPSC) has, in the short time since their discovery, revolutionized the field of stem cell biology. This technology allows the generation of a virtually unlimited supply of cells with pluripotent potential similar to that of embryonic stem cells (ESC). However, in contrast to ESC, iPSC are not subject to the same ethical concerns and can be easily generated from living individuals. For the first time, patient-specific iPSC can be generated and offer a supply of genetically identical cells that can be differentiated into all somatic cell types for potential use in regenerative therapies or drug screening and testing. As the techniques for generation of iPSC lines are constantly evolving, new uses for human iPSC are emerging from in-vitro disease modeling to high throughput drug discovery and screening. This technology promises to revolutionize the field of medicine and offers new hope for understanding and treatment of numerous diseases. Copyright © 2011 Elsevier B.V. All rights reserved.

Bioinformatics in protein kinases regulatory network and drug discovery.

PubMed

Chen, Qingfeng; Luo, Haiqiong; Zhang, Chengqi; Chen, Yi-Ping Phoebe

2015-04-01

Protein kinases have been implicated in a number of diseases, where kinases participate many aspects that control cell growth, movement and death. The deregulated kinase activities and the knowledge of these disorders are of great clinical interest of drug discovery. The most critical issue is the development of safe and efficient disease diagnosis and treatment for less cost and in less time. It is critical to develop innovative approaches that aim at the root cause of a disease, not just its symptoms. Bioinformatics including genetic, genomic, mathematics and computational technologies, has become the most promising option for effective drug discovery, and has showed its potential in early stage of drug-target identification and target validation. It is essential that these aspects are understood and integrated into new methods used in drug discovery for diseases arisen from deregulated kinase activity. This article reviews bioinformatics techniques for protein kinase data management and analysis, kinase pathways and drug targets and describes their potential application in pharma ceutical industry. Copyright © 2015 Elsevier Inc. All rights reserved.

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

PubMed Central

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

2003-01-01

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

42 CFR 1005.7 - Discovery.

Code of Federal Regulations, 2011 CFR

2011-10-01

... data stored in an electronic data storage system will be produced in a form accessible to the... information, reports, answers, records, accounts, papers and other data and documentary evidence. Nothing...

42 CFR 1005.7 - Discovery.

Code of Federal Regulations, 2013 CFR

2013-10-01

... data stored in an electronic data storage system will be produced in a form accessible to the... information, reports, answers, records, accounts, papers and other data and documentary evidence. Nothing...

42 CFR 3.516 - Discovery.

Code of Federal Regulations, 2014 CFR

2014-10-01

... data stored in an electronic data storage system must be produced in a form accessible to the... information, reports, answers, records, accounts, papers and other data and documentary evidence. Nothing...

42 CFR 1005.7 - Discovery.

Code of Federal Regulations, 2014 CFR

2014-10-01

... data stored in an electronic data storage system will be produced in a form accessible to the... information, reports, answers, records, accounts, papers and other data and documentary evidence. Nothing...

42 CFR 3.516 - Discovery.

Code of Federal Regulations, 2011 CFR

2011-10-01

... data stored in an electronic data storage system must be produced in a form accessible to the... information, reports, answers, records, accounts, papers and other data and documentary evidence. Nothing...

42 CFR 1005.7 - Discovery.

Code of Federal Regulations, 2012 CFR

2012-10-01

... data stored in an electronic data storage system will be produced in a form accessible to the... information, reports, answers, records, accounts, papers and other data and documentary evidence. Nothing...

42 CFR 3.516 - Discovery.

Code of Federal Regulations, 2013 CFR

2013-10-01

... data stored in an electronic data storage system must be produced in a form accessible to the... information, reports, answers, records, accounts, papers and other data and documentary evidence. Nothing...

42 CFR 3.516 - Discovery.

Code of Federal Regulations, 2012 CFR

2012-10-01

... data stored in an electronic data storage system must be produced in a form accessible to the... information, reports, answers, records, accounts, papers and other data and documentary evidence. Nothing...

Simulated JWST/NIRISS Transit Spectroscopy of Anticipated Tess Planets Compared to Select Discoveries from Space-based and Ground-based Surveys

NASA Astrophysics Data System (ADS)

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

2018-04-01

The Transiting Exoplanet Survey Satellite (TESS) will embark in 2018 on a 2 year wide-field survey mission, discovering over a thousand terrestrial, super-Earth and sub-Neptune-sized exoplanets ({R}pl}≤slant 4 {R}\\oplus ) potentially suitable for follow-up observations using the James Webb Space Telescope (JWST). This work aims to understand the suitability of anticipated TESS planet discoveries for atmospheric characterization by JWST’s Near InfraRed Imager and Slitless Spectrograph (NIRISS) by employing a simulation tool to estimate the signal-to-noise (S/N) achievable in transmission spectroscopy. We applied this tool to Monte Carlo predictions of the TESS expected planet yield and then compared the S/N for anticipated TESS discoveries to our estimates of S/N for 18 known exoplanets. We analyzed the sensitivity of our results to planetary composition, cloud cover, and presence of an observational noise floor. We find that several hundred anticipated TESS discoveries with radii 1.5 {R}\\oplus < {R}pl}≤slant 2.5 {R}\\oplus will produce S/N higher than currently known exoplanets in this radius regime, such as K2-3b or K2-3c. In the terrestrial planet regime, we find that only a few anticipated TESS discoveries will result in higher S/N than currently known exoplanets, such as the TRAPPIST-1 planets, GJ1132b, and LHS1140b. However, we emphasize that this outcome is based upon Kepler-derived occurrence rates, and that co-planar compact multi-planet systems (e.g., TRAPPIST-1) may be under-represented in the predicted TESS planet yield. Finally, we apply our calculations to estimate the required magnitude of a JWST follow-up program devoted to mapping the transition region between hydrogen-dominated and high molecular weight atmospheres. We find that a modest observing program of between 60 and 100 hr of charged JWST time can define the nature of that transition (e.g., step function versus a power law).

Mass spectrometry-based biomarker discovery: toward a global proteome index of individuality.

PubMed

Hawkridge, Adam M; Muddiman, David C

2009-01-01

Biomarker discovery and proteomics have become synonymous with mass spectrometry in recent years. Although this conflation is an injustice to the many essential biomolecular techniques widely used in biomarker-discovery platforms, it underscores the power and potential of contemporary mass spectrometry. Numerous novel and powerful technologies have been developed around mass spectrometry, proteomics, and biomarker discovery over the past 20 years to globally study complex proteomes (e.g., plasma). However, very few large-scale longitudinal studies have been carried out using these platforms to establish the analytical variability relative to true biological variability. The purpose of this review is not to cover exhaustively the applications of mass spectrometry to biomarker discovery, but rather to discuss the analytical methods and strategies that have been developed for mass spectrometry-based biomarker-discovery platforms and to place them in the context of the many challenges and opportunities yet to be addressed.

Orphan diseases: state of the drug discovery art.

PubMed

Volmar, Claude-Henry; Wahlestedt, Claes; Brothers, Shaun P

2017-06-01

Since 1983 more than 300 drugs have been developed and approved for orphan diseases. However, considering the development of novel diagnosis tools, the number of rare diseases vastly outpaces therapeutic discovery. Academic centers and nonprofit institutes are now at the forefront of rare disease R&D, partnering with pharmaceutical companies when academic researchers discover novel drugs or targets for specific diseases, thus reducing the failure risk and cost for pharmaceutical companies. Considerable progress has occurred in the art of orphan drug discovery, and a symbiotic relationship now exists between pharmaceutical industry, academia, and philanthropists that provides a useful framework for orphan disease therapeutic discovery. Here, the current state-of-the-art of drug discovery for orphan diseases is reviewed. Current technological approaches and challenges for drug discovery are considered, some of which can present somewhat unique challenges and opportunities in orphan diseases, including the potential for personalized medicine, gene therapy, and phenotypic screening.

Analysis of latency performance of bluetooth low energy (BLE) networks.

PubMed

Cho, Keuchul; Park, Woojin; Hong, Moonki; Park, Gisu; Cho, Wooseong; Seo, Jihoon; Han, Kijun

2014-12-23

Bluetooth Low Energy (BLE) is a short-range wireless communication technology aiming at low-cost and low-power communication. The performance evaluation of classical Bluetooth device discovery have been intensively studied using analytical modeling and simulative methods, but these techniques are not applicable to BLE, since BLE has a fundamental change in the design of the discovery mechanism, including the usage of three advertising channels. Recently, there several works have analyzed the topic of BLE device discovery, but these studies are still far from thorough. It is thus necessary to develop a new, accurate model for the BLE discovery process. In particular, the wide range settings of the parameters introduce lots of potential for BLE devices to customize their discovery performance. This motivates our study of modeling the BLE discovery process and performing intensive simulation. This paper is focused on building an analytical model to investigate the discovery probability, as well as the expected discovery latency, which are then validated via extensive experiments. Our analysis considers both continuous and discontinuous scanning modes. We analyze the sensitivity of these performance metrics to parameter settings to quantitatively examine to what extent parameters influence the performance metric of the discovery processes.

Analysis of Latency Performance of Bluetooth Low Energy (BLE) Networks

PubMed Central

Cho, Keuchul; Park, Woojin; Hong, Moonki; Park, Gisu; Cho, Wooseong; Seo, Jihoon; Han, Kijun

2015-01-01

Bluetooth Low Energy (BLE) is a short-range wireless communication technology aiming at low-cost and low-power communication. The performance evaluation of classical Bluetooth device discovery have been intensively studied using analytical modeling and simulative methods, but these techniques are not applicable to BLE, since BLE has a fundamental change in the design of the discovery mechanism, including the usage of three advertising channels. Recently, there several works have analyzed the topic of BLE device discovery, but these studies are still far from thorough. It is thus necessary to develop a new, accurate model for the BLE discovery process. In particular, the wide range settings of the parameters introduce lots of potential for BLE devices to customize their discovery performance. This motivates our study of modeling the BLE discovery process and performing intensive simulation. This paper is focused on building an analytical model to investigate the discovery probability, as well as the expected discovery latency, which are then validated via extensive experiments. Our analysis considers both continuous and discontinuous scanning modes. We analyze the sensitivity of these performance metrics to parameter settings to quantitatively examine to what extent parameters influence the performance metric of the discovery processes. PMID:25545266

21 CFR 17.23 - Discovery.

Code of Federal Regulations, 2011 CFR

2011-04-01

... requested data stored in an electronic data storage system must be produced in a form readily accessible to... includes information, reports, answers, records, accounts, papers and other data and documentary evidence...

21 CFR 17.23 - Discovery.

Code of Federal Regulations, 2012 CFR

2012-04-01

... requested data stored in an electronic data storage system must be produced in a form readily accessible to... includes information, reports, answers, records, accounts, papers and other data and documentary evidence...

21 CFR 17.23 - Discovery.

Code of Federal Regulations, 2014 CFR

2014-04-01

... requested data stored in an electronic data storage system must be produced in a form readily accessible to... includes information, reports, answers, records, accounts, papers and other data and documentary evidence...

21 CFR 17.23 - Discovery.

Code of Federal Regulations, 2013 CFR

2013-04-01

... requested data stored in an electronic data storage system must be produced in a form readily accessible to... includes information, reports, answers, records, accounts, papers and other data and documentary evidence...

Crisis or self-correction: Rethinking media narratives about the well-being of science

PubMed Central

Jamieson, Kathleen Hall

2018-01-01

After documenting the existence and exploring some implications of three alternative news narratives about science and its challenges, this essay outlines ways in which those who communicate science can more accurately convey its investigatory process, self-correcting norms, and remedial actions, without in the process legitimizing an unwarranted “science is broken/in crisis” narrative. The three storylines are: (i) quest discovery, which features scientists producing knowledge through an honorable journey; (ii) counterfeit quest discovery, which centers on an individual or group of scientists producing a spurious finding through a dishonorable one; and (iii) a systemic problem structure, which suggests that some of the practices that protect science are broken, or worse, that science is no longer self-correcting or in crisis. PMID:29531076

Flexible Design and Manufacturing Systems for Automotive Components and Sheet Metal Parts

DTIC Science & Technology

1999-10-01

sometimes shocking discoveries you will make, discoveries that can help you avoid potential crises down the road if you take the necessary steps now...ISSUE Guest Lecture John Swanson, VP Qualcomm 10-Feb Fast, Flexible, Lilly, US Robotics, Economist, Upton & Agile Manufacturing Readings

The Discovery of Penicillin—New Insights After More Than 75 Years of Clinical Use

PubMed Central

2017-01-01

After just over 75 years of penicillin’s clinical use, the world can see that its impact was immediate and profound. In 1928, a chance event in Alexander Fleming’s London laboratory changed the course of medicine. However, the purification and first clinical use of penicillin would take more than a decade. Unprecedented United States/Great Britain cooperation to produce penicillin was incredibly successful by 1943. This success overshadowed efforts to produce penicillin during World War II in Europe, particularly in the Netherlands. Information about these efforts, available only in the last 10–15 years, provides new insights into the story of the first antibiotic. Researchers in the Netherlands produced penicillin using their own production methods and marketed it in 1946, which eventually increased the penicillin supply and decreased the price. The unusual serendipity involved in the discovery of penicillin demonstrates the difficulties in finding new antibiotics and should remind health professionals to expertly manage these extraordinary medicines.

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

PubMed

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

2012-01-01

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

From Toxins Targeting Ligand Gated Ion Channels to Therapeutic Molecules

PubMed Central

Nasiripourdori, Adak; Taly, Valérie; Grutter, Thomas; Taly, Antoine

2011-01-01

Ligand-gated ion channels (LGIC) play a central role in inter-cellular communication. This key function has two consequences: (i) these receptor channels are major targets for drug discovery because of their potential involvement in numerous human brain diseases; (ii) they are often found to be the target of plant and animal toxins. Together this makes toxin/receptor interactions important to drug discovery projects. Therefore, toxins acting on LGIC are presented and their current/potential therapeutic uses highlighted. PMID:22069709

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.

Importance of microbial natural products and the need to revitalize their discovery.

PubMed

Demain, Arnold L

2014-02-01

Microbes are the leading producers of useful natural products. Natural products from microbes and plants make excellent drugs. Significant portions of the microbial genomes are devoted to production of these useful secondary metabolites. A single microbe can make a number of secondary metabolites, as high as 50 compounds. The most useful products include antibiotics, anticancer agents, immunosuppressants, but products for many other applications, e.g., antivirals, anthelmintics, enzyme inhibitors, nutraceuticals, polymers, surfactants, bioherbicides, and vaccines have been commercialized. Unfortunately, due to the decrease in natural product discovery efforts, drug discovery has decreased in the past 20 years. The reasons include excessive costs for clinical trials, too short a window before the products become generics, difficulty in discovery of antibiotics against resistant organisms, and short treatment times by patients for products such as antibiotics. Despite these difficulties, technology to discover new drugs has advanced, e.g., combinatorial chemistry of natural product scaffolds, discoveries in biodiversity, genome mining, and systems biology. Of great help would be government extension of the time before products become generic.

A Discovery-Based Experiment Involving Rearrangement in the Conversion of Alcohols to Alkyl Halides: Permanent Magnet [to the thirteenth power]C NMR in the First-Semester Organic Chemistry Lab

ERIC Educational Resources Information Center

Kjonaas, Richard A.; Tucker, Ryand J. F.

2008-01-01

The use of permanent magnet [to the thirteenth power]C NMR in large-section first-semester organic chemistry lab courses is limited by the availability of experiments that not only hinge on first-semester lecture topics, but which also produce at least 0.5 mL of neat liquid sample. This article reports a discovery-based experiment that meets both…

Discovery of νμ → ντ oscillations in the OPERA experiment

NASA Astrophysics Data System (ADS)

Vasina, S.

2017-11-01

The OPERA experiment was designed to search for νμ → ντ oscillations in appearance mode, i.e. by detecting the τ leptons produced in charge current ντ interactions. The experiment took data from 2008 to 2012 in the CNGS beam. Five observed ντ candidates together with low background 0.25 ± 0.05 allow to assess the discovery of νμ → ντ oscillations in appearance mode with significance larger than 5σ.

Exploring the potential for actinobacteria as defensive symbionts in fungus-growing termites.

PubMed

Visser, Anna A; Nobre, Tânia; Currie, Cameron R; Aanen, Duur K; Poulsen, Michael

2012-05-01

In fungus-growing termites, fungi of the subgenus Pseudoxylaria threaten colony health through substrate competition with the termite fungus (Termitomyces). The potential mechanisms with which termites suppress Pseudoxylaria have remained unknown. Here we explore if Actinobacteria potentially play a role as defensive symbionts against Pseudoxylaria in fungus-growing termites. We sampled for Actinobacteria from 30 fungus-growing termite colonies, spanning the three main termite genera and two geographically distant sites. Our isolations yielded 360 Actinobacteria, from which we selected subsets for morphological (288 isolates, grouped in 44 morphotypes) and for 16S rRNA (35 isolates, spanning the majority of morphotypes) characterisation. Actinobacteria were found throughout all sampled nests and colony parts and, phylogenetically, they are interspersed with Actinobacteria from origins other than fungus-growing termites, indicating lack of specificity. Antibiotic-activity screening of 288 isolates against the fungal cultivar and competitor revealed that most of the Actinobacteria-produced molecules with antifungal activity. A more detailed bioassay on 53 isolates, to test the specificity of antibiotics, showed that many Actinobacteria inhibit both Pseudoxylaria and Termitomyces, and that the cultivar fungus generally is more susceptible to inhibition than the competitor. This suggests that either defensive symbionts are not present in the system or that they, if present, represent a subset of the community isolated. If so, the antibiotics must be used in a targeted fashion, being applied to specific areas by the termites. We describe the first discovery of an assembly of antibiotic-producing Actinobacteria occurring in fungus-growing termite nests. However, due to the diversity found, and the lack of both phylogenetic and bioactivity specificity, further work is necessary for a better understanding of the putative role of antibiotic-producing bacteria in the fungus-growing termite mutualistic system.

27 CFR 70.24 - Enforcement of summonses.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., DEPARTMENT OF THE TREASURY (CONTINUED) PROCEDURES AND PRACTICES PROCEDURE AND ADMINISTRATION Discovery of... produce books, papers, records, or other data, or to give testimony, as required, application may be made...

Computer-aided drug discovery.

PubMed

Bajorath, Jürgen

2015-01-01

Computational approaches are an integral part of interdisciplinary drug discovery research. Understanding the science behind computational tools, their opportunities, and limitations is essential to make a true impact on drug discovery at different levels. If applied in a scientifically meaningful way, computational methods improve the ability to identify and evaluate potential drug molecules, but there remain weaknesses in the methods that preclude naïve applications. Herein, current trends in computer-aided drug discovery are reviewed, and selected computational areas are discussed. Approaches are highlighted that aid in the identification and optimization of new drug candidates. Emphasis is put on the presentation and discussion of computational concepts and methods, rather than case studies or application examples. As such, this contribution aims to provide an overview of the current methodological spectrum of computational drug discovery for a broad audience.

Dung-inhabiting fungi: a potential reservoir of novel secondary metabolites for the control of plant pathogens.

PubMed

Sarrocco, Sabrina

2016-04-01

Coprophilous fungi are a large group of saprotrophic fungi mostly found in herbivore dung. The number of these fungi undergoing investigation is continually increasing, and new species and genera continue to be described. Dung-inhabiting fungi play an important ecological role in decomposing and recycling nutrients from animal dung. They produce a large array of bioactive secondary metabolites and have a potent enzymatic arsenal able to utilise even complex molecules. Bioactive secondary metabolites are actively involved in interaction with and defence against other organisms whose growth can be inhibited, resulting in an enhanced ecological fitness of producer strains. Currently, these antibiotics and bioactive secondary metabolites are of interest in medicine in particular, while very little information is available concerning their potential use in agriculture. This review introduces the ecology of dung-inhabiting fungi, with particular emphasis on the production of antibiotic compounds as a means to compete with other microorganisms. Owing to the fast pace of technological progress, new approaches to predicting the biosynthesis of bioactive metabolites are proposed. Coprophilous fungi should be considered as elite candidate organisms for the discovery of novel antifungal compounds, above all in view of their exploitation for crop protection. © 2015 Society of Chemical Industry.

Marine Microorganism: An Underexplored Source of l-Asparaginase.

PubMed

Prihanto, A A; Wakayama, M

l-Asparaginase (EC 3.5.1.1) is an enzyme that catalyzes the hydrolysis of l-asparagine to l-aspartic acid. This enzyme has an important role in medicine and food. l-Asparaginase is a potential drug in cancer therapy. Furthermore, it is also applied for reducing acrylamide, a carcinogenic compound in baked and fried foods. Until now, approved l-asparaginases for both applications are few due to their lack of appropriate properties. As a result, researchers have been enthusiastically seeking new sources of enzyme with better performance. A great number of terrestrial l-asparaginase-producing microorganisms have been reported but unfortunately, almost all failed to meet criteria for cancer therapy and acrylamide reducing agent. As a largest area than Earth, marine environment, by contrast, has not been optimally explored yet. So far, a great challenge facing an exploration of marine microorganisms is mainly due to their harsh, mysterious, and dangerous environment. It is clear that marine environment, a gigantic potential source for marine natural products is scantily revealed, although several approaches and technologies have been developed. This chapter presents the historical of l-asparaginase discovery and applications. It is also discussed, how the marine environment, even though offering a great potency but is still one of the less explored area for l-asparaginase-producing microorganisms. © 2016 Elsevier Inc. All rights reserved.

Blueprint for antimicrobial hit discovery targeting metabolic networks

PubMed Central

Shen, Y.; Liu, J.; Estiu, G.; Isin, B.; Ahn, Y-Y.; Lee, D-S.; Barabási, A-L.; Kapatral, V.; Wiest, O.; Oltvai, Z. N.

2010-01-01

Advances in genome analysis, network biology, and computational chemistry have the potential to revolutionize drug discovery by combining system-level identification of drug targets with the atomistic modeling of small molecules capable of modulating their activity. To demonstrate the effectiveness of such a discovery pipeline, we deduced common antibiotic targets in Escherichia coli and Staphylococcus aureus by identifying shared tissue-specific or uniformly essential metabolic reactions in their metabolic networks. We then predicted through virtual screening dozens of potential inhibitors for several enzymes of these reactions and showed experimentally that a subset of these inhibited both enzyme activities in vitro and bacterial cell viability. This blueprint is applicable for any sequenced organism with high-quality metabolic reconstruction and suggests a general strategy for strain-specific antiinfective therapy. PMID:20080587

Stem cell technology for drug discovery and development.

PubMed

Hook, Lilian A

2012-04-01

Stem cells have enormous potential to revolutionise the drug discovery process at all stages, from target identification through to toxicology studies. Their ability to generate physiologically relevant cells in limitless supply makes them an attractive alternative to currently used recombinant cell lines or primary cells. However, realisation of the full potential of stem cells is currently hampered by the difficulty in routinely directing stem cell differentiation to reproducibly and cost effectively generate pure populations of specific cell types. In this article we discuss how stem cells have already been used in the drug discovery process and how novel technologies, particularly in relation to stem cell differentiation, can be applied to attain widespread adoption of stem cell technology by the pharmaceutical industry. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

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

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

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

MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development | Office of Cancer Genomics

Cancer.gov

Protein-protein interactions (PPIs) mediate the transmission and regulation of oncogenic signals that are essential to cellular proliferation and survival, and thus represent potential targets for anti-cancer therapeutic discovery. Despite their significance, there is no method to experimentally disrupt and interrogate the essentiality of individual endogenous PPIs. The ability to computationally predict or infer PPI essentiality would help prioritize PPIs for drug discovery and help advance understanding of cancer biology.

Mars extant-life campaign using an approach based on Earth-analog habitats

NASA Technical Reports Server (NTRS)

Palkovic, Lawrence A.; Wilson, Thomas J.

2005-01-01

The Mars Robotic Outpost group at JPL has identified sixteen potential momentous discoveries that if found on Mars would alter planning for the future Mars exploration program. This paper details one possible approach to the discovery of and response to the 'momentous discovery'' of extant life on Mars. The approach detailed in this paper, the Mars Extant-Life (MEL) campaign, is a comprehensive and flexible program to find living organisms on Mars by studying Earth-analog habitats of extremophile communities.

Final Report for Geometric Analysis for Data Reduction and Structure Discovery DE-FG02-10ER25983, STRIPES award # DE-SC0004096

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

Vixie, Kevin R.

This is the final report for the project "Geometric Analysis for Data Reduction and Structure Discovery" in which insights and tools from geometric analysis were developed and exploited for their potential to large scale data challenges.

The Next Step: 25 Discoveries That Could Change Our Lives.

ERIC Educational Resources Information Center

Science85, 1985

1985-01-01

Describes (in separate articles) 25 developments in science, technology, and medicine that have potential impact on the near future. They include discoveries related to space butterflies, drugs, twenty-first century software, experimental mathematics, brain drugs, egg development, ultrasmall microchips, the biology of birth, cancer-causing genes,…

Collaborative Assessment for Employment Planning: Transition Assessment and the Discovery Process

ERIC Educational Resources Information Center

Stevenson, Bradley S.; Fowler, Catherine H.

2016-01-01

As the Workforce Innovation and Opportunities Act (WIOA) is implemented across the nation, special education and vocational rehabilitation professionals will need to increase their level of collaboration. One area of potential collaboration is assessment--transition assessment for the field of special education and the discovery process for adult…

Drug Discovery and Development of Antimalarial Agents: Recent Advances.

PubMed

Thota, Sreekanth; Yerra, Rajeshwar

2016-01-01

Malaria, a deadly infectious parasitic disease, is a major issue of public health in the world today and already produces serious economic constraints in the endemic countries. Most of the malarial infections and deaths are due to Plasmodium falciparum and Plasmodium vivax species. The recent emergence of resistance necessitates the search for new antimalarial drugs, which overcome the resistance and act through new mechanisms. Although much effort has been directed towards the discovery of novel antimalarial drugs. 4-anilino quinolone triazines as potent antimalarial agents, their in silico modelling and bioevaluation as Plasmodium falciparum transketolase and β-hematin inhibitors has been reported. This review is primarily focused on the drug discovery of the recent advances in the development of antimalarial agents and their mechanism of action.

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

PubMed

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

2017-10-01

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

NCI Program for Natural Product Discovery: A Publicly-Accessible Library of Natural Product Fractions for High-Throughput Screening.

PubMed

Thornburg, Christopher C; Britt, John R; Evans, Jason R; Akee, Rhone K; Whitt, James A; Trinh, Spencer K; Harris, Matthew J; Thompson, Jerell R; Ewing, Teresa L; Shipley, Suzanne M; Grothaus, Paul G; Newman, David J; Schneider, Joel P; Grkovic, Tanja; O'Keefe, Barry R

2018-06-13

The US National Cancer Institute's (NCI) Natural Product Repository is one of the world's largest, most diverse collections of natural products containing over 230,000 unique extracts derived from plant, marine, and microbial organisms that have been collected from biodiverse regions throughout the world. Importantly, this national resource is available to the research community for the screening of extracts and the isolation of bioactive natural products. However, despite the success of natural products in drug discovery, compatibility issues that make extracts challenging for liquid handling systems, extended timelines that complicate natural product-based drug discovery efforts and the presence of pan-assay interfering compounds have reduced enthusiasm for the high-throughput screening (HTS) of crude natural product extract libraries in targeted assay systems. To address these limitations, the NCI Program for Natural Product Discovery (NPNPD), a newly launched, national program to advance natural product discovery technologies and facilitate the discovery of structurally defined, validated lead molecules ready for translation will create a prefractionated library from over 125,000 natural product extracts with the aim of producing a publicly-accessible, HTS-amenable library of >1,000,000 fractions. This library, representing perhaps the largest accumulation of natural-product based fractions in the world, will be made available free of charge in 384-well plates for screening against all disease states in an effort to reinvigorate natural product-based drug discovery.

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

USGS Publications Warehouse

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

1980-01-01

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

The DataBridge: A System For Optimizing The Use Of Dark Data From The Long Tail Of Science

NASA Astrophysics Data System (ADS)

Lander, H.; Rajasekar, A.

2015-12-01

The DataBridge is a National Science Foundation funded collaborative project (OCI-1247652, OCI-1247602, OCI-1247663) designed to assist in the discovery of dark data sets from the long tail of science. The DataBridge aims to to build queryable communities of datasets using sociometric network analysis. This approach is being tested to evaluate the ability to leverage various forms of metadata to facilitate discovery of new knowledge. Each dataset in the Databridge has an associated name space used as a first level partitioning. In addition to testing known algorithms for SNA community building, the DataBridge project has built a message-based platform that allows users to provide their own algorithms for each of the stages in the community building process. The stages are: Signature Generation (SG): An SG algorithm creates a metadata signature for a dataset. Signature algorithms might use text metadata provided by the dataset creator or derive metadata. Relevance Algorithm (RA): An RA compares a pair of datasets and produces a similarity value between 0 and 1 for the two datasets. Sociometric Network Analysis (SNA): The SNA will operate on a similarity matrix produced by an RA to partition all of the datasets in the name space into a set of clusters. These clusters represent communities of closely related datasets. The DataBridge also includes a web application that produces a visual representation of the clustering. Future work includes a more complete application that will allow different types of searching of the network of datasets. The DataBridge approach is relevant to geoscience research and informatics. In this presentation we will outline the project, illustrate the deployment of the approach, and discuss other potential applications and next steps for the research such as applying this approach to models. In addition we will explore the relevance of DataBridge to other geoscience projects such as various EarthCube Building Blocks and DIBBS projects.

Limitations and potentials of current motif discovery algorithms

PubMed Central

Hu, Jianjun; Li, Bin; Kihara, Daisuke

2005-01-01

Computational methods for de novo identification of gene regulation elements, such as transcription factor binding sites, have proved to be useful for deciphering genetic regulatory networks. However, despite the availability of a large number of algorithms, their strengths and weaknesses are not sufficiently understood. Here, we designed a comprehensive set of performance measures and benchmarked five modern sequence-based motif discovery algorithms using large datasets generated from Escherichia coli RegulonDB. Factors that affect the prediction accuracy, scalability and reliability are characterized. It is revealed that the nucleotide and the binding site level accuracy are very low, while the motif level accuracy is relatively high, which indicates that the algorithms can usually capture at least one correct motif in an input sequence. To exploit diverse predictions from multiple runs of one or more algorithms, a consensus ensemble algorithm has been developed, which achieved 6–45% improvement over the base algorithms by increasing both the sensitivity and specificity. Our study illustrates limitations and potentials of existing sequence-based motif discovery algorithms. Taking advantage of the revealed potentials, several promising directions for further improvements are discussed. Since the sequence-based algorithms are the baseline of most of the modern motif discovery algorithms, this paper suggests substantial improvements would be possible for them. PMID:16284194

Single nucleotide polymorphism (SNP) discovery in duplicated genomes: intron-primed exon-crossing (IPEC) as a strategy for avoiding amplification of duplicated loci in Atlantic salmon (Salmo salar) and other salmonid fishes

PubMed Central

Ryynänen, Heikki J; Primmer, Craig R

2006-01-01

Background Single nucleotide polymorphisms (SNPs) represent the most abundant type of DNA variation in the vertebrate genome, and their applications as genetic markers in numerous studies of molecular ecology and conservation of natural populations are emerging. Recent large-scale sequencing projects in several fish species have provided a vast amount of data in public databases, which can be utilized in novel SNP discovery in salmonids. However, the suggested duplicated nature of the salmonid genome may hamper SNP characterization if the primers designed in conserved gene regions amplify multiple loci. Results Here we introduce a new intron-primed exon-crossing (IPEC) method in an attempt to overcome this duplication problem, and also evaluate different priming methods for SNP discovery in Atlantic salmon (Salmo salar) and other salmonids. A total of 69 loci with differing priming strategies were screened in S. salar, and 27 of these produced ~13 kb of high-quality sequence data consisting of 19 SNPs or indels (one per 680 bp). The SNP frequency and the overall nucleotide diversity (3.99 × 10-4) in S. salar was lower than reported in a majority of other organisms, which may suggest a relative young population history for Atlantic salmon. A subset of primers used in cross-species analyses revealed considerable variation in the SNP frequencies and nucleotide diversities in other salmonids. Conclusion Sequencing success was significantly higher with the new IPEC primers; thus the total number of loci to screen in order to identify one potential polymorphic site was six times less with this new strategy. Given that duplication may hamper SNP discovery in some species, the IPEC method reported here is an alternative way of identifying novel polymorphisms in such cases. PMID:16872523

Chronicles in drug discovery.

PubMed

Davies, Shelley L; Ferrer, Elisa; Moral, Maria Angels

2006-06-01

Chronicles in Drug Discovery features special interest reports on advances in drug discovery. This month we highlight new options to prevent oral mucositis, a treatment-limiting adverse effect of chemotherapy. Studies are currently focusing on mechanism-based therapies to prevent or repair DNA damage to epithelial and submucosal cells and the cascade or events that follow to cause tissue damage or analgesics to ease the associated oral cavity pain. Therapeutic limitations also exist for the use of the highly effective antibiotic gentamicin, as it evokes acute renal failure. Mechanistic investigations have shed some light on potential targets: the kallikreins, peroxynitrite-related pathways, superoxide production and the accumulation of aminoglycosides. New antibiotic strategies for trachoma, the leading cause of preventable blindness, are also explored along with studies to aid the development of vaccine candidates. Finally, we discuss the utility of allosteric-potentiating ligands to modulate nicotinic acetylcholine receptors, mimicking the reward/addictive effects of nicotine, as potential strategies for smoking cessation. (c) 2006 Prous Science. All rights reserved.

High-content screening for the discovery of pharmacological compounds: advantages, challenges and potential benefits of recent technological developments.

PubMed

Soleilhac, Emmanuelle; Nadon, Robert; Lafanechere, Laurence

2010-02-01

Screening compounds with cell-based assays and microscopy image-based analysis is an approach currently favored for drug discovery. Because of its high information yield, the strategy is called high-content screening (HCS). This review covers the application of HCS in drug discovery and also in basic research of potential new pathways that can be targeted for treatment of pathophysiological diseases. HCS faces several challenges, however, including the extraction of pertinent information from the massive amount of data generated from images. Several proposed approaches to HCS data acquisition and analysis are reviewed. Different solutions from the fields of mathematics, bioinformatics and biotechnology are presented. Potential applications and limits of these recent technical developments are also discussed. HCS is a multidisciplinary and multistep approach for understanding the effects of compounds on biological processes at the cellular level. Reliable results depend on the quality of the overall process and require strong interdisciplinary collaborations.

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

PubMed

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

2017-01-01

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

Discovery of Boolean metabolic networks: integer linear programming based approach.

PubMed

Qiu, Yushan; Jiang, Hao; Ching, Wai-Ki; Cheng, Xiaoqing

2018-04-11

Traditional drug discovery methods focused on the efficacy of drugs rather than their toxicity. However, toxicity and/or lack of efficacy are produced when unintended targets are affected in metabolic networks. Thus, identification of biological targets which can be manipulated to produce the desired effect with minimum side-effects has become an important and challenging topic. Efficient computational methods are required to identify the drug targets while incurring minimal side-effects. In this paper, we propose a graph-based computational damage model that summarizes the impact of enzymes on compounds in metabolic networks. An efficient method based on Integer Linear Programming formalism is then developed to identify the optimal enzyme-combination so as to minimize the side-effects. The identified target enzymes for known successful drugs are then verified by comparing the results with those in the existing literature. Side-effects reduction plays a crucial role in the study of drug development. A graph-based computational damage model is proposed and the theoretical analysis states the captured problem is NP-completeness. The proposed approaches can therefore contribute to the discovery of drug targets. Our developed software is available at " http://hkumath.hku.hk/~wkc/APBC2018-metabolic-network.zip ".

Biomimicry as a basis for drug discovery.

PubMed

Kolb, V M

1998-01-01

Selected works are discussed which clearly demonstrate that mimicking various aspects of the process by which natural products evolved is becoming a powerful tool in contemporary drug discovery. Natural products are an established and rich source of drugs. The term "natural product" is often used synonymously with "secondary metabolite." Knowledge of genetics and molecular evolution helps us understand how biosynthesis of many classes of secondary metabolites evolved. One proposed hypothesis is termed "inventive evolution." It invokes duplication of genes, and mutation of the gene copies, among other genetic events. The modified duplicate genes, per se or in conjunction with other genetic events, may give rise to new enzymes, which, in turn, may generate new products, some of which may be selected for. Steps of the inventive evolution can be mimicked in several ways for purpose of drug discovery. For example, libraries of chemical compounds of any imaginable structure may be produced by combinatorial synthesis. Out of these libraries new active compounds can be selected. In another example, genetic system can be manipulated to produce modified natural products ("unnatural natural products"), from which new drugs can be selected. In some instances, similar natural products turn up in species that are not direct descendants of each other. This is presumably due to a horizontal gene transfer. The mechanism of this inter-species gene transfer can be mimicked in therapeutic gene delivery. Mimicking specifics or principles of chemical evolution including experimental and test-tube evolution also provides leads for new drug discovery.

New generation NMR bioreactor coupled with high-resolution NMR spectroscopy leads to novel discoveries in Moorella thermoaceticum metabolic profiles

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

Xue, Junfeng; Isern, Nancy G.; Ewing, R James

An in-situ nuclear magnetic resonance (NMR) bioreactor was developed and employed to monitor microbial metabolism under batch-growth conditions in real time. We selected Moorella thermoacetica ATCC 49707 as a test case. M. thermoacetica (formerly Clostridium thermoaceticum) is a strictly anaerobic, thermophilic, acetogenic, gram-positive bacterium with potential for industrial production of chemicals. The metabolic profiles of M. thermoacetica were characterized during growth in batch mode on xylose (a component of lignocellulosic biomass) using the new generation NMR bioreactor in combination with high-resolution, high sensitivity NMR (HR-NMR) spectroscopy. In-situ NMR measurements were performed using water-suppressed H-1 NMR spectroscopy at an NMR frequencymore » of 500 MHz, and aliquots of the bioreactor contents were taken for 600 MHz HR-NMR spectroscopy at specific intervals to confirm metabolite identifications and expand metabolite coverage. M. thermoacetica demonstrated the metabolic potential to produce formate, ethanol and methanol from xylose, in addition to its known capability of producing acetic acid. Real-time monitoring of bioreactor conditions showed a temporary pH decrease, with a concomitant increase in formic acid during exponential growth. Fermentation experiments performed outside of the magnet showed that the strong magnetic field employed for NMR detection did not significantly affect cell metabolism. Use of the in-situ NMR bioreactor facilitated monitoring of the fermentation process in real time, enabling identification of intermediate and end-point metabolites and their correlation with pH and biomass produced during culture growth. Real-time monitoring of culture metabolism using the NMR bioreactor in combination with the HR-NMR spectroscopy will allow optimization of the metabolism of microorganisms producing valuable bioproducts.« less

Efficient Modeling and Active Learning Discovery of Biological Responses

PubMed Central

Naik, Armaghan W.; Kangas, Joshua D.; Langmead, Christopher J.; Murphy, Robert F.

2013-01-01

High throughput and high content screening involve determination of the effect of many compounds on a given target. As currently practiced, screening for each new target typically makes little use of information from screens of prior targets. Further, choices of compounds to advance to drug development are made without significant screening against off-target effects. The overall drug development process could be made more effective, as well as less expensive and time consuming, if potential effects of all compounds on all possible targets could be considered, yet the cost of such full experimentation would be prohibitive. In this paper, we describe a potential solution: probabilistic models that can be used to predict results for unmeasured combinations, and active learning algorithms for efficiently selecting which experiments to perform in order to build those models and determining when to stop. Using simulated and experimental data, we show that our approaches can produce powerful predictive models without exhaustive experimentation and can learn them much faster than by selecting experiments at random. PMID:24358322

Development of GIS-based Wind Potential Map of Makkah Province, Saudi Arabia

NASA Astrophysics Data System (ADS)

Nayyar, Z. A.; Zaigham, N. A.; Aburizaiza, O. S.; Mahar, G. A.; Eusufi, S. N.

2011-12-01

Global energy scenario is changing drastically toward decline, as new major discoveries of fossil fuel are not coming up significantly on regional basis. In case of Saudi Arabia, one of the largest fossil fuel producers, the major oil fields have started exhausting significantly as revealed from the literature research study. Considering the future energy crisis, different other renewable options presently have became imperative to be consider anticipating for the national development. Wind energy in one of them. The development of wind energy technology requires the baseline data relevant to the wind trends and their potentials. Under the present study, an attempt has been made to develop wind power density map of the Makkah Province of Saudi Arabia based on the meteorological data collected at different sparsely located weather stations. GIS application has provided a good option to interpolate the gap areas between the sparsely located weather recording stations. This paper describe the methodology and results of the present study.

Endophytic Fungi—Alternative Sources of Cytotoxic Compounds: A Review

PubMed Central

Uzma, Fazilath; Mohan, Chakrabhavi D.; Hashem, Abeer; Konappa, Narasimha M.; Rangappa, Shobith; Kamath, Praveen V.; Singh, Bhim P.; Mudili, Venkataramana; Gupta, Vijai K.; Siddaiah, Chandra N.; Chowdappa, Srinivas; Alqarawi, Abdulaziz A.; Abd_Allah, Elsayed F.

2018-01-01

Cancer is a major cause of death worldwide, with an increasing number of cases being reported annually. The elevated rate of mortality necessitates a global challenge to explore newer sources of anticancer drugs. Recent advancements in cancer treatment involve the discovery and development of new and improved chemotherapeutics derived from natural or synthetic sources. Natural sources offer the potential of finding new structural classes with unique bioactivities for cancer therapy. Endophytic fungi represent a rich source of bioactive metabolites that can be manipulated to produce desirable novel analogs for chemotherapy. This review offers a current and integrative account of clinically used anticancer drugs such as taxol, podophyllotoxin, camptothecin, and vinca alkaloids in terms of their mechanism of action, isolation from endophytic fungi and their characterization, yield obtained, and fungal strain improvement strategies. It also covers recent literature on endophytic fungal metabolites from terrestrial, mangrove, and marine sources as potential anticancer agents and emphasizes the findings for cytotoxic bioactive compounds tested against specific cancer cell lines. PMID:29755344

Hyperspectral surveying for mineral resources in Alaska

USGS Publications Warehouse

Kokaly, Raymond F.; Graham, Garth E.; Hoefen, Todd M.; Kelley, Karen D.; Johnson, Michaela R.; Hubbard, Bernard E.

2016-07-07

Alaska is a major producer of base and precious metals and has a high potential for additional undiscovered mineral resources. However, discovery is hindered by Alaska’s vast size, remoteness, and rugged terrain. New methods are needed to overcome these obstacles in order to fully evaluate Alaska’s geology and mineral resource potential. Hyperspectral surveying is one method that can be used to rapidly acquire data about the distributions of surficial materials, including different types of bedrock and ground cover. In 2014, the U.S. Geological Survey began the Alaska Hyperspectral Project to assess the applicability of this method in Alaska. The primary study area is a remote part of the eastern Alaska Range where porphyry deposits are exposed. In collaboration with the Alaska Division of Geological and Geophysical Surveys, the University of Alaska Fairbanks, and the National Park Service, the U.S. Geological Survey is collecting and analyzing hyperspectral data with the goals of enhancing geologic mapping and developing methods to identify and characterize mineral deposits elsewhere in Alaska.

Animals living in polluted environments are potential source of antimicrobials against infectious agents

PubMed Central

Lee, Simon; Siddiqui, Ruqaiyyah; Khan, Naveed Ahmed

2012-01-01

The antimicrobials crisis is a ticking time bomb which could lead to millions of people dying from untreatable infections. With the worsening trends of antimicrobial resistance, we are heading towards a pre-antibiotic era. Thus, there is a need for newer and more powerful antibiotic agents. The search for new antibiotic compounds originating from natural resources is a promising research area. Animals living in germ-infested environments are a potent source of antimicrobials. Under polluted milieus, organisms such as cockroaches encounter different types of bacteria, including superbugs. Such creatures survive the onslaught of superbugs and are able to ward off disease by producing antimicrobial substances which show potent activity in the nervous system. We hope that the discovery of antimicrobial activity in the cockroach brain will stimulate research in finding antimicrobials from unusual sources, and has potential for the development of novel antibiotics. Nevertheless, intensive research in the next few years will be required to approach or realize these expectations. PMID:23265422

Ontogeny of Manipulative Behavior and Nut-Cracking in Young Tufted Capuchin Monkeys ("Cebus Apella"): A Perception-Action Perspective

ERIC Educational Resources Information Center

de Resende, Briseida Dogo; Ottoni, Eduardo B.; Fragaszy, Dorothy M.

2008-01-01

How do capuchin monkeys learn to use stones to crack open nuts? Perception-action theory posits that individuals explore producing varying spatial and force relations among objects and surfaces, thereby learning about affordances of such relations and how to produce them. Such learning supports the discovery of tool use. We present longitudinal…

Evolution of Shiga toxin-producing Escherichia coli O157: eight major lineages of human and cattle origin strain signature genotypes

USDA-ARS?s Scientific Manuscript database

Cattle are a major reservoir for Shiga toxin-producing Escherichia coli O157 (STEC O157) and harbor genetic subtypes that do not all associate with human disease. STEC O157 evolved from an E. coli O55:H7 progenitor, however, depauperate nucleotide polymorphism discovery from cattle and human origin...

Bacterial symbionts and natural products.

PubMed

Crawford, Jason M; Clardy, Jon

2011-07-21

The study of bacterial symbionts of eukaryotic hosts has become a powerful discovery engine for chemistry. This highlight looks at four case studies that exemplify the range of chemistry and biology involved in these symbioses: a bacterial symbiont of a fungus and a marine invertebrate that produce compounds with significant anticancer activity, and bacterial symbionts of insects and nematodes that produce compounds that regulate multilateral symbioses.

Strategies to support drug discovery through integration of systems and data.

PubMed

Waller, Chris L; Shah, Ajay; Nolte, Matthias

2007-08-01

Much progress has been made over the past several years to provide technologies for the integration of drug discovery software applications and the underlying data bits. Integration at the application layer has focused primarily on developing and delivering applications that support specific workflows within the drug discovery arena. A fine balance between creating behemoth applications and providing business value must be maintained. Heterogeneous data sources have typically been integrated at the data level in an effort to provide a more holistic view of the data packages supporting key decision points. This review will highlight past attempts, current status, and potential future directions for systems and data integration strategies in support of drug discovery efforts.

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

PubMed Central

2013-01-01

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

Semiconductor technology in protein kinase research and drug discovery: sensing a revolution.

PubMed

Bhalla, Nikhil; Di Lorenzo, Mirella; Estrela, Pedro; Pula, Giordano

2017-02-01

Since the discovery of protein kinase activity in 1954, close to 600 kinases have been discovered that have crucial roles in cell physiology. In several pathological conditions, aberrant protein kinase activity leads to abnormal cell and tissue physiology. Therefore, protein kinase inhibitors are investigated as potential treatments for several diseases, including dementia, diabetes, cancer and autoimmune and cardiovascular disease. Modern semiconductor technology has recently been applied to accelerate the discovery of novel protein kinase inhibitors that could become the standard-of-care drugs of tomorrow. Here, we describe current techniques and novel applications of semiconductor technologies in protein kinase inhibitor drug discovery. Copyright © 2016 Elsevier Ltd. All rights reserved.

An Efficient Composition for Bengal Lights.

ERIC Educational Resources Information Center

Comet, M.; Schreyeck, L.; Fuzellier, H.

2002-01-01

Reports the discovery of an efficient base composition for making bengal lights that is obtained with potassium chlorate and thiourea. Combining this mixture with appropriate flame coloring can produce several impressive bengal lights. (DDR)

Overview of aldosterone-related genetic syndromes and recent advances.

PubMed

Zennaro, Maria-Christina; Fernandes-Rosa, Fabio L; Boulkroun, Sheerazed

2018-06-01

Primary aldosteronism is the most common form of secondary hypertension. Early diagnosis and treatment are key to cure of hypertension and prevention of cardiovascular complications. Recent genetic discoveries have improved our understanding on the pathophysiology of aldosterone production and triggered the development of new diagnostic procedures and targeted treatments for primary aldosteronism. Different inherited genetic abnormalities distinguish specific forms of familial hyperaldosteronism. Somatic mutations are found not only in aldosterone-producing adenoma (APA), leading to primary aldosteronism, but also in aldosterone producing cell clusters of normal and micronodules from image-negative adrenal glands. Genetic knowledge has allowed the discovery of surrogate biomarkers and specific pharmacological inhibitors. Ageing appears to be associated with dysregulated and relatively autonomous aldosterone production. New biochemical markers and pharmacological approaches may allow preoperative identification of somatic mutation carriers and use of targeted treatments.

Discovery, biosynthesis, and rational engineering of novel enterocin and wailupemycin polyketide analogues.

PubMed

Kalaitzis, John A

2013-01-01

The marine actinomycete Streptomyces maritimus produces a structurally diverse set of unusual polyketide natural products including the major metabolite enterocin. Investigations of enterocin biosynthesis revealed that the unique carbon skeleton is derived from an aromatic polyketide pathway which is genetically coded by the 21.3 kb enc gene cluster in S. maritimus. Characterization of the enc biosynthesis gene cluster and subsequent manipulation of it via heterologous expression and/or mutagenesis enabled the discovery of other enc-based metabolites that were produced in only very minor amounts in the wild type. Also described are techniques used to harness the enterocin biosynthetic machinery in order to generate unnatural enc-derived polyketide analogues. This review focuses upon the molecular methods used in combination with classical natural products detection and isolation techniques to access minor metabolites of the S. maritimus secondary metabolome.

Computational methods in drug discovery

PubMed Central

Leelananda, Sumudu P

2016-01-01

The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery projects. Additionally, increasing knowledge of biological structures, as well as increasing computer power have made it possible to use computational methods effectively in various phases of the drug discovery and development pipeline. The importance of in silico tools is greater than ever before and has advanced pharmaceutical research. Here we present an overview of computational methods used in different facets of drug discovery and highlight some of the recent successes. In this review, both structure-based and ligand-based drug discovery methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein–ligand docking, pharmacophore modeling and QSAR techniques are reviewed. PMID:28144341

Computational methods in drug discovery.

PubMed

Leelananda, Sumudu P; Lindert, Steffen

2016-01-01

The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery projects. Additionally, increasing knowledge of biological structures, as well as increasing computer power have made it possible to use computational methods effectively in various phases of the drug discovery and development pipeline. The importance of in silico tools is greater than ever before and has advanced pharmaceutical research. Here we present an overview of computational methods used in different facets of drug discovery and highlight some of the recent successes. In this review, both structure-based and ligand-based drug discovery methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein-ligand docking, pharmacophore modeling and QSAR techniques are reviewed.

Phenotypic screening in cancer drug discovery - past, present and future.

PubMed

Moffat, John G; Rudolph, Joachim; Bailey, David

2014-08-01

There has been a resurgence of interest in the use of phenotypic screens in drug discovery as an alternative to target-focused approaches. Given that oncology is currently the most active therapeutic area, and also one in which target-focused approaches have been particularly prominent in the past two decades, we investigated the contribution of phenotypic assays to oncology drug discovery by analysing the origins of all new small-molecule cancer drugs approved by the US Food and Drug Administration (FDA) over the past 15 years and those currently in clinical development. Although the majority of these drugs originated from target-based discovery, we identified a significant number whose discovery depended on phenotypic screening approaches. We postulate that the contribution of phenotypic screening to cancer drug discovery has been hampered by a reliance on 'classical' nonspecific drug effects such as cytotoxicity and mitotic arrest, exacerbated by a paucity of mechanistically defined cellular models for therapeutically translatable cancer phenotypes. However, technical and biological advances that enable such mechanistically informed phenotypic models have the potential to empower phenotypic drug discovery in oncology.

Dickinson field lodgepole reservoir: Significance of this Waulsortian-type mound to exploration in the Williston Basin

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

Johnson, M.S.

1995-07-01

Conoco`s No. 74 Dickinson State well, a deep test in Dickinson Field, Stark County, North Dakota, was completed in early 1993 capable of producing over 2,000 BOPD. It represents the first commercial oil production from the Lower Mississippian Lodgepole Formation in the U.S. portion of the Williston Basin. Three additional oil producers have now been completed and this Lodgepole discovery is fully developed. The producing reservoir, at depths of 9,700 to 10,000 ft, is a Waulsortian-type mound approximately 300 ft thick with a characteristic faunal assemblage of bryozoans and crinoids. The mound has an areal extent of slightly more thanmore » 1 square mile. Similar Waulsortian-type mounds have been recognized in rocks of Paleozoic age around the world, but have only been reported in the Williston Basin during the past decade. Such mounds are shallow to deep water deposits, tend to develop over structurally or topographically-positive areas, and may form by algal or by current action in conjunction with baffling action caused by bryozoans. The prolific nature of the Conoco discovery, plus several more-recent excellent mound discoveries in this same area, have caused renewed drilling and leasing activity. These events have also encouraged a review of existing seismic data, the shooting of new 3-D seismic programs and re-analysis of wells previously drilled through the Lodgepole Formation for evidence of similar mounds elsewhere in the basin.« less

Exploration and development offshore southern Vietnam

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

Ferguson, A.M.

1996-01-01

In Vietnam, the major focus of the oil and gas industry is on the Nam Con Son and Cuu Long Basins in the southern offshore area. Major licensing first occurred here in the early 1970s. Some exploration was also undertaken by foreign companies in the early 1980s. In 1981, the Soviet Union undertook to assist Vietnam with the development of oil and gas. Vietsovpetro, a joint venture between the then Soviet Oil and Gas Ministry and the Vietnam Oil and Gas Corporation was formed. Most of Vietsovpetro's efforts have been to develop the Bach Ho field in the Cuu Longmore » Basin. This now produces [approximately]130000 bopd. The most recent large scale licensing round occurred in 1992, and, at present, there are over thirty foreign companies active in these Basins' blocks . The first phase of exploration is ending and successes in the Nam Con Son Basin include the BP-led Lan Tay/Lan Do gas discoveries and Pedco's gas discoveries. Mitsubishi's and Petronas' oil discoveries in the Cuu Long Basin have attracted much attention also. The Dai Hung oil field (BHP-operated) has been producing since late 1994. Certain blocks are being appraised, and exploration work is also continuing. Areas of the Cuu Long Basin that were part of Vietsovpetro's acreage, but which may soon be re-licensed, have generated keen interest. The presence of an active upstream industry - exploring, appraising, developing and producing - indicates the emergence of Vietnam as an important East Asian oil and gas player.« less

Research Informed Science Enrichment Programs at the Gravity Discovery Centre

ERIC Educational Resources Information Center

Venville, Grady; Blair, David; Coward, David; Deshon, Fred; Gargano, Mark; Gondwe, Mzamose; Heary, Auriol; Longnecker, Nancy; Pitts, Marina; Zadnik, Marjan

2012-01-01

Excursions to museums and science centres generally are great fun for students and teachers. The potential educational benefits beyond enjoyment, however, are rarely realised or analysed for their efficacy. The purpose of this paper is to describe four educational enrichment programs delivered at the Gravity Discovery Centre (GDC), near Gingin,…

Perfect launch for Space Shuttle Discovery on mission STS-105

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- Trailing a fiery-looking column of smoke, Space Shuttle Discovery hurtles into a blue sky on mission STS-105 to the International Space Station. Viewed from the top of the Vehicle Assembly Building, liftoff occurred at 5:10:14 p.m. EDT on this second launch attempt. Launch countdown activities for the 12-day mission were called off Aug. 9 during the T-9 minute hold due to the high potential for lightning, a thick cloud cover and the potential for showers. Besides the Shuttle crew of four, Discovery carries the Expedition Three crew who will replace Expedition Two on the International Space Station. The mission includes the third flight of an Italian-built Multi-Purpose Logistics Module delivering additional scientific racks, equipment and supplies for the Space Station, and two spacewalks. Part of the payload is the Early Ammonia Servicer (EAS) tank, which will be attached to the Station during the spacewalks. The EAS contains spare ammonia for the Station'''s cooling system. The three-member Expedition Two crew will be returning to Earth aboard Discovery after a five-month stay on the Station.

Perfect launch for Space Shuttle Discovery on mission STS-105

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- Smoke billows out from Launch Pad 39A as Space Shuttle Discovery soars into the blue sky on mission STS-105 to the International Space Station. Liftoff occurred at 5:10:14 p.m. EDT on this second launch attempt. Launch countdown activities for the 12-day mission were called off Aug. 9 during the T-9 minute hold due to the high potential for lightning, a thick cloud cover and the potential for showers. Besides the Shuttle crew of four, Discovery carries the Expedition Three crew who will replace Expedition Two on the International Space Station. The mission includes the third flight of an Italian-built Multi-Purpose Logistics Module delivering additional scientific racks, equipment and supplies for the Space Station, and two spacewalks. Part of the payload is the Early Ammonia Servicer (EAS) tank, which will be attached to the Station during the spacewalks. The EAS contains spare ammonia for the Station'''s cooling system. The three-member Expedition Two crew will be returning to Earth aboard Discovery after a five-month stay on the Station.

Virtual Observatories, Data Mining, and Astroinformatics

NASA Astrophysics Data System (ADS)

Borne, Kirk

The historical, current, and future trends in knowledge discovery from data in astronomy are presented here. The story begins with a brief history of data gathering and data organization. A description of the development ofnew information science technologies for astronomical discovery is then presented. Among these are e-Science and the virtual observatory, with its data discovery, access, display, and integration protocols; astroinformatics and data mining for exploratory data analysis, information extraction, and knowledge discovery from distributed data collections; new sky surveys' databases, including rich multivariate observational parameter sets for large numbers of objects; and the emerging discipline of data-oriented astronomical research, called astroinformatics. Astroinformatics is described as the fourth paradigm of astronomical research, following the three traditional research methodologies: observation, theory, and computation/modeling. Astroinformatics research areas include machine learning, data mining, visualization, statistics, semantic science, and scientific data management.Each of these areas is now an active research discipline, with significantscience-enabling applications in astronomy. Research challenges and sample research scenarios are presented in these areas, in addition to sample algorithms for data-oriented research. These information science technologies enable scientific knowledge discovery from the increasingly large and complex data collections in astronomy. The education and training of the modern astronomy student must consequently include skill development in these areas, whose practitioners have traditionally been limited to applied mathematicians, computer scientists, and statisticians. Modern astronomical researchers must cross these traditional discipline boundaries, thereby borrowing the best of breed methodologies from multiple disciplines. In the era of large sky surveys and numerous large telescopes, the potential for astronomical discovery is equally large, and so the data-oriented research methods, algorithms, and techniques that are presented here will enable the greatest discovery potential from the ever-growing data and information resources in astronomy.

Phage display as a technology delivering on the promise of peptide drug discovery.

PubMed

Hamzeh-Mivehroud, Maryam; Alizadeh, Ali Akbar; Morris, Michael B; Church, W Bret; Dastmalchi, Siavoush

2013-12-01

Phage display represents an important approach in the development pipeline for producing peptides and peptidomimetics therapeutics. Using randomly generated DNA sequences and molecular biology techniques, large diverse peptide libraries can be displayed on the phage surface. The phage library can be incubated with a target of interest and the phage which bind can be isolated and sequenced to reveal the displayed peptides' primary structure. In this review, we focus on the 'mechanics' of the phage display process, whilst highlighting many diverse and subtle ways it has been used to further the drug-development process, including the potential for the phage particle itself to be used as a drug carrier targeted to a particular pathogen or cell type in the body. Copyright © 2013 Elsevier Ltd. All rights reserved.

Tire Changes, Fresh Air, and Yellow Flags: Challenges in Predictive Analytics for Professional Racing.

PubMed

Tulabandhula, Theja; Rudin, Cynthia

2014-06-01

Our goal is to design a prediction and decision system for real-time use during a professional car race. In designing a knowledge discovery process for racing, we faced several challenges that were overcome only when domain knowledge of racing was carefully infused within statistical modeling techniques. In this article, we describe how we leveraged expert knowledge of the domain to produce a real-time decision system for tire changes within a race. Our forecasts have the potential to impact how racing teams can optimize strategy by making tire-change decisions to benefit their rank position. Our work significantly expands previous research on sports analytics, as it is the only work on analytical methods for within-race prediction and decision making for professional car racing.

Meditation, Health and Scientific Investigations: Review of the Literature.

PubMed

Sampaio, Cynthia Vieira Sanches; Lima, Manuela Garcia; Ladeia, Ana Marice

2017-04-01

A growing number of people are seeking health recovery treatments with a holistic approach to the human being. Meditation is a mental training capable of producing connection between the mind, body and spirit. Its practice helps people to achieve balance, relaxation and self-control, in addition to the development of consciousness. At present, meditation is classified as a complementary and integrative technique in the area of health. The purpose of this review of the literature was to describe what meditation is, its practices and effects on health, demonstrated by consistent scientific investigations. Recently, the advances in researches with meditation, the discovery of its potential as an instrument of self-regulation of the human body and its benefits to health have shown that it is a consistent alternative therapy when associated with conventional medical treatments.

Constructing a Graph Database for Semantic Literature-Based Discovery.

PubMed

Hristovski, Dimitar; Kastrin, Andrej; Dinevski, Dejan; Rindflesch, Thomas C

2015-01-01

Literature-based discovery (LBD) generates discoveries, or hypotheses, by combining what is already known in the literature. Potential discoveries have the form of relations between biomedical concepts; for example, a drug may be determined to treat a disease other than the one for which it was intended. LBD views the knowledge in a domain as a network; a set of concepts along with the relations between them. As a starting point, we used SemMedDB, a database of semantic relations between biomedical concepts extracted with SemRep from Medline. SemMedDB is distributed as a MySQL relational database, which has some problems when dealing with network data. We transformed and uploaded SemMedDB into the Neo4j graph database, and implemented the basic LBD discovery algorithms with the Cypher query language. We conclude that storing the data needed for semantic LBD is more natural in a graph database. Also, implementing LBD discovery algorithms is conceptually simpler with a graph query language when compared with standard SQL.

Botulinum Toxin Type a as a Therapeutic Agent against Headache and Related Disorders.

PubMed

Luvisetto, Siro; Gazerani, Parisa; Cianchetti, Carlo; Pavone, Flaminia

2015-09-23

Botulinum neurotoxin A (BoNT/A) is a toxin produced by the naturally-occurring Clostridium botulinum that causes botulism. The potential of BoNT/A as a useful medical intervention was discovered by scientists developing a vaccine to protect against botulism. They found that, when injected into a muscle, BoNT/A causes a flaccid paralysis. Following this discovery, BoNT/A has been used for many years in the treatment of conditions of pathological muscle hyperactivity, like dystonias and spasticities. In parallel, the toxin has become a "glamour" drug due to its power to ward off facial wrinkles, particularly frontal, due to the activity of the mimic muscles. After the discovery that the drug also appeared to have a preventive effect on headache, scientists spent many efforts to study the potentially-therapeutic action of BoNT/A against pain. BoNT/A is effective at reducing pain in a number of disease states, including cervical dystonia, neuropathic pain, lower back pain, spasticity, myofascial pain and bladder pain. In 2010, regulatory approval for the treatment of chronic migraine with BoNT/A was given, notwithstanding the fact that the mechanism of action is still not completely elucidated. In the present review, we summarize experimental evidence that may help to clarify the mechanisms of action of BoNT/A in relation to the alleviation of headache pain, with particular emphasis on preclinical studies, both in animals and humans. Moreover, we summarize the latest clinical trials that show evidence on headache conditions that may obtain benefits from therapy with BoNT/A.

Biotechnological applications of functional metagenomics in the food and pharmaceutical industries

PubMed Central

Coughlan, Laura M.; Cotter, Paul D.; Hill, Colin; Alvarez-Ordóñez, Avelino

2015-01-01

Microorganisms are found throughout nature, thriving in a vast range of environmental conditions. The majority of them are unculturable or difficult to culture by traditional methods. Metagenomics enables the study of all microorganisms, regardless of whether they can be cultured or not, through the analysis of genomic data obtained directly from an environmental sample, providing knowledge of the species present, and allowing the extraction of information regarding the functionality of microbial communities in their natural habitat. Function-based screenings, following the cloning and expression of metagenomic DNA in a heterologous host, can be applied to the discovery of novel proteins of industrial interest encoded by the genes of previously inaccessible microorganisms. Functional metagenomics has considerable potential in the food and pharmaceutical industries, where it can, for instance, aid (i) the identification of enzymes with desirable technological properties, capable of catalyzing novel reactions or replacing existing chemically synthesized catalysts which may be difficult or expensive to produce, and able to work under a wide range of environmental conditions encountered in food and pharmaceutical processing cycles including extreme conditions of temperature, pH, osmolarity, etc; (ii) the discovery of novel bioactives including antimicrobials active against microorganisms of concern both in food and medical settings; (iii) the investigation of industrial and societal issues such as antibiotic resistance development. This review article summarizes the state-of-the-art functional metagenomic methods available and discusses the potential of functional metagenomic approaches to mine as yet unexplored environments to discover novel genes with biotechnological application in the food and pharmaceutical industries. PMID:26175729

Biotechnological applications of functional metagenomics in the food and pharmaceutical industries.

PubMed

Coughlan, Laura M; Cotter, Paul D; Hill, Colin; Alvarez-Ordóñez, Avelino

2015-01-01

Microorganisms are found throughout nature, thriving in a vast range of environmental conditions. The majority of them are unculturable or difficult to culture by traditional methods. Metagenomics enables the study of all microorganisms, regardless of whether they can be cultured or not, through the analysis of genomic data obtained directly from an environmental sample, providing knowledge of the species present, and allowing the extraction of information regarding the functionality of microbial communities in their natural habitat. Function-based screenings, following the cloning and expression of metagenomic DNA in a heterologous host, can be applied to the discovery of novel proteins of industrial interest encoded by the genes of previously inaccessible microorganisms. Functional metagenomics has considerable potential in the food and pharmaceutical industries, where it can, for instance, aid (i) the identification of enzymes with desirable technological properties, capable of catalyzing novel reactions or replacing existing chemically synthesized catalysts which may be difficult or expensive to produce, and able to work under a wide range of environmental conditions encountered in food and pharmaceutical processing cycles including extreme conditions of temperature, pH, osmolarity, etc; (ii) the discovery of novel bioactives including antimicrobials active against microorganisms of concern both in food and medical settings; (iii) the investigation of industrial and societal issues such as antibiotic resistance development. This review article summarizes the state-of-the-art functional metagenomic methods available and discusses the potential of functional metagenomic approaches to mine as yet unexplored environments to discover novel genes with biotechnological application in the food and pharmaceutical industries.

Botulinum Toxin Type A as a Therapeutic Agent against Headache and Related Disorders

PubMed Central

Luvisetto, Siro; Gazerani, Parisa; Cianchetti, Carlo; Pavone, Flaminia

2015-01-01

Botulinum neurotoxin A (BoNT/A) is a toxin produced by the naturally-occurring Clostridium botulinum that causes botulism. The potential of BoNT/A as a useful medical intervention was discovered by scientists developing a vaccine to protect against botulism. They found that, when injected into a muscle, BoNT/A causes a flaccid paralysis. Following this discovery, BoNT/A has been used for many years in the treatment of conditions of pathological muscle hyperactivity, like dystonias and spasticities. In parallel, the toxin has become a “glamour” drug due to its power to ward off facial wrinkles, particularly frontal, due to the activity of the mimic muscles. After the discovery that the drug also appeared to have a preventive effect on headache, scientists spent many efforts to study the potentially-therapeutic action of BoNT/A against pain. BoNT/A is effective at reducing pain in a number of disease states, including cervical dystonia, neuropathic pain, lower back pain, spasticity, myofascial pain and bladder pain. In 2010, regulatory approval for the treatment of chronic migraine with BoNT/A was given, notwithstanding the fact that the mechanism of action is still not completely elucidated. In the present review, we summarize experimental evidence that may help to clarify the mechanisms of action of BoNT/A in relation to the alleviation of headache pain, with particular emphasis on preclinical studies, both in animals and humans. Moreover, we summarize the latest clinical trials that show evidence on headache conditions that may obtain benefits from therapy with BoNT/A. PMID:26404377

AFLP fragment isolation technique as a method to produce random sequences for single nucleotide polymorphism discovery in the green turtle, Chelonia mydas.

PubMed

Roden, Suzanne E; Dutton, Peter H; Morin, Phillip A

2009-01-01

The green sea turtle, Chelonia mydas, was used as a case study for single nucleotide polymorphism (SNP) discovery in a species that has little genetic sequence information available. As green turtles have a complex population structure, additional nuclear markers other than microsatellites could add to our understanding of their complex life history. Amplified fragment length polymorphism technique was used to generate sets of random fragments of genomic DNA, which were then electrophoretically separated with precast gels, stained with SYBR green, excised, and directly sequenced. It was possible to perform this method without the use of polyacrylamide gels, radioactive or fluorescent labeled primers, or hybridization methods, reducing the time, expense, and safety hazards of SNP discovery. Within 13 loci, 2547 base pairs were screened, resulting in the discovery of 35 SNPs. Using this method, it was possible to yield a sufficient number of loci to screen for SNP markers without the availability of prior sequence information.

Better cancer biomarker discovery through better study design.

PubMed

Rundle, Andrew; Ahsan, Habibul; Vineis, Paolo

2012-12-01

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

Sensitivity and Discovery Potential of CUORE to Neutrinoless Double-Beta Decay

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

Alessandria, F; Ardito, R; Artusa, DR

We present a study of the sensitivity and discovery potential of CUORE, a bolometric double-beta decay experiment under construction at the Laboratori Nazionali del Gran Sasso in Italy. Two approaches to the computation of experimental sensitivity for various background scenarios are presented, and an extension of the sensitivity formulation to the discovery potential case is also discussed. Assuming a background rate of 10 -2 cts/(keV kg y), we find that, after 5 years of live time, CUORE has a 1 sigma sensitivity to the neutrinoless double-beta decay half-life of Tmore » $$0v\\atop{1/2}$$(1θ) = 1.6 \\times 10 26 y and thus a potential to probe the effective Majorana neutrino mass down to 40-100 meV; the sensitivity at 1.64 sigma, which corresponds to 90% C.L., will be T$$0v\\atop{1/2}$$(1.64θ) = 9.5 \\times 10 25 y. This range is compared with the claim of observation of neutrinoless double-beta decay in 76Ge and the preferred range of the neutrino mass parameter space from oscillation results.« less

Potential Inhibitors for Isocitrate Lyase of Mycobacterium tuberculosis and Non-M. tuberculosis: A Summary

PubMed Central

Lee, Yie-Vern; Wahab, Habibah A.

2015-01-01

Isocitrate lyase (ICL) is the first enzyme involved in glyoxylate cycle. Many plants and microorganisms are relying on glyoxylate cycle enzymes to survive upon downregulation of tricarboxylic acid cycle (TCA cycle), especially Mycobacterium tuberculosis (MTB). In fact, ICL is a potential drug target for MTB in dormancy. With the urge for new antitubercular drug to overcome tuberculosis treat such as multidrug resistant strain and HIV-coinfection, the pace of drug discovery has to be increased. There are many approaches to discovering potential inhibitor for MTB ICL and we hereby review the updated list of them. The potential inhibitors can be either a natural compound or synthetic compound. Moreover, these compounds are not necessary to be discovered only from MTB ICL, as it can also be discovered by a non-MTB ICL. Our review is categorized into four sections, namely, (a) MTB ICL with natural compounds; (b) MTB ICL with synthetic compounds; (c) non-MTB ICL with natural compounds; and (d) non-MTB ICL with synthetic compounds. Each of the approaches is capable of overcoming different challenges of inhibitor discovery. We hope that this paper will benefit the discovery of better inhibitor for ICL. PMID:25649791

Understanding price discovery in interconnected markets: Generalized Langevin process approach and simulation

NASA Astrophysics Data System (ADS)

Schenck, Natalya A.; Horvath, Philip A.; Sinha, Amit K.

2018-02-01

While the literature on price discovery process and information flow between dominant and satellite market is exhaustive, most studies have applied an approach that can be traced back to Hasbrouck (1995) or Gonzalo and Granger (1995). In this paper, however, we propose a Generalized Langevin process with asymmetric double-well potential function, with co-integrated time series and interconnected diffusion processes to model the information flow and price discovery process in two, a dominant and a satellite, interconnected markets. A simulated illustration of the model is also provided.

Avoiding false discoveries in association studies.

PubMed

Sabatti, Chiara

2007-01-01

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

IMG-ABC: An Atlas of Biosynthetic Gene Clusters to Fuel the Discovery of Novel Secondary Metabolites

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

Chen, I-Min; Chu, Ken; Ratner, Anna

2014-10-28

In the discovery of secondary metabolites (SMs), large-scale analysis of sequence data is a promising exploration path that remains largely underutilized due to the lack of relevant computational resources. We present IMG-ABC (https://img.jgi.doe.gov/abc/) -- An Atlas of Biosynthetic gene Clusters within the Integrated Microbial Genomes (IMG) system1. IMG-ABC is a rich repository of both validated and predicted biosynthetic clusters (BCs) in cultured isolates, single-cells and metagenomes linked with the SM chemicals they produce and enhanced with focused analysis tools within IMG. The underlying scalable framework enables traversal of phylogenetic dark matter and chemical structure space -- serving as a doorwaymore » to a new era in the discovery of novel molecules.« less

Broad spectrum antibiotic compounds and use thereof

DOEpatents

Koglin, Alexander; Strieker, Matthias

2016-07-05

The discovery of a non-ribosomal peptide synthetase (NRPS) gene cluster in the genome of Clostridium thermocellum that produces a secondary metabolite that is assembled outside of the host membrane is described. Also described is the identification of homologous NRPS gene clusters from several additional microorganisms. The secondary metabolites produced by the NRPS gene clusters exhibit broad spectrum antibiotic activity. Thus, antibiotic compounds produced by the NRPS gene clusters, and analogs thereof, their use for inhibiting bacterial growth, and methods of making the antibiotic compounds are described.

An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs.

PubMed

Kim, Wooseong; Hendricks, Gabriel Lambert; Lee, Kiho; Mylonakis, Eleftherios

2017-06-01

The emergence of antibiotic-resistant and -tolerant bacteria is a major threat to human health. Although efforts for drug discovery are ongoing, conventional bacteria-centered screening strategies have thus far failed to yield new classes of effective antibiotics. Therefore, new paradigms for discovering novel antibiotics are of critical importance. Caenorhabditis elegans, a model organism used for in vivo, offers a promising solution for identification of anti-infective compounds. Areas covered: This review examines the advantages of C. elegans-based high-throughput screening over conventional, bacteria-centered in vitro screens. It discusses major anti-infective compounds identified from large-scale C. elegans-based screens and presents the first clinically-approved drugs, then known bioactive compounds, and finally novel small molecules. Expert opinion: There are clear advantages of using a C. elegans-infection based screening method. A C. elegans-based screen produces an enriched pool of non-toxic, efficacious, potential anti-infectives, covering: conventional antimicrobial agents, immunomodulators, and anti-virulence agents. Although C. elegans-based screens do not denote the mode of action of hit compounds, this can be elucidated in secondary studies by comparing the results to target-based screens, or conducting subsequent target-based screens, including the genetic knock-down of host or bacterial genes.

Automatic Classification of Time-variable X-Ray Sources

NASA Astrophysics Data System (ADS)

Lo, Kitty K.; Farrell, Sean; Murphy, Tara; Gaensler, B. M.

2014-05-01

To maximize the discovery potential of future synoptic surveys, especially in the field of transient science, it will be necessary to use automatic classification to identify some of the astronomical sources. The data mining technique of supervised classification is suitable for this problem. Here, we present a supervised learning method to automatically classify variable X-ray sources in the Second XMM-Newton Serendipitous Source Catalog (2XMMi-DR2). Random Forest is our classifier of choice since it is one of the most accurate learning algorithms available. Our training set consists of 873 variable sources and their features are derived from time series, spectra, and other multi-wavelength contextual information. The 10 fold cross validation accuracy of the training data is ~97% on a 7 class data set. We applied the trained classification model to 411 unknown variable 2XMM sources to produce a probabilistically classified catalog. Using the classification margin and the Random Forest derived outlier measure, we identified 12 anomalous sources, of which 2XMM J180658.7-500250 appears to be the most unusual source in the sample. Its X-ray spectra is suggestive of a ultraluminous X-ray source but its variability makes it highly unusual. Machine-learned classification and anomaly detection will facilitate scientific discoveries in the era of all-sky surveys.

Fungi treated with small chemicals exhibit increased antimicrobial activity against facultative bacterial and yeast pathogens.

PubMed

Zutz, Christoph; Bandian, Dragana; Neumayer, Bernhard; Speringer, Franz; Gorfer, Markus; Wagner, Martin; Strauss, Joseph; Rychli, Kathrin

2014-01-01

For decades, fungi have been the main source for the discovery of novel antimicrobial drugs. Recent sequencing efforts revealed a still high number of so far unknown "cryptic" secondary metabolites. The production of these metabolites is presumably epigenetically silenced under standard laboratory conditions. In this study, we investigated the effect of six small mass chemicals, of which some are known to act as epigenetic modulators, on the production of antimicrobial compounds in 54 spore forming fungi. The antimicrobial effect of fungal samples was tested against clinically facultative pathogens and multiresistant clinical isolates. In total, 30 samples of treated fungi belonging to six different genera reduced significantly growth of different test organisms compared to the untreated fungal sample (growth log reduction 0.3-4.3). For instance, the pellet of Penicillium restrictum grown in the presence of butyrate revealed significant higher antimicrobial activity against Staphylococcus (S.) aureus and multiresistant S. aureus strains and displayed no cytotoxicity against human cells, thus making it an ideal candidate for antimicrobial compound discovery. Our study shows that every presumable fungus, even well described fungi, has the potential to produce novel antimicrobial compounds and that our approach is capable of rapidly filling the pipeline for yet undiscovered antimicrobial substances.

Fungi Treated with Small Chemicals Exhibit Increased Antimicrobial Activity against Facultative Bacterial and Yeast Pathogens

PubMed Central

Zutz, Christoph; Bandian, Dragana; Neumayer, Bernhard; Speringer, Franz; Wagner, Martin; Strauss, Joseph

2014-01-01

For decades, fungi have been the main source for the discovery of novel antimicrobial drugs. Recent sequencing efforts revealed a still high number of so far unknown “cryptic” secondary metabolites. The production of these metabolites is presumably epigenetically silenced under standard laboratory conditions. In this study, we investigated the effect of six small mass chemicals, of which some are known to act as epigenetic modulators, on the production of antimicrobial compounds in 54 spore forming fungi. The antimicrobial effect of fungal samples was tested against clinically facultative pathogens and multiresistant clinical isolates. In total, 30 samples of treated fungi belonging to six different genera reduced significantly growth of different test organisms compared to the untreated fungal sample (growth log reduction 0.3–4.3). For instance, the pellet of Penicillium restrictum grown in the presence of butyrate revealed significant higher antimicrobial activity against Staphylococcus (S.) aureus and multiresistant S. aureus strains and displayed no cytotoxicity against human cells, thus making it an ideal candidate for antimicrobial compound discovery. Our study shows that every presumable fungus, even well described fungi, has the potential to produce novel antimicrobial compounds and that our approach is capable of rapidly filling the pipeline for yet undiscovered antimicrobial substances. PMID:25121102

Accelerated discovery of new magnets in the Heusler alloy family

PubMed Central

Sanvito, Stefano; Oses, Corey; Xue, Junkai; Tiwari, Anurag; Zic, Mario; Archer, Thomas; Tozman, Pelin; Venkatesan, Munuswamy; Coey, Michael; Curtarolo, Stefano

2017-01-01

Magnetic materials underpin modern technologies, ranging from data storage to energy conversion to contactless sensing. However, the development of a new high-performance magnet is a long and often unpredictable process, and only about two dozen magnets are featured in mainstream applications. We describe a systematic pathway to the design of novel magnetic materials, which demonstrates a high throughput and discovery speed. On the basis of an extensive electronic structure library of Heusler alloys containing 236,115 prototypical compounds, we filtered those displaying magnetic order and established whether they can be fabricated at thermodynamic equilibrium. Specifically, we carried out a full stability analysis of intermetallic Heusler alloys made only of transition metals. Among the possible 36,540 prototypes, 248 were thermodynamically stable but only 20 were magnetic. The magnetic ordering temperature, TC, was estimated by a regression calibrated on the experimental TC of about 60 known compounds. As a final validation, we attempted the synthesis of a few of the predicted compounds and produced two new magnets: Co2MnTi, which displays a remarkably high TC in perfect agreement with the predictions, and Mn2PtPd, which is an antiferromagnet. Our work paves the way for large-scale design of novel magnetic materials at potentially high speed. PMID:28439545

IMG-ABC: new features for bacterial secondary metabolism analysis and targeted biosynthetic gene cluster discovery in thousands of microbial genomes.

PubMed

Hadjithomas, Michalis; Chen, I-Min A; Chu, Ken; Huang, Jinghua; Ratner, Anna; Palaniappan, Krishna; Andersen, Evan; Markowitz, Victor; Kyrpides, Nikos C; Ivanova, Natalia N

2017-01-04

Secondary metabolites produced by microbes have diverse biological functions, which makes them a great potential source of biotechnologically relevant compounds with antimicrobial, anti-cancer and other activities. The proteins needed to synthesize these natural products are often encoded by clusters of co-located genes called biosynthetic gene clusters (BCs). In order to advance the exploration of microbial secondary metabolism, we developed the largest publically available database of experimentally verified and predicted BCs, the Integrated Microbial Genomes Atlas of Biosynthetic gene Clusters (IMG-ABC) (https://img.jgi.doe.gov/abc/). Here, we describe an update of IMG-ABC, which includes ClusterScout, a tool for targeted identification of custom biosynthetic gene clusters across 40 000 isolate microbial genomes, and a new search capability to query more than 700 000 BCs from isolate genomes for clusters with similar Pfam composition. Additional features enable fast exploration and analysis of BCs through two new interactive visualization features, a BC function heatmap and a BC similarity network graph. These new tools and features add to the value of IMG-ABC's vast body of BC data, facilitating their in-depth analysis and accelerating secondary metabolite discovery. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Medicinal applications of fullerenes

PubMed Central

Bakry, Rania; Vallant, Rainer M; Najam-ul-Haq, Muhammad; Rainer, Matthias; Szabo, Zoltan; Huck, Christian W; Bonn, Günther K

2007-01-01

Fullerenes have attracted considerable attention in different fields of science since their discovery in 1985. Investigations of physical, chemical and biological properties of fullerenes have yielded promising information. It is inferred that size, hydrophobicity, three-dimensionality and electronic configurations make them an appealing subject in medicinal chemistry. Their unique carbon cage structure coupled with immense scope for derivatization make them a potential therapeutic agent. The study of biological applications has attracted increasing attention despite the low solubility of carbon spheres in physiological media. The fullerene family, and especially C60, has appealing photo, electrochemical and physical properties, which can be exploited in various medical fields. Fullerene is able to fit inside the hydrophobic cavity of HIV proteases, inhibiting the access of substrates to the catalytic site of enzyme. It can be used as radical scavenger and antioxidant. At the same time, if exposed to light, fullerene can produce singlet oxygen in high quantum yields. This action, together with direct electron transfer from excited state of fullerene and DNA bases, can be used to cleave DNA. In addition, fullerenes have been used as a carrier for gene and drug delivery systems. Also they are used for serum protein profiling as MELDI material for biomarker discovery. In this review we report the aspects of medicinal applications of fullerenes. PMID:18203430

The Lightcurve Legacy of COS and STIS

NASA Astrophysics Data System (ADS)

Ely, Justin; Bourque, Matthew; Debes, John; Kriss, Gerard; McCullough, Peter R.

2015-08-01

The Cosmic Origin Spectrograph (COS) and Space Telescope Imaging Spectrograph (STIS) onboard the Hubble Space Telescope (HST) have been advancing astronomy with high quality spectroscopic products for years, and in the case of STIS, more than a decade. Though already incredibly productive, there remains an untapped potential of discovery in the data of these instruments. Due to their specific detector designs, both of these instruments can operate in a TIME-TAG mode where each individual photon's arrival time is recorded. Though this ability is typically utilized to provide second-by-second calibrations to the final spectral data, this mode can also be exploited to re-examine the data in the time domain, turning spectra into lightcurves with high temporal and spectral resolution.Nearly all COS and many STIS observations are taken in TIME-TAG mode. For observations that were not specifically designed to carry out time-resolved spectroscopy, the archived data represent an untapped space for discovery. We present here the current status of our on-going efforts to produce a collection of high-level science lightcurves for the entire COS and STIS TIME-TAG archives. Included are details of the time-series reduction software, instrument capabilities in the time-domain, and demonstrations of the current reduced products for a wide range of variable targets such as transits, stellar flares, and white dwarf pulsations.

David and Goliath: chemical perturbation of eukaryotes by bacteria.

PubMed

Ho, Louis K; Nodwell, Justin R

2016-03-01

Environmental microbes produce biologically active small molecules that have been mined extensively as antibiotics and a smaller number of drugs that act on eukaryotic cells. It is known that there are additional bioactives to be discovered from this source. While the discovery of new antibiotics is challenged by the frequent discovery of known compounds, we contend that the eukaryote-active compounds may be less saturated. Indeed, despite there being far fewer eukaryotic-active natural products these molecules interact with a far richer diversity of molecular and cellular targets.

KSC-06pd0002

NASA Image and Video Library

2006-01-05

KENNEDY SPACE CENTER, FLA. - In NASA Kennedy Space Center’s Orbiter Processing Facility bay 3, a fuel cell removed from the orbiter Discovery is lowered toward a work stand. Fuel cells are located under the forward portion of the payload bay. They make power for the orbiter by mixing hydrogen and oxygen to produce electricity. Fuel cells also create potable water that is pumped into storage tanks for the crew to use in orbit. Discovery is the designated orbiter for the second return-to-flight mission, STS-121, scheduled for launch in May. Photo credit: NASA/Kim Shiflett

KSC-06pd0006

NASA Image and Video Library

2006-01-05

KENNEDY SPACE CENTER, FLA. - In NASA Kennedy Space Center’s Orbiter Processing Facility bay 3, technicians begin dismantling the fuel cell removed from the orbiter Discovery. Fuel cells are located under the forward portion of the payload bay. They make power for the orbiter by mixing hydrogen and oxygen to produce electricity. Fuel cells also create potable water that is pumped into storage tanks for the crew to use in orbit. Discovery is the designated orbiter for the second return-to-flight mission, STS-121, scheduled for launch in May. Photo credit: NASA/Kim Shiflett

KSC-06pd0001

NASA Image and Video Library

2006-01-05

KENNEDY SPACE CENTER, FLA. - In NASA Kennedy Space Center’s Orbiter Processing Facility bay 3, a fuel cell removed from the orbiter Discovery is lowered toward the floor. Fuel cells are located under the forward portion of the payload bay. They make power for the orbiter by mixing hydrogen and oxygen to produce electricity. Fuel cells also create potable water that is pumped into storage tanks for the crew to use in orbit. Discovery is the designated orbiter for the second return-to-flight mission, STS-121, scheduled for launch in May. Photo credit: NASA/Kim Shiflett

Genomics-driven discovery of the pneumocandin biosynthetic gene cluster in the fungus Glarea lozoyensis

PubMed Central

2013-01-01

Background The antifungal therapy caspofungin is a semi-synthetic derivative of pneumocandin B0, a lipohexapeptide produced by the fungus Glarea lozoyensis, and was the first member of the echinocandin class approved for human therapy. The nonribosomal peptide synthetase (NRPS)-polyketide synthases (PKS) gene cluster responsible for pneumocandin biosynthesis from G. lozoyensis has not been elucidated to date. In this study, we report the elucidation of the pneumocandin biosynthetic gene cluster by whole genome sequencing of the G. lozoyensis wild-type strain ATCC 20868. Results The pneumocandin biosynthetic gene cluster contains a NRPS (GLNRPS4) and a PKS (GLPKS4) arranged in tandem, two cytochrome P450 monooxygenases, seven other modifying enzymes, and genes for L-homotyrosine biosynthesis, a component of the peptide core. Thus, the pneumocandin biosynthetic gene cluster is significantly more autonomous and organized than that of the recently characterized echinocandin B gene cluster. Disruption mutants of GLNRPS4 and GLPKS4 no longer produced the pneumocandins (A0 and B0), and the Δglnrps4 and Δglpks4 mutants lost antifungal activity against the human pathogenic fungus Candida albicans. In addition to pneumocandins, the G. lozoyensis genome encodes a rich repertoire of natural product-encoding genes including 24 PKSs, six NRPSs, five PKS-NRPS hybrids, two dimethylallyl tryptophan synthases, and 14 terpene synthases. Conclusions Characterization of the gene cluster provides a blueprint for engineering new pneumocandin derivatives with improved pharmacological properties. Whole genome estimation of the secondary metabolite-encoding genes from G. lozoyensis provides yet another example of the huge potential for drug discovery from natural products from the fungal kingdom. PMID:23688303

De novo sequencing analysis of the Rosa roxburghii fruit transcriptome reveals putative ascorbate biosynthetic genes and EST-SSR markers.

PubMed

Yan, Xiuqin; Zhang, Xue; Lu, Min; He, Yong; An, Huaming

2015-04-25

Rosa roxburghii Tratt. is a well-known ornamental rose species native to China. In addition, the fruits of this species are valued for their nutritional and medicinal characteristics, especially their high ascorbic acid (AsA) levels. Nevertheless, AsA biosynthesis in R. roxburghii fruit has not been explored in detail because of a lack of genomic resources for this species. High-throughput transcriptomic sequencing generating large volumes of transcript sequence data can aid in gene discovery and molecular marker development. In this study, we generated more than 53 million clean reads using Illumina paired-end sequencing technology. De novo assembly yielded 106,590 unigenes, with an average length of 343 bp. On the basis of sequence similarity to known proteins, 9301 and 2393 unigenes were classified into Gene Ontology and Clusters of Orthologous Group categories, respectively. There were 7480 unigenes assigned to 124 pathways in the Kyoto Encyclopedia of Gene and Genome pathway database. BLASTx searches identified 498 unique putative transcripts encoding various transcription factors, some known to regulate fruit development. qRT-PCR validated the expressions of most of the genes encoding the main enzymes involved in ascorbate biosynthesis. In addition, 9131 potential simple sequence repeat (SSR) loci were identified among the unigenes. One hundred and two primer pairs were synthesized and 71 pairs produced an amplification product during initial screening. Among the amplified products, 30 were polymorphic in the 16 R. roxburghii germplasms tested. Our study was the first to produce a large volume of transcriptome data from R. roxburghii. The resulting sequence collection is a valuable resource for gene discovery and marker-assisted selective breeding in this rose species. Copyright © 2015 Elsevier B.V. All rights reserved.

Open source drug discovery--a new paradigm of collaborative research in tuberculosis drug development.

PubMed

Bhardwaj, Anshu; Scaria, Vinod; Raghava, Gajendra Pal Singh; Lynn, Andrew Michael; Chandra, Nagasuma; Banerjee, Sulagna; Raghunandanan, Muthukurussi V; Pandey, Vikas; Taneja, Bhupesh; Yadav, Jyoti; Dash, Debasis; Bhattacharya, Jaijit; Misra, Amit; Kumar, Anil; Ramachandran, Srinivasan; Thomas, Zakir; Brahmachari, Samir K

2011-09-01

It is being realized that the traditional closed-door and market driven approaches for drug discovery may not be the best suited model for the diseases of the developing world such as tuberculosis and malaria, because most patients suffering from these diseases have poor paying capacity. To ensure that new drugs are created for patients suffering from these diseases, it is necessary to formulate an alternate paradigm of drug discovery process. The current model constrained by limitations for collaboration and for sharing of resources with confidentiality hampers the opportunities for bringing expertise from diverse fields. These limitations hinder the possibilities of lowering the cost of drug discovery. The Open Source Drug Discovery project initiated by Council of Scientific and Industrial Research, India has adopted an open source model to power wide participation across geographical borders. Open Source Drug Discovery emphasizes integrative science through collaboration, open-sharing, taking up multi-faceted approaches and accruing benefits from advances on different fronts of new drug discovery. Because the open source model is based on community participation, it has the potential to self-sustain continuous development by generating a storehouse of alternatives towards continued pursuit for new drug discovery. Since the inventions are community generated, the new chemical entities developed by Open Source Drug Discovery will be taken up for clinical trial in a non-exclusive manner by participation of multiple companies with majority funding from Open Source Drug Discovery. This will ensure availability of drugs through a lower cost community driven drug discovery process for diseases afflicting people with poor paying capacity. Hopefully what LINUX the World Wide Web have done for the information technology, Open Source Drug Discovery will do for drug discovery. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

PubMed

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

2017-05-30

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

From the Old to the New World of Nuclear Physics

NASA Astrophysics Data System (ADS)

Stuewer, Roger H.

Physicists passed from the Old to the New World of Nuclear Physics in the two decades between the first and second world wars. The transition occurred against the background of the Great War, the postwar hyperinflation in Germany and Austria, and the greatest intellection migrations in history after the Nazi Civil Service law of 1933, the Anschlussof Austria in March 1938, and the Fascist anti-Semitic laws that fall. It involved Rutherford's discovery of artificial disintegration, Pettersson and Kirsch's challenge of it, and the concomitant rise and fall of Rutherford's satellite model of the nucleus; Gamow's quantum-mechanical theory of alpha decay and his liquid-drop model of the nucleus; the discoveries of deuterium and the deuteron, neutron, and positron, and the inventions of the Cockcroft-Walton accelerator and the cyclotron; the influence of the seventh Solvay Conference; Joliot and Curie's discovery of artificial radioactivity; Pauli's neutrino hypothesis, Fermi's theory of beta decay, and his discovery of the efficacy of slow neutrons in producing nuclear reactions; Bohr's theory of the compound nucleus and Breit and Wigner's theory of neutron-nucleus resonances; and the discovery of nuclear fission, Meitner and Frisch's interpretation of it, and Bohr and Fermi revelation of both in America.

Citation Discovery Tools for Conducting Adaptive Meta-analyses to Update Systematic Reviews.

PubMed

Bae, Jong-Myon; Kim, Eun Hee

2016-03-01

The systematic review (SR) is a research methodology that aims to synthesize related evidence. Updating previously conducted SRs is necessary when new evidence has been produced, but no consensus has yet emerged on the appropriate update methodology. The authors have developed a new SR update method called 'adaptive meta-analysis' (AMA) using the 'cited by', 'similar articles', and 'related articles' citation discovery tools in the PubMed and Scopus databases. This study evaluates the usefulness of these citation discovery tools for updating SRs. Lists were constructed by applying the citation discovery tools in the two databases to the articles analyzed by a published SR. The degree of overlap between the lists and distribution of excluded results were evaluated. The articles ultimately selected for the SR update meta-analysis were found in the lists obtained from the 'cited by' and 'similar' tools in PubMed. Most of the selected articles appeared in both the 'cited by' lists in Scopus and PubMed. The Scopus 'related' tool did not identify the appropriate articles. The AMA, which involves using both citation discovery tools in PubMed, and optionally, the 'related' tool in Scopus, was found to be useful for updating an SR.

The 2013 Discovery Award from the Society for Free Radical Biology and Medicine: Selected Discoveries from the Butterfield Laboratory of Oxidative Stress and Its Sequelae in Brain in Cognitive Disorders Exemplified by Alzheimer Disease and Chemotherapy Induced Cognitive Impairment

PubMed Central

Butterfield, D. Allan

2014-01-01

This retrospective review on discoveries of the roles of oxidative stress in brain of subjects with Alzheimer disease (AD) and animal models thereof as well as brain from animal models of chemotherapy induced cognitive impairment (CICI) results from the author receiving the 2013 Discovery Award from the Society for Free Radical Biology and Medicine. The paper reviews our laboratory's discovery of: protein oxidation and lipid peroxidation in AD brain regions rich in amyloid β-peptide (Aβ) but not in Aβ-poor cerebellum; redox proteomics as a means to identify oxidatively modified brain proteins in AD and its earlier forms that are consistent with the pathology, biochemistry, and clinical presentation of these disorders; how Aβ in in vivo, ex vivo, and in vitro studies can lead to oxidative modification of key proteins that also are oxidatively modified in AD brain; the role of the single methionine residue of Aβ(1-42) in these processes; and some of the potential mechanisms in the pathogenesis and progression of AD. CICI affects a significant fraction of the 14 million American cancer survivors, and due to diminished cognitive function, reduced quality of life of the persons with CICI (called “chemobrain” by patients) often results. A proposed mechanism for CICI employed the prototypical ROS-generating and non-blood brain barrier (BBB)-penetrating chemotherapeutic agent doxorubicin (Dox, also called adriamycin, ADR). Because of the quinone moiety within the structure of Dox, this agent undergoes redox cycling to produce superoxide free radical peripherally. This, in turn, leads to oxidative modification of the key plasma protein, Apolipoprotein A1 (ApoA1). Oxidized ApoA1 leads to elevated peripheral TNFα, a pro-inflammatory cytokine that crosses the BBB to induce oxidative stress in brain parenchyma that affects negatively brain mitochondria. This subsequently leads to apoptotic cell death resulting in CICI. This review outlines aspects of CICI consistent with the clinical presentation, biochemistry, and pathology of this disorder. To the author's knowledge this is the only plausible and self-consistent mechanism to explain CICI. These two different disorders of the CNS affect millions of persons worldwide. Both AD and CICI share free radical-mediated oxidative stress in brain, but the source of oxidative stress is not the same. Continued research is necessary to better understand both AD and CICI. The discoveries about these disorders from the Butterfield laboratory that led to the 2013 Discovery Award from the Society of Free Radical and Medicine provides a significant foundation from which this future research can be launched. PMID:24996204

Towards a Marriage of Two Minds: The Word Processor and Natural Habits of Thought in the "Discovery" Stage of Composing.

ERIC Educational Resources Information Center

Aschauer, Mary Ann; White, Fred D.

Word processing programs offer five capabilities that can help students over the physical and psychological constraints associated with writing. First, producing text on a word processor is more tentative and more noncommital than producing text on paper. This reassures the writer that it is all right to experiment with words. Second, the blinking…

Computational functional genomics-based approaches in analgesic drug discovery and repurposing.

PubMed

Lippmann, Catharina; Kringel, Dario; Ultsch, Alfred; Lötsch, Jörn

2018-06-01

Persistent pain is a major healthcare problem affecting a fifth of adults worldwide with still limited treatment options. The search for new analgesics increasingly includes the novel research area of functional genomics, which combines data derived from various processes related to DNA sequence, gene expression or protein function and uses advanced methods of data mining and knowledge discovery with the goal of understanding the relationship between the genome and the phenotype. Its use in drug discovery and repurposing for analgesic indications has so far been performed using knowledge discovery in gene function and drug target-related databases; next-generation sequencing; and functional proteomics-based approaches. Here, we discuss recent efforts in functional genomics-based approaches to analgesic drug discovery and repurposing and highlight the potential of computational functional genomics in this field including a demonstration of the workflow using a novel R library 'dbtORA'.

Cancer epigenetics drug discovery and development: the challenge of hitting the mark

PubMed Central

Campbell, Robert M.; Tummino, Peter J.

2014-01-01

Over the past several years, there has been rapidly expanding evidence of epigenetic dysregulation in cancer, in which histone and DNA modification play a critical role in tumor growth and survival. These findings have gained the attention of the drug discovery and development community, and offer the potential for a second generation of cancer epigenetic agents for patients following the approved “first generation” of DNA methylation (e.g., Dacogen, Vidaza) and broad-spectrum HDAC inhibitors (e.g., Vorinostat, Romidepsin). This Review provides an analysis of prospects for discovery and development of novel cancer agents that target epigenetic proteins. We will examine key examples of epigenetic dysregulation in tumors as well as challenges to epigenetic drug discovery with emerging biology and novel classes of drug targets. We will also highlight recent successes in cancer epigenetics drug discovery and consider important factors for clinical success in this burgeoning area. PMID:24382391

INSECTS AND THEIR CHEMICAL WEAPONRY: GREAT POTENTIAL AND NEW DISCOVERIES FROM THE ORDER PHASMATODEA

USDA-ARS?s Scientific Manuscript database

With over 1,000,000 species of insects known, Class Insecta (Phyllum Arthropoda), the largest and most diverse group of organisms, is one of the least explored in natural product drug discovery (Dossey, A. T., Nat. Prod Rep. 2010, 27, 1737–1757). Over the past five our research stick insect chemical...

Mothers' Initial Discovery of Childhood Disability: Exploring Maternal Identification of Developmental Issues in Young Children

ERIC Educational Resources Information Center

Silbersack, Elionora W.

2014-01-01

The purpose of this qualitative study was to expand the scarce information available on how mothers first observe their children's early development, assess potential problems, and then come to recognize their concerns. In-depth knowledge about mothers' perspectives on the discovery process can help social workers to promote identification of…

Practice-Based Knowledge Discovery for Comparative Effectiveness Research: An Organizing Framework

PubMed Central

Lucero, Robert J.; Bakken, Suzanne

2014-01-01

Electronic health information systems can increase the ability of health-care organizations to investigate the effects of clinical interventions. The authors present an organizing framework that integrates outcomes and informatics research paradigms to guide knowledge discovery in electronic clinical databases. They illustrate its application using the example of hospital acquired pressure ulcers (HAPU). The Knowledge Discovery through Informatics for Comparative Effectiveness Research (KDI-CER) framework was conceived as a heuristic to conceptualize study designs and address potential methodological limitations imposed by using a single research perspective. Advances in informatics research can play a complementary role in advancing the field of outcomes research including CER. The KDI-CER framework can be used to facilitate knowledge discovery from routinely collected electronic clinical data. PMID:25278645

Marinopyrroles: Unique Drug Discoveries Based on Marine Natural Products.

PubMed

Li, Rongshi

2016-01-01

Natural products provide a successful supply of new chemical entities (NCEs) for drug discovery to treat human diseases. Approximately half of the NCEs are based on natural products and their derivatives. Notably, marine natural products, a largely untapped resource, have contributed to drug discovery and development with eight drugs or cosmeceuticals approved by the U.S. Food and Drug Administration and European Medicines Agency, and ten candidates undergoing clinical trials. Collaborative efforts from drug developers, biologists, organic, medicinal, and natural product chemists have elevated drug discoveries to new levels. These efforts are expected to continue to improve the efficiency of natural product-based drugs. Marinopyrroles are examined here as a case study for potential anticancer and antibiotic agents. © 2015 Wiley Periodicals, Inc.

Revisiting lab-on-a-chip technology for drug discovery.

PubMed

Neuži, Pavel; Giselbrecht, Stefan; Länge, Kerstin; Huang, Tony Jun; Manz, Andreas

2012-08-01

The field of microfluidics or lab-on-a-chip technology aims to improve and extend the possibilities of bioassays, cell biology and biomedical research based on the idea of miniaturization. Microfluidic systems allow more accurate modelling of physiological situations for both fundamental research and drug development, and enable systematic high-volume testing for various aspects of drug discovery. Microfluidic systems are in development that not only model biological environments but also physically mimic biological tissues and organs; such 'organs on a chip' could have an important role in expediting early stages of drug discovery and help reduce reliance on animal testing. This Review highlights the latest lab-on-a-chip technologies for drug discovery and discusses the potential for future developments in this field.

The complete genome sequence of Streptomyces albolongus YIM 101047, the producer of novel bafilomycins and odoriferous sesquiterpenoids.

PubMed

Yin, Min; Li, Guiding; Jiang, Yi; Han, Li; Huang, Xueshi; Lu, Tao; Jiang, Chenglin

2017-11-20

Streptomyces albolongus YIM 101047 produces novel bafilomycins and odoriferous sesquiterpenoids with cytotoxic and antimicrobial activities. Here, we report the complete genome sequence of S. albolongus YIM 101047, which consists of an 8,027,788bp linear chromosome. Forty-six putative biosynthetic gene clusters of secondary metabolites were found. The sesquiterpenoid gene cluster was on the left arm (0.09-0.10Mb), and the bafilomycin biosynthetic gene cluster was on the right arm (7.46-7.64Mb) of the chromosome. Twenty-two putative gene clusters with high or moderate similarity to important antibiotic biosynthetic gene clusters were found, including the antitumor agents bafilomycin, epothilone and hedamycin; the antibacterial/antifungal agents clavulanic acid, collismycin A, frontalamides, kanamycin, streptomycin and streptothricin; the protein phosphatase inhibitor RK-682; and the acute iron poisoning medication desferrioxamine B. The genome sequence reported here will enable us to study the biosynthetic mechanism of these important antibiotics and will facilitate the discovery of novel secondary metabolites with potential applications to human health. Copyright © 2017 Elsevier B.V. All rights reserved.

An analysis of the sponge Acanthostrongylophora igens’ microbiome yields an actinomycete that produces the natural product manzamine A

PubMed Central

Waters, Amanda L.; Peraud, Olivier; Kasanah, Noer; Sims, James W.; Kothalawala, Nuwan; Anderson, Matthew A.; Abbas, Samuel H.; Rao, Karumanchi V.; Jupally, Vijay R.; Kelly, Michelle; Dass, Amala; Hill, Russell T.; Hamann, Mark T.

2016-01-01

Sponges have generated significant interest as a source of bioactive and elaborate secondary metabolites that hold promise for the development of novel therapeutics for the control of an array of human diseases. However, research and development of marine natural products can often be hampered by the difficulty associated with obtaining a stable and sustainable production source. Herein we report the first successful characterization and utilization of the microbiome of a marine invertebrate to identify a sustainable production source for an important natural product scaffold. Through molecular-microbial community analysis, optimization of fermentation conditions and MALDI-MS imaging, we provide the first report of a sponge-associated bacterium (Micromonospora sp.) that produces the manzamine class of antimalarials from the Indo-Pacific sponge Acanthostrongylophora ingens (Thiele, 1899) (Class Demospongiae, Order Haplosclerida, Family Petrosiidae). These findings suggest that a general strategy of analysis of the macroorganism’s microbiome could significantly transform the field of natural products drug discovery by gaining access to not only novel drug leads, but the potential for sustainable production sources and biosynthetic genes at the same time. PMID:27785452

Expanding the chemical space for natural products by Aspergillus-Streptomyces co-cultivation and biotransformation

PubMed Central

Wu, Changsheng; Zacchetti, Boris; Ram, Arthur F.J.; van Wezel, Gilles P.; Claessen, Dennis; Hae Choi, Young

2015-01-01

Actinomycetes and filamentous fungi produce a wide range of bioactive compounds, with applications as antimicrobials, anticancer agents or agrochemicals. Their genomes contain a far larger number of gene clusters for natural products than originally anticipated, and novel approaches are required to exploit this potential reservoir of new drugs. Here, we show that co-cultivation of the filamentous model microbes Streptomyces coelicolor and Aspergillus niger has a major impact on their secondary metabolism. NMR-based metabolomics combined with multivariate data analysis revealed several compounds that correlated specifically to co-cultures, including the cyclic dipeptide cyclo(Phe-Phe) and 2-hydroxyphenylacetic acid, both of which were produced by A. niger in response to S. coelicolor. Furthermore, biotransformation studies with o-coumaric acid and caffeic acid resulted in the production of the novel compounds (E)-2-(3-hydroxyprop-1-en-1-yl)-phenol and (2E,4E)-3-(2-carboxy-1-hydroxyethyl)-2,4-hexadienedioxic acid, respectively. This highlights the utility of microbial co-cultivation combined with NMR-based metabolomics as an efficient pipeline for the discovery of novel natural products. PMID:26040782

Rational biosynthetic approaches for the production of new-to-nature compounds in fungi.

PubMed

Boecker, Simon; Zobel, Sophia; Meyer, Vera; Süssmuth, Roderich D

2016-04-01

Filamentous fungi have the ability to produce a wide range of secondary metabolites some of which are potent toxins whereas others are exploited as food additives or drugs. Fungal natural products still play an important role in the discovery of new chemical entities for potential use as pharmaceuticals. However, in most cases they cannot be directly used as drugs due to toxic side effects or suboptimal pharmacokinetics. To improve drug-like properties, including bioactivity and stability or to produce better precursors for semi-synthetic routes, one needs to generate non-natural derivatives from known fungal secondary metabolites. In this minireview, we describe past and recent biosynthetic approaches for the diversification of fungal natural products, covering examples from precursor-directed biosynthesis, mutasynthesis, metabolic engineering and biocombinatorial synthesis. To illustrate the current state-of-the-art, challenges and pitfalls, we lay particular emphasis on the class of fungal cyclodepsipeptides which have been studied longtime for product diversification and which are of pharmaceutical relevance as drugs. Copyright © 2016 Elsevier Inc. All rights reserved.

Traversing the fungal terpenome

PubMed Central

Quin, Maureen B.; Flynn, Christopher M.; Schmidt-Dannert, Claudia

2014-01-01

Fungi (Ascomycota and Basidiomycota) are prolific producers of structurally diverse terpenoid compounds. Classes of terpenoids identified in fungi include the sesqui-, di- and triterpenoids. Biosynthetic pathways and enzymes to terpenoids from each of these classes have been described. These typically involve the scaffold generating terpene synthases and cyclases, and scaffold tailoring enzymes such as e.g. cytochrome P450 monoxygenases, NAD(P)+ and flavin dependent oxidoreductases, and various group transferases that generate the final bioactive structures. The biosynthesis of several sesquiterpenoid mycotoxins and bioactive diterpenoids has been well-studied in Ascomycota (e.g. filamentous fungi). Little is known about the terpenoid biosynthetic pathways in Basidiomycota (e.g. mushroom forming fungi), although they produce a huge diversity of terpenoid natural products. Specifically, many trans-humulyl cation derived sesquiterpenoid natural products with potent bioactivities have been isolated. Biosynthetic gene clusters responsible for the production of trans-humulyl cation derived protoilludanes, and other sesquiterpenoids, can be rapidly identified by genome sequencing and bioinformatic methods. Genome mining combined with heterologous biosynthetic pathway refactoring has the potential to facilitate discovery and production of pharmaceutically relevant fungal terpenoids. PMID:25171145

Encoding of point of view during action observation in the local field potentials of macaque area F5.

PubMed

Caggiano, Vittorio; Giese, Martin; Thier, Peter; Casile, Antonino

2015-02-01

The discovery of mirror neurons compellingly shows that the monkey premotor area F5 is active not only during the execution but also during the observation of goal-directed motor acts. Previous studies have addressed the functioning of the mirror-neuron system at the single-unit level. Here, we tackled this research question at the network level by analysing local field potentials in area F5 while the monkey was presented with goal-directed actions executed by a human or monkey actor and observed either from a first-person or third-person perspective. Our analysis showed that rhythmic responses are not only present in area F5 during action observation, but are also modulated by the point of view. Observing an action from a subjective point of view produced significantly higher power in the low-frequency band (2-10 Hz) than observing the same action from a frontal view. Interestingly, an increase in power in the 2-10 Hz band was also produced by the execution of goal-directed motor acts. Independently of the point of view, action observation also produced a significant decrease in power in the 15-40 Hz band and an increase in the 60-100 Hz band. These results suggest that, depending on the point of view, action observation might activate different processes in area F5. Furthermore, they may provide information about the functional architecture of action perception in primates. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Snake venom: From fieldwork to the clinic: Recent insights into snake biology, together with new technology allowing high-throughput screening of venom, bring new hope for drug discovery.

PubMed

Vonk, Freek J; Jackson, Kate; Doley, Robin; Madaras, Frank; Mirtschin, Peter J; Vidal, Nicolas

2011-04-01

Snake venoms are recognized here as a grossly under-explored resource in pharmacological prospecting. Discoveries in snake systematics demonstrate that former taxonomic bias in research has led to the neglect of thousands of species of potential medical use. Recent discoveries reveal an unexpectedly vast degree of variation in venom composition among snakes, from different species down to litter mates. The molecular mechanisms underlying this diversity are only beginning to be understood. However, the enormous potential that this resource represents for pharmacological prospecting is clear. New high-throughput screening systems offer greatly increased speed and efficiency in identifying and extracting therapeutically useful molecules. At the same time a global biodiversity crisis is threatening the very snake populations on which hopes for new venom-derived medications depend. Biomedical researchers, pharmacologists, clinicians, herpetologists, and conservation biologists must combine their efforts if the full potential of snake venom-derived medications is to be realized. Copyright © 2011 WILEY Periodicals, Inc.

Discovery of digestive enzymes in carnivorous plants with focus on proteases.

PubMed

Ravee, Rishiesvari; Mohd Salleh, Faris 'Imadi; Goh, Hoe-Han

2018-01-01

Carnivorous plants have been fascinating researchers with their unique characters and bioinspired applications. These include medicinal trait of some carnivorous plants with potentials for pharmaceutical industry. This review will cover recent progress based on current studies on digestive enzymes secreted by different genera of carnivorous plants: Drosera (sundews), Dionaea (Venus flytrap) , Nepenthes (tropical pitcher plants), Sarracenia (North American pitcher plants) , Cephalotus (Australian pitcher plants) , Genlisea (corkscrew plants) , and Utricularia (bladderworts). Since the discovery of secreted protease nepenthesin in Nepenthes pitcher, digestive enzymes from carnivorous plants have been the focus of many studies. Recent genomics approaches have accelerated digestive enzyme discovery. Furthermore, the advancement in recombinant technology and protein purification helped in the identification and characterisation of enzymes in carnivorous plants. These different aspects will be described and discussed in this review with focus on the role of secreted plant proteases and their potential industrial applications.

A novel multiple-stage antimalarial agent that inhibits protein synthesis.

PubMed

Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus C S; Norcross, Neil R; Grimaldi, Raffaella; Otto, Thomas D; Proto, William R; Blagborough, Andrew M; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M; Abraham, Tara S; Almeida, Mariana J; Pradhan, Anupam; Porzelle, Achim; Luksch, Torsten; Martínez, María Santos; Luksch, Torsten; Bolscher, Judith M; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M; Churcher, Tom S; Sala, Katarzyna A; Zakutansky, Sara E; Jiménez-Díaz, María Belén; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M; Sauerwein, Robert W; Dechering, Koen J; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A; Angulo-Barturen, Iñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G; Leroy, Didier; Siegl, Peter; Delves, Michael J; Kyle, Dennis E; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N; Sinden, Robert E; Winzeler, Elizabeth A; Charman, Susan A; Bebrevska, Lidiya; Gray, David W; Campbell, Simon; Fairlamb, Alan H; Willis, Paul A; Rayner, Julian C; Fidock, David A; Read, Kevin D; Gilbert, Ian H

2015-06-18

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

Bioactive secondary metabolites from marine microbes for drug discovery.

PubMed

Nikapitiya, Chamilani

2012-01-01

The isolation and extraction of novel bioactive secondary metabolites from marine microorganisms have a biomedical potential for future drug discovery as the oceans cover 70% of the planet's surface and life on earth originates from sea. Wide range of novel bioactive secondary metabolites exhibiting pharmacodynamic properties has been isolated from marine microorganisms and many to be discovered. The compounds isolated from marine organisms (macro and micro) are important in their natural form and also as templates for synthetic modifications for the treatments for variety of deadly to minor diseases. Many technical issues are yet to overcome before wide-scale bioprospecting of marine microorganisms becomes a reality. This chapter focuses on some novel secondary metabolites having antitumor, antivirus, enzyme inhibitor, and other bioactive properties identified and isolated from marine microorganisms including bacteria, actinomycetes, fungi, and cyanobacteria, which could serve as potentials for drug discovery after their clinical trials. Copyright © 2012 Elsevier Inc. All rights reserved.

Leveraging ecological theory to guide natural product discovery.

PubMed

Smanski, Michael J; Schlatter, Daniel C; Kinkel, Linda L

2016-03-01

Technological improvements have accelerated natural product (NP) discovery and engineering to the point that systematic genome mining for new molecules is on the horizon. NP biosynthetic potential is not equally distributed across organisms, environments, or microbial life histories, but instead is enriched in a number of prolific clades. Also, NPs are not equally abundant in nature; some are quite common and others markedly rare. Armed with this knowledge, random 'fishing expeditions' for new NPs are increasingly harder to justify. Understanding the ecological and evolutionary pressures that drive the non-uniform distribution of NP biosynthesis provides a rational framework for the targeted isolation of strains enriched in new NP potential. Additionally, ecological theory leads to testable hypotheses regarding the roles of NPs in shaping ecosystems. Here we review several recent strain prioritization practices and discuss the ecological and evolutionary underpinnings for each. Finally, we offer perspectives on leveraging microbial ecology and evolutionary biology for future NP discovery.

A novel multiple-stage antimalarial agent that inhibits protein synthesis

NASA Astrophysics Data System (ADS)

Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus C. S.; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana J.; Pradhan, Anupam; Porzelle, Achim; Martínez, María Santos; Bolscher, Judith M.; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Jiménez-Díaz, María Belén; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M.; Sauerwein, Robert W.; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Iñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, Peter; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth A.; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon; Fairlamb, Alan H.; Willis, Paul A.; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.

2015-06-01

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

Natural Products from Mangrove Actinomycetes

PubMed Central

Xu, Dong-Bo; Ye, Wan-Wan; Han, Ying; Deng, Zi-Xin; Hong, Kui

2014-01-01

Mangroves are woody plants located in tropical and subtropical intertidal coastal regions. The mangrove ecosystem is becoming a hot spot for natural product discovery and bioactivity survey. Diverse mangrove actinomycetes as promising and productive sources are worth being explored and uncovered. At the time of writing, we report 73 novel compounds and 49 known compounds isolated from mangrove actinomycetes including alkaloids, benzene derivatives, cyclopentenone derivatives, dilactones, macrolides, 2-pyranones and sesquiterpenes. Attractive structures such as salinosporamides, xiamycins and novel indolocarbazoles are highlighted. Many exciting compounds have been proven as potential new antibiotics, antitumor and antiviral agents, anti-fibrotic agents and antioxidants. Furthermore, some of their biosynthetic pathways have also been revealed. This review is an attempt to consolidate and summarize the past and the latest studies on mangrove actinomycetes natural product discovery and to draw attention to their immense potential as novel and bioactive compounds for marine drugs discovery. PMID:24798926

Growing PAINS in academic drug discovery.

PubMed

Whitty, Adrian

2011-05-01

In a recent article it was argued that compounds published as drug leads by academic laboratories commonly contain functionality that identifies them as nonspecific 'pan-assay interference compounds' (PAINS). The article raises broad questions about why best practices for hit and lead qualification that are well known in industry are not more widely employed in academia, as well as about the role of journals in publishing manuscripts that report drug leads of little potential value. Barriers to adoption of best practices for some academic drug-discovery researchers include knowledge gaps and infrastructure deficiencies, but they also arise from fundamental differences in how academic research is structured and how success is measured. Academic drug discovery should not seek to become identical to commercial pharmaceutical research, but we can do a better job of assessing and communicating the true potential of the drug leads we publish, thereby reducing the wastage of resources on nonviable compounds.

Robustness of disaggregate oil and gas discovery forecasting models

USGS Publications Warehouse

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

1989-01-01

The trend in forecasting oil and gas discoveries has been to develop and use models that allow forecasts of the size distribution of future discoveries. From such forecasts, exploration and development costs can more readily be computed. Two classes of these forecasting models are the Arps-Roberts type models and the 'creaming method' models. This paper examines the robustness of the forecasts made by these models when the historical data on which the models are based have been subject to economic upheavals or when historical discovery data are aggregated from areas having widely differing economic structures. Model performance is examined in the context of forecasting discoveries for offshore Texas State and Federal areas. The analysis shows how the model forecasts are limited by information contained in the historical discovery data. Because the Arps-Roberts type models require more regularity in discovery sequence than the creaming models, prior information had to be introduced into the Arps-Roberts models to accommodate the influence of economic changes. The creaming methods captured the overall decline in discovery size but did not easily allow introduction of exogenous information to compensate for incomplete historical data. Moreover, the predictive log normal distribution associated with the creaming model methods appears to understate the importance of the potential contribution of small fields. ?? 1989.

Theoretical physics: Quarks fuse to release energy

NASA Astrophysics Data System (ADS)

Miller, Gerald A.

2017-11-01

In nuclear fusion, energy is produced by the rearrangement of protons and neutrons. The discovery of an analogue of this process involving particles called quarks has implications for both nuclear and particle physics. See Letter p.89

Strategies for enhancing the effectiveness of metagenomic-based enzyme discovery in lignocellulytic microbial communities

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

DeAngelis, K.M.; Gladden, J.G.; Allgaier, M.

2010-03-01

Producing cellulosic biofuels from plant material has recently emerged as a key U.S. Department of Energy goal. For this technology to be commercially viable on a large scale, it is critical to make production cost efficient by streamlining both the deconstruction of lignocellulosic biomass and fuel production. Many natural ecosystems efficiently degrade lignocellulosic biomass and harbor enzymes that, when identified, could be used to increase the efficiency of commercial biomass deconstruction. However, ecosystems most likely to yield relevant enzymes, such as tropical rain forest soil in Puerto Rico, are often too complex for enzyme discovery using current metagenomic sequencing technologies.more » One potential strategy to overcome this problem is to selectively cultivate the microbial communities from these complex ecosystems on biomass under defined conditions, generating less complex biomass-degrading microbial populations. To test this premise, we cultivated microbes from Puerto Rican soil or green waste compost under precisely defined conditions in the presence dried ground switchgrass (Panicum virgatum L.) or lignin, respectively, as the sole carbon source. Phylogenetic profiling of the two feedstock-adapted communities using SSU rRNA gene amplicon pyrosequencing or phylogenetic microarray analysis revealed that the adapted communities were significantly simplified compared to the natural communities from which they were derived. Several members of the lignin-adapted and switchgrass-adapted consortia are related to organisms previously characterized as biomass degraders, while others were from less well-characterized phyla. The decrease in complexity of these communities make them good candidates for metagenomic sequencing and will likely enable the reconstruction of a greater number of full length genes, leading to the discovery of novel lignocellulose-degrading enzymes adapted to feedstocks and conditions of interest.« less

Zebrafish Heart Failure Models for the Evaluation of Chemical Probes and Drugs

PubMed Central

Monte, Aaron; Cook, James M.; Kabir, Mohd Shahjahan; Peterson, Karl P.

2013-01-01

Abstract Heart failure is a complex disease that involves genetic, environmental, and physiological factors. As a result, current medication and treatment for heart failure produces limited efficacy, and better medication is in demand. Although mammalian models exist, simple and low-cost models will be more beneficial for drug discovery and mechanistic studies of heart failure. We previously reported that aristolochic acid (AA) caused cardiac defects in zebrafish embryos that resemble heart failure. Here, we showed that cardiac troponin T and atrial natriuretic peptide were expressed at significantly higher levels in AA-treated embryos, presumably due to cardiac hypertrophy. In addition, several human heart failure drugs could moderately attenuate the AA-induced heart failure by 10%–40%, further verifying the model for drug discovery. We then developed a drug screening assay using the AA-treated zebrafish embryos and identified three compounds. Mitogen-activated protein kinase kinase inhibitor (MEK-I), an inhibitor for the MEK-1/2 known to be involved in cardiac hypertrophy and heart failure, showed nearly 60% heart failure attenuation. C25, a chalcone derivative, and A11, a phenolic compound, showed around 80% and 90% attenuation, respectively. Time course experiments revealed that, to obtain 50% efficacy, these compounds were required within different hours of AA treatment. Furthermore, quantitative polymerase chain reaction showed that C25, not MEK-I or A11, strongly suppressed inflammation. Finally, C25 and MEK-I, but not A11, could also rescue the doxorubicin-induced heart failure in zebrafish embryos. In summary, we have established two tractable heart failure models for drug discovery and three potential drugs have been identified that seem to attenuate heart failure by different mechanisms. PMID:24351044

Creating Mobile and Web Application Programming Interfaces (APIs) for NASA Science Data

NASA Astrophysics Data System (ADS)

Oostra, D.; Chambers, L. H.; Lewis, P. M.; Moore, S. W.

2011-12-01

The Atmospheric Science Data Center (ASDC) at the NASA Langley Research Center in Virginia houses almost three petabytes of data, a collection that increases every day. To put it into perspective, it is estimated that three petabytes of data storage could store a digitized copy of all printed material in U.S. research libraries. There are more than ten other NASA data centers like the ASDC. Scientists and the public use this data for research, science education, and to understand our environment. Most importantly these data provide the potential for all of us make new discoveries. NASA is about making discoveries. Galileo was quoted as saying, "All discoveries are easy to understand once they are discovered. The point is to discover them." To that end, NASA stores vast amounts of publicly available data. This paper examines an approach to create web applications that serve NASA data in ways that specifically address the mobile web application technologies that are quickly emerging. Mobile data is not a new concept. What is new, is that user driven tools have recently become available that allow users to create their own mobile applications. Through the use of these cloud-based tools users can produce complete native mobile applications. Thus, mobile apps can now be created by everyone, regardless of their programming experience or expertise. This work will explore standards and methods for creating dynamic and malleable application programming interfaces (APIs) that allow users to access and use NASA science data for their own needs. The focus will be on experiences that broaden and increase the scope and usage of NASA science data sets.

Phage display-derived human antibodies in clinical development and therapy

PubMed Central

Frenzel, André; Schirrmann, Thomas; Hust, Michael

2016-01-01

ABSTRACT Over the last 3 decades, monoclonal antibodies have become the most important class of therapeutic biologicals on the market. Development of therapeutic antibodies was accelerated by recombinant DNA technologies, which allowed the humanization of murine monoclonal antibodies to make them more similar to those of the human body and suitable for a broad range of chronic diseases like cancer and autoimmune diseases. In the early 1990s in vitro antibody selection technologies were developed that enabled the discovery of “fully” human antibodies with potentially superior clinical efficacy and lowest immunogenicity. Antibody phage display is the first and most widely used of the in vitro selection technologies. It has proven to be a robust, versatile platform technology for the discovery of human antibodies and a powerful engineering tool to improve antibody properties. As of the beginning of 2016, 6 human antibodies discovered or further developed by phage display were approved for therapy. In 2002, adalimumab (Humira®) became the first phage display-derived antibody granted a marketing approval. Humira® was also the first approved human antibody, and it is currently the best-selling antibody drug on the market. Numerous phage display-derived antibodies are currently under advanced clinical investigation, and, despite the availability of other technologies such as human antibody-producing transgenic mice, phage display has not lost its importance for the discovery and engineering of therapeutic antibodies. Here, we provide a comprehensive overview about phage display-derived antibodies that are approved for therapy or in clinical development. A selection of these antibodies is described in more detail to demonstrate different aspects of the phage display technology and its development over the last 25 years. PMID:27416017

Phage display-derived human antibodies in clinical development and therapy.

PubMed

Frenzel, André; Schirrmann, Thomas; Hust, Michael

2016-10-01

Over the last 3 decades, monoclonal antibodies have become the most important class of therapeutic biologicals on the market. Development of therapeutic antibodies was accelerated by recombinant DNA technologies, which allowed the humanization of murine monoclonal antibodies to make them more similar to those of the human body and suitable for a broad range of chronic diseases like cancer and autoimmune diseases. In the early 1990s in vitro antibody selection technologies were developed that enabled the discovery of "fully" human antibodies with potentially superior clinical efficacy and lowest immunogenicity. Antibody phage display is the first and most widely used of the in vitro selection technologies. It has proven to be a robust, versatile platform technology for the discovery of human antibodies and a powerful engineering tool to improve antibody properties. As of the beginning of 2016, 6 human antibodies discovered or further developed by phage display were approved for therapy. In 2002, adalimumab (Humira®) became the first phage display-derived antibody granted a marketing approval. Humira® was also the first approved human antibody, and it is currently the best-selling antibody drug on the market. Numerous phage display-derived antibodies are currently under advanced clinical investigation, and, despite the availability of other technologies such as human antibody-producing transgenic mice, phage display has not lost its importance for the discovery and engineering of therapeutic antibodies. Here, we provide a comprehensive overview about phage display-derived antibodies that are approved for therapy or in clinical development. A selection of these antibodies is described in more detail to demonstrate different aspects of the phage display technology and its development over the last 25 years.

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.

Metadata improvements driving new tools and services at a NASA data center

NASA Astrophysics Data System (ADS)

Moroni, D. F.; Hausman, J.; Foti, G.; Armstrong, E. M.

2011-12-01

The NASA Physical Oceanography DAAC (PO.DAAC) is responsible for distributing and maintaining satellite derived oceanographic data from a number of NASA and non-NASA missions for the physical disciplines of ocean winds, sea surface temperature, ocean topography and gravity. Currently its holdings consist of over 600 datasets with a data archive in excess of 200 Terrabytes. The PO.DAAC has recently embarked on a metadata quality and completeness project to migrate, update and improve metadata records for over 300 public datasets. An interactive database management tool has been developed to allow data scientists to enter, update and maintain metadata records. This tool communicates directly with PO.DAAC's Data Management and Archiving System (DMAS), which serves as the new archival and distribution backbone as well as a permanent repository of dataset and granule-level metadata. Although we will briefly discuss the tool, more important ramifications are the ability to now expose, propagate and leverage the metadata in a number of ways. First, the metadata are exposed directly through a faceted and free text search interface directly from drupal-based PO.DAAC web pages allowing for quick browsing and data discovery especially by "drilling" through the various facet levels that organize datasets by time/space resolution, processing level, sensor, measurement type etc. Furthermore, the metadata can now be exposed through web services to produce metadata records in a number of different formats such as FGDC and ISO 19115, or potentially propagated to visualization and subsetting tools, and other discovery interfaces. The fundamental concept is that the metadata forms the essential bridge between the user, and the tool or discovery mechanism for a broad range of ocean earth science data records.

Discovery Strategies of Bioactive Compounds Synthesized by Nonribosomal Peptide Synthetases and Type-I Polyketide Synthases Derived from Marine Microbiomes

PubMed Central

Amoutzias, Grigoris D.; Chaliotis, Anargyros; Mossialos, Dimitris

2016-01-01

Considering that 70% of our planet’s surface is covered by oceans, it is likely that undiscovered biodiversity is still enormous. A large portion of marine biodiversity consists of microbiomes. They are very attractive targets of bioprospecting because they are able to produce a vast repertoire of secondary metabolites in order to adapt in diverse environments. In many cases secondary metabolites of pharmaceutical and biotechnological interest such as nonribosomal peptides (NRPs) and polyketides (PKs) are synthesized by multimodular enzymes named nonribosomal peptide synthetases (NRPSes) and type-I polyketide synthases (PKSes-I), respectively. Novel findings regarding the mechanisms underlying NRPS and PKS evolution demonstrate how microorganisms could leverage their metabolic potential. Moreover, these findings could facilitate synthetic biology approaches leading to novel bioactive compounds. Ongoing advances in bioinformatics and next-generation sequencing (NGS) technologies are driving the discovery of NRPs and PKs derived from marine microbiomes mainly through two strategies: genome-mining and metagenomics. Microbial genomes are now sequenced at an unprecedented rate and this vast quantity of biological information can be analyzed through genome mining in order to identify gene clusters encoding NRPSes and PKSes of interest. On the other hand, metagenomics is a fast-growing research field which directly studies microbial genomes and their products present in marine environments using culture-independent approaches. The aim of this review is to examine recent developments regarding discovery strategies of bioactive compounds synthesized by NRPS and type-I PKS derived from marine microbiomes and to highlight the vast diversity of NRPSes and PKSes present in marine environments by giving examples of recently discovered bioactive compounds. PMID:27092515

Cracking the regulatory code of biosynthetic gene clusters as a strategy for natural product discovery.

PubMed

Rigali, Sébastien; Anderssen, Sinaeda; Naômé, Aymeric; van Wezel, Gilles P

2018-01-05

The World Health Organization (WHO) describes antibiotic resistance as "one of the biggest threats to global health, food security, and development today", as the number of multi- and pan-resistant bacteria is rising dangerously. Acquired resistance phenomena also impair antifungals, antivirals, anti-cancer drug therapy, while herbicide resistance in weeds threatens the crop industry. On the positive side, it is likely that the chemical space of natural products goes far beyond what has currently been discovered. This idea is fueled by genome sequencing of microorganisms which unveiled numerous so-called cryptic biosynthetic gene clusters (BGCs), many of which are transcriptionally silent under laboratory culture conditions, and by the fact that most bacteria cannot yet be cultivated in the laboratory. However, brute force antibiotic discovery does not yield the same results as it did in the past, and researchers have had to develop creative strategies in order to unravel the hidden potential of microorganisms such as Streptomyces and other antibiotic-producing microorganisms. Identifying the cis elements and their corresponding transcription factors(s) involved in the control of BGCs through bioinformatic approaches is a promising strategy. Theoretically, we are a few 'clicks' away from unveiling the culturing conditions or genetic changes needed to activate the production of cryptic metabolites or increase the production yield of known compounds to make them economically viable. In this opinion article, we describe and illustrate the idea beyond 'cracking' the regulatory code for natural product discovery, by presenting a series of proofs of concept, and discuss what still should be achieved to increase the rate of success of this strategy. Copyright © 2018 Elsevier Inc. All rights reserved.

Biosynthesis of therapeutic natural products using synthetic biology.

PubMed

Awan, Ali R; Shaw, William M; Ellis, Tom

2016-10-01

Natural products are a group of bioactive structurally diverse chemicals produced by microorganisms and plants. These molecules and their derivatives have contributed to over a third of the therapeutic drugs produced in the last century. However, over the last few decades traditional drug discovery pipelines from natural products have become far less productive and far more expensive. One recent development with promise to combat this trend is the application of synthetic biology to therapeutic natural product biosynthesis. Synthetic biology is a young discipline with roots in systems biology, genetic engineering, and metabolic engineering. In this review, we discuss the use of synthetic biology to engineer improved yields of existing therapeutic natural products. We further describe the use of synthetic biology to combine and express natural product biosynthetic genes in unprecedented ways, and how this holds promise for opening up completely new avenues for drug discovery and production. Copyright © 2016 Elsevier B.V. All rights reserved.

Computational modeling in melanoma for novel drug discovery.

PubMed

Pennisi, Marzio; Russo, Giulia; Di Salvatore, Valentina; Candido, Saverio; Libra, Massimo; Pappalardo, Francesco

2016-06-01

There is a growing body of evidence highlighting the applications of computational modeling in the field of biomedicine. It has recently been applied to the in silico analysis of cancer dynamics. In the era of precision medicine, this analysis may allow the discovery of new molecular targets useful for the design of novel therapies and for overcoming resistance to anticancer drugs. According to its molecular behavior, melanoma represents an interesting tumor model in which computational modeling can be applied. Melanoma is an aggressive tumor of the skin with a poor prognosis for patients with advanced disease as it is resistant to current therapeutic approaches. This review discusses the basics of computational modeling in melanoma drug discovery and development. Discussion includes the in silico discovery of novel molecular drug targets, the optimization of immunotherapies and personalized medicine trials. Mathematical and computational models are gradually being used to help understand biomedical data produced by high-throughput analysis. The use of advanced computer models allowing the simulation of complex biological processes provides hypotheses and supports experimental design. The research in fighting aggressive cancers, such as melanoma, is making great strides. Computational models represent the key component to complement these efforts. Due to the combinatorial complexity of new drug discovery, a systematic approach based only on experimentation is not possible. Computational and mathematical models are necessary for bringing cancer drug discovery into the era of omics, big data and personalized medicine.

New marine natural products from sponges (Porifera) of the order Dictyoceratida (2001 to 2012); a promising source for drug discovery, exploration and future prospects.

PubMed

Mehbub, Mohammad F; Perkins, Michael V; Zhang, Wei; Franco, Christopher M M

2016-01-01

The discovery of new drugs can no longer rely primarily on terrestrial resources, as they have been heavily exploited for over a century. During the last few decades marine sources, particularly sponges, have proven to be a most promising source of new natural products for drug discovery. This review considers the order Dictyoceratida in the Phylum Porifera from which the largest number of new marine natural products have been reported over the period 2001-2012. This paper examines all the sponges from the order Dictyoceratida that were reported as new compounds during the time period in a comprehensive manner. The distinctive physical characteristics and the geographical distribution of the different families are presented. The wide structural diversity of the compounds produced and the variety of biological activities they exhibited is highlighted. As a representative of sponges, insights into this order and avenues for future effective natural product discovery are presented. The research institutions associated with the various studies are also highlighted with the aim of facilitating collaborative relationships, as well as to acknowledge the major international contributors to the discovery of novel sponge metabolites. The order Dictyoceratida is a valuable source of novel chemical structures which will continue to contribute to a new era of drug discovery. Copyright © 2015 Elsevier Inc. All rights reserved.

Merging chemical ecology with bacterial genome mining for secondary metabolite discovery.

PubMed

Vizcaino, Maria I; Guo, Xun; Crawford, Jason M

2014-02-01

The integration of chemical ecology and bacterial genome mining can enhance the discovery of structurally diverse natural products in functional contexts. By examining bacterial secondary metabolism in the framework of its ecological niche, insights into the upregulation of orphan biosynthetic pathways and the enhancement of the enzyme substrate supply can be obtained, leading to the discovery of new secondary metabolic pathways that would otherwise be silent or undetected under typical laboratory cultivation conditions. Access to these new natural products (i.e., the chemotypes) facilitates experimental genotype-to-phenotype linkages. Here, we describe certain functional natural products produced by Xenorhabdus and Photorhabdus bacteria with experimentally linked biosynthetic gene clusters as illustrative examples of the synergy between chemical ecology and bacterial genome mining in connecting genotypes to phenotypes through chemotype characterization. These Gammaproteobacteria share a mutualistic relationship with nematodes and a pathogenic relationship with insects and, in select cases, humans. The natural products encoded by these bacteria distinguish their interactions with their animal hosts and other microorganisms in their multipartite symbiotic lifestyles. Though both genera have similar lifestyles, their genetic, chemical, and physiological attributes are distinct. Both undergo phenotypic variation and produce a profuse number of bioactive secondary metabolites. We provide further detail in the context of regulation, production, processing, and function for these genetically encoded small molecules with respect to their roles in mutualism and pathogenicity. These collective insights more widely promote the discovery of atypical orphan biosynthetic pathways encoding novel small molecules in symbiotic systems, which could open up new avenues for investigating and exploiting microbial chemical signaling in host-bacteria interactions.

Functional Genome Mining for Metabolites Encoded by Large Gene Clusters through Heterologous Expression of a Whole-Genome Bacterial Artificial Chromosome Library in Streptomyces spp.

PubMed Central

Xu, Min; Wang, Yemin; Zhao, Zhilong; Gao, Guixi; Huang, Sheng-Xiong; Kang, Qianjin; He, Xinyi; Lin, Shuangjun; Pang, Xiuhua; Deng, Zixin

2016-01-01

ABSTRACT Genome sequencing projects in the last decade revealed numerous cryptic biosynthetic pathways for unknown secondary metabolites in microbes, revitalizing drug discovery from microbial metabolites by approaches called genome mining. In this work, we developed a heterologous expression and functional screening approach for genome mining from genomic bacterial artificial chromosome (BAC) libraries in Streptomyces spp. We demonstrate mining from a strain of Streptomyces rochei, which is known to produce streptothricins and borrelidin, by expressing its BAC library in the surrogate host Streptomyces lividans SBT5, and screening for antimicrobial activity. In addition to the successful capture of the streptothricin and borrelidin biosynthetic gene clusters, we discovered two novel linear lipopeptides and their corresponding biosynthetic gene cluster, as well as a novel cryptic gene cluster for an unknown antibiotic from S. rochei. This high-throughput functional genome mining approach can be easily applied to other streptomycetes, and it is very suitable for the large-scale screening of genomic BAC libraries for bioactive natural products and the corresponding biosynthetic pathways. IMPORTANCE Microbial genomes encode numerous cryptic biosynthetic gene clusters for unknown small metabolites with potential biological activities. Several genome mining approaches have been developed to activate and bring these cryptic metabolites to biological tests for future drug discovery. Previous sequence-guided procedures relied on bioinformatic analysis to predict potentially interesting biosynthetic gene clusters. In this study, we describe an efficient approach based on heterologous expression and functional screening of a whole-genome library for the mining of bioactive metabolites from Streptomyces. The usefulness of this function-driven approach was demonstrated by the capture of four large biosynthetic gene clusters for metabolites of various chemical types, including streptothricins, borrelidin, two novel lipopeptides, and one unknown antibiotic from Streptomyces rochei Sal35. The transfer, expression, and screening of the library were all performed in a high-throughput way, so that this approach is scalable and adaptable to industrial automation for next-generation antibiotic discovery. PMID:27451447

An integrative model for in-silico clinical-genomics discovery science.

PubMed

Lussier, Yves A; Sarkar, Indra Nell; Cantor, Michael

2002-01-01

Human Genome discovery research has set the pace for Post-Genomic Discovery Research. While post-genomic fields focused at the molecular level are intensively pursued, little effort is being deployed in the later stages of molecular medicine discovery research, such as clinical-genomics. The objective of this study is to demonstrate the relevance and significance of integrating mainstream clinical informatics decision support systems to current bioinformatics genomic discovery science. This paper is a feasibility study of an original model enabling novel "in-silico" clinical-genomic discovery science and that demonstrates its feasibility. This model is designed to mediate queries among clinical and genomic knowledge bases with relevant bioinformatic analytic tools (e.g. gene clustering). Briefly, trait-disease-gene relationships were successfully illustrated using QMR, OMIM, SNOMED-RT, GeneCluster and TreeView. The analyses were visualized as two-dimensional dendrograms of clinical observations clustered around genes. To our knowledge, this is the first study using knowledge bases of clinical decision support systems for genomic discovery. Although this study is a proof of principle, it provides a framework for the development of clinical decision-support-system driven, high-throughput clinical-genomic technologies which could potentially unveil significant high-level functions of genes.

The pivotal role of multimodality reporter sensors in drug discovery: from cell based assays to real time molecular imaging.

PubMed

Ray, Pritha

2011-04-01

Development and marketing of new drugs require stringent validation that are expensive and time consuming. Non-invasive multimodality molecular imaging using reporter genes holds great potential to expedite these processes at reduced cost. New generations of smarter molecular imaging strategies such as Split reporter, Bioluminescence resonance energy transfer, Multimodality fusion reporter technologies will further assist to streamline and shorten the drug discovery and developmental process. This review illustrates the importance and potential of molecular imaging using multimodality reporter genes in drug development at preclinical phases.

Exploration and development offshore southern Vietnam

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

Ferguson, A.M.

1996-12-31

In Vietnam, the major focus of the oil and gas industry is on the Nam Con Son and Cuu Long Basins in the southern offshore area. Major licensing first occurred here in the early 1970s. Some exploration was also undertaken by foreign companies in the early 1980s. In 1981, the Soviet Union undertook to assist Vietnam with the development of oil and gas. Vietsovpetro, a joint venture between the then Soviet Oil and Gas Ministry and the Vietnam Oil and Gas Corporation was formed. Most of Vietsovpetro`s efforts have been to develop the Bach Ho field in the Cuu Longmore » Basin. This now produces {approximately}130000 bopd. The most recent large scale licensing round occurred in 1992, and, at present, there are over thirty foreign companies active in these Basins` blocks . The first phase of exploration is ending and successes in the Nam Con Son Basin include the BP-led Lan Tay/Lan Do gas discoveries and Pedco`s gas discoveries. Mitsubishi`s and Petronas` oil discoveries in the Cuu Long Basin have attracted much attention also. The Dai Hung oil field (BHP-operated) has been producing since late 1994. Certain blocks are being appraised, and exploration work is also continuing. Areas of the Cuu Long Basin that were part of Vietsovpetro`s acreage, but which may soon be re-licensed, have generated keen interest. The presence of an active upstream industry - exploring, appraising, developing and producing - indicates the emergence of Vietnam as an important East Asian oil and gas player.« less

Perceptual uncertainty facilitates creative discovery

NASA Astrophysics Data System (ADS)

Tseng, Winger Sei-Wo

2018-06-01

In this study, unstructured and ambiguous figures used as visual stimuli were classified as having high, moderate, and low ambiguity and presented to participants. The Experiment was designed to explore how the perceptual ambiguity that is inherent within presented visual cues can affect novice and expert designers' visual discovery during design development. A total number of 42 participants, half of them were recruited from non-design departments as novices. The remaining were chosen from design companies regarded as experts. The participants were tasked with discovering a sub-shape from the presented sketch and using this shape as a cue to design a concept. To this end, two types of sub-shapes were defined: known feature sub-shapes and innovative feature sub-shapes (IFSs). The experimental results strongly evidence that with an increase in the ambiguity of the visual stimuli, expert designers produce more ideas and IFSs, whereas novice designers produce fewer. The capability of expert designers to exploit visual ambiguity is interesting, and its absence in novice designers suggests that this capability is likely a unique skill gained, at least in part, through professional practice. Our results can be applied in design learning and education to generalize the principles and strategies of visual discovery by expert designers during concept sketching in order to train novice designers in addressing design problems.

Immense essence of excellence: marine microbial bioactive compounds.

PubMed

Bhatnagar, Ira; Kim, Se-Kwon

2010-10-15

Oceans have borne most of the biological activities on our planet. A number of biologically active compounds with varying degrees of action, such as anti-tumor, anti-cancer, anti-microtubule, anti-proliferative, cytotoxic, photo protective, as well as antibiotic and antifouling properties, have been isolated to date from marine sources. The marine environment also represents a largely unexplored source for isolation of new microbes (bacteria, fungi, actinomycetes, microalgae-cyanobacteria and diatoms) that are potent producers of bioactive secondary metabolites. Extensive research has been done to unveil the bioactive potential of marine microbes (free living and symbiotic) and the results are amazingly diverse and productive. Some of these bioactive secondary metabolites of microbial origin with strong antibacterial and antifungal activities are being intensely used as antibiotics and may be effective against infectious diseases such as HIV, conditions of multiple bacterial infections (penicillin, cephalosporines, streptomycin, and vancomycin) or neuropsychiatric sequelae. Research is also being conducted on the general aspects of biophysical and biochemical properties, chemical structures and biotechnological applications of the bioactive substances derived from marine microorganisms, and their potential use as cosmeceuticals and nutraceuticals. This review is an attempt to consolidate the latest studies and critical research in this field, and to showcase the immense competence of marine microbial flora as bioactive metabolite producers. In addition, the present review addresses some effective and novel approaches of procuring marine microbial compounds utilizing the latest screening strategies of drug discovery.

Immense Essence of Excellence: Marine Microbial Bioactive Compounds

PubMed Central

Bhatnagar, Ira; Kim, Se-Kwon

2010-01-01

Oceans have borne most of the biological activities on our planet. A number of biologically active compounds with varying degrees of action, such as anti-tumor, anti-cancer, anti-microtubule, anti-proliferative, cytotoxic, photo protective, as well as antibiotic and antifouling properties, have been isolated to date from marine sources. The marine environment also represents a largely unexplored source for isolation of new microbes (bacteria, fungi, actinomycetes, microalgae-cyanobacteria and diatoms) that are potent producers of bioactive secondary metabolites. Extensive research has been done to unveil the bioactive potential of marine microbes (free living and symbiotic) and the results are amazingly diverse and productive. Some of these bioactive secondary metabolites of microbial origin with strong antibacterial and antifungal activities are being intensely used as antibiotics and may be effective against infectious diseases such as HIV, conditions of multiple bacterial infections (penicillin, cephalosporines, streptomycin, and vancomycin) or neuropsychiatric sequelae. Research is also being conducted on the general aspects of biophysical and biochemical properties, chemical structures and biotechnological applications of the bioactive substances derived from marine microorganisms, and their potential use as cosmeceuticals and nutraceuticals. This review is an attempt to consolidate the latest studies and critical research in this field, and to showcase the immense competence of marine microbial flora as bioactive metabolite producers. In addition, the present review addresses some effective and novel approaches of procuring marine microbial compounds utilizing the latest screening strategies of drug discovery. PMID:21116414

Dark Higgs bosons at the ForwArd Search ExpeRiment

NASA Astrophysics Data System (ADS)

Feng, Jonathan L.; Galon, Iftah; Kling, Felix; Trojanowski, Sebastian

2018-03-01

FASER, ForwArd Search ExpeRiment at the LHC, has been proposed as a small, very far forward detector to discover new, light, weakly-coupled particles. Previous work showed that with a total volume of just ˜0.1 - 1 m3 , FASER can discover dark photons in a large swath of currently unconstrained parameter space, extending the discovery reach of the LHC program. Here we explore FASER's discovery prospects for dark Higgs bosons. These scalar particles are an interesting foil for dark photons, as they probe a different renormalizable portal interaction and are produced dominantly through B and K meson decays, rather than pion decays, leading to less collimated signals. Nevertheless, we find that FASER is also a highly sensitive probe of dark Higgs bosons with significant discovery prospects that are comparable to, and complementary to, much larger proposed experiments.

The Role of HTS in Drug Discovery at the University of Michigan

PubMed Central

Larsen, Martha J.; Larsen, Scott D.; Fribley, Andrew; Grembecka, Jolanta; Homan, Kristoff; Mapp, Anna; Haak, Andrew; Nikolovska-Coleska, Zaneta; Stuckey, Jeanne A.; Sun, Duxin

2014-01-01

High throughput screening (HTS) is an integral part of a highly collaborative approach to drug discovery at the University of Michigan. The HTS lab is one of four core centers that provide services to identify, produce, screen and follow-up on biomedical targets for faculty. Key features of this system are: protein cloning and purification, protein crystallography, small molecule and siRNA HTS, medicinal chemistry and pharmacokinetics. Therapeutic areas that have been targeted include anti-bacterial, metabolic, neurodegenerative, cardiovascular, anti-cancer and anti-viral. The centers work in a coordinated, interactive environment to affordably provide academic investigators with the technology, informatics and expertise necessary for successful drug discovery. This review provides an overview of these centers at the University of Michigan, along with case examples of successful collaborations with faculty. PMID:24409957

The discovery of the Higgs boson at the Large Hadron Collider

NASA Astrophysics Data System (ADS)

Nisati, A.; Tonelli, G.

2015-11-01

This paper summarises the work done by the ATLAS and CMS collaborations, and by the teams of the Large Hadron Collider at CERN, that led to the discovery of a new particle, with mass near 125GeV and properties consistent with the ones predicted for the Standard Model Higgs boson. An overview of the Standard Model, with a description of the role of the Higgs boson in the theory, and a summary of the searches for this particle prior to the LHC operations is also given. The paper presents the results obtained by ATLAS and CMS from the analysis of the full data set produced in the first physics run of LHC. After a short discussion on the implications of the discovery, the future prospects for the precision study of the new particle are lastly discussed.

The role of nanobiotechnology in drug discovery.

PubMed

Jain, Kewal K

2009-01-01

The potential applications of nanotechnology in life sciences, particularly nanobiotechnology, include those for drug discovery. This chapter shows how several of the nanotechnologies including nanoparticles and various nanodevices such as nanobiosensors and nanobiochips are being used to improve drug discovery. Nanoscale assays using nanoliter volumes contribute to cost saving. Some nanosubstances such as fullerenes are drug candidates. There are some safety concerns about the in vivo use of nanoparticles that are being investigated. However, future prospects for applications in healthcare of drugs discovered through nanotechnology and their role in the development of personalized medicine appear to be excellent.

Biology-driven library design for probe discovery.

PubMed

Inglese, James; Hasson, Samuel A

2011-10-28

Libraries of diverse small molecules are important to probe and drug discovery. The current trend toward building massive screening collections to support drug development, a special application of chemical biology, can limit their broader potential. Biology-driven construction methods (Wallace et al., 2011) are rapidly emerging to bring chemical libraries back on a viable path. Copyright © 2011 Elsevier Ltd. All rights reserved.

Discovery and Observations of a Stem-Boring Weevil (Myrmex sp.) a Potentially Useful Biocontrol of Mistletoe

Treesearch

J. D. Solomon; L. Newsome; T. H. Filer

1984-01-01

A stem-boring weevil obtained from infested clusters of mistletoe was subsequently reared and identified as Myrmex sp. To our knowledge its discovery in Mississippi is the easternmost record of mistletoe-feeding Myrmex, previously recorded only from the West and Southwest. Based on current studies, the weevil overwinters as larvae in tunnels within mistletoe stems....

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.

Molecular signatures from omics data: from chaos to consensus.

PubMed

Sung, Jaeyun; Wang, Yuliang; Chandrasekaran, Sriram; Witten, Daniela M; Price, Nathan D

2012-08-01

In the past 15 years, new "omics" technologies have made it possible to obtain high-resolution molecular snapshots of organisms, tissues, and even individual cells at various disease states and experimental conditions. It is hoped that these developments will usher in a new era of personalized medicine in which an individual's molecular measurements are used to diagnose disease, guide therapy, and perform other tasks more accurately and effectively than is possible using standard approaches. There now exists a vast literature of reported "molecular signatures". However, despite some notable exceptions, many of these signatures have suffered from limited reproducibility in independent datasets, insufficient sensitivity or specificity to meet clinical needs, or other challenges. In this paper, we discuss the process of molecular signature discovery on the basis of omics data. In particular, we highlight potential pitfalls in the discovery process, as well as strategies that can be used to increase the odds of successful discovery. Despite the difficulties that have plagued the field of molecular signature discovery, we remain optimistic about the potential to harness the vast amounts of available omics data in order to substantially impact clinical practice. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

VIP: an integrated pipeline for metagenomics of virus identification and discovery

PubMed Central

Li, Yang; Wang, Hao; Nie, Kai; Zhang, Chen; Zhang, Yi; Wang, Ji; Niu, Peihua; Ma, Xuejun

2016-01-01

Identification and discovery of viruses using next-generation sequencing technology is a fast-developing area with potential wide application in clinical diagnostics, public health monitoring and novel virus discovery. However, tremendous sequence data from NGS study has posed great challenge both in accuracy and velocity for application of NGS study. Here we describe VIP (“Virus Identification Pipeline”), a one-touch computational pipeline for virus identification and discovery from metagenomic NGS data. VIP performs the following steps to achieve its goal: (i) map and filter out background-related reads, (ii) extensive classification of reads on the basis of nucleotide and remote amino acid homology, (iii) multiple k-mer based de novo assembly and phylogenetic analysis to provide evolutionary insight. We validated the feasibility and veracity of this pipeline with sequencing results of various types of clinical samples and public datasets. VIP has also contributed to timely virus diagnosis (~10 min) in acutely ill patients, demonstrating its potential in the performance of unbiased NGS-based clinical studies with demand of short turnaround time. VIP is released under GPLv3 and is available for free download at: https://github.com/keylabivdc/VIP. PMID:27026381

Perfect launch for Space Shuttle Discovery on mission STS-105

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- Viewed from between the trees, Space Shuttle Discovery rises above the smoke as it soars into the blue sky on mission STS-105 to the International Space Station. Viewed from the top of the Vehicle Assembly Building, liftoff occurred at 5:10:14 p.m. EDT on this second launch attempt. Launch countdown activities for the 12-day mission were called off Aug. 9 during the T-9 minute hold due to the high potential for lightning, a thick cloud cover and the potential for showers. Besides the Shuttle crew of four, Discovery carries the Expedition Three crew who will replace Expedition Two on the International Space Station. The mission includes the third flight of an Italian-built Multi-Purpose Logistics Module delivering additional scientific racks, equipment and supplies for the Space Station, and two spacewalks. Part of the payload is the Early Ammonia Servicer (EAS) tank, which will be attached to the Station during the spacewalks. The EAS contains spare ammonia for the Station'''s cooling system. The three-member Expedition Two crew will be returning to Earth aboard Discovery after a five-month stay on the Station.

Future Sky Surveys: New Discovery Frontiers

NASA Astrophysics Data System (ADS)

Tyson, J. Anthony; Borne, Kirk D.

2012-03-01

Driven by the availability of new instrumentation, there has been an evolution in astronomical science toward comprehensive investigations of new phenomena. Major advances in our understanding of the Universe over the history of astronomy have often arisen from dramatic improvements in our capability to observe the sky to greater depth, in previously unexplored wavebands, with higher precision, or with improved spatial, spectral, or temporal resolution. Substantial progress in the important scientific problems of the next decade (determining the nature of dark energy and dark matter, studying the evolution of galaxies and the structure of our own Milky Way, opening up the time domain to discover faint variable objects, and mapping both the inner and outer Solar System) can be achieved through the application of advanced data mining methods and machine learning algorithms operating on the numerous large astronomical databases that will be generated from a variety of revolutionary future sky surveys. Over the next decade, astronomy will irrevocably enter the era of big surveys and of really big telescopes. New sky surveys (some of which will produce petabyte-scale data collections) will begin their operations, and one or more very large telescopes (ELTs = Extremely Large Telescopes) will enter the construction phase. These programs and facilities will generate a remarkable wealth of data of high complexity, endowed with enormous scientific knowledge discovery potential. New parameter spaces will be opened, in multiple wavelength domains as well as the time domain, across wide areas of the sky, and down to unprecedented faint source flux limits. The synergies of grand facilities, massive data collections, and advanced machine learning algorithms will come together to enable discoveries within most areas of astronomical science, including Solar System, exo-planets, star formation, stellar populations, stellar death, galaxy assembly, galaxy evolution, quasar evolution, and cosmology. Current and future sky surveys, comprising an alphabet soup of project names (e.g., Pan- STARRS, WISE, Kepler, DES, VST, VISTA, GAIA, EUCLID, SKA, LSST, and WFIRST; some of which are discussed in Chapters 17, 18, and 20),will contribute to the exponential explosion of complex data in astronomy. The scientific goals of these projects are as monumental as the programs themselves. The core scientific output of all of these will be their scientific data collection. Consequently, data mining and machine learning algorithms and specialists will become a common component of future astronomical research with these facilities. This synergistic combination and collaboration among multiple disciplines are essential in order to maximize the scientific discovery potential, the science output, the research efficiency, and the success of these projects.

Research Women’s Shirt Production

DTIC Science & Technology

1992-04-17

there was no sense in producing, for fit or wear test, garments which were inherently imprecise due to pattern problems. The resulting discoveries pointed...the approval of additional prototypes, 48 shirts were produced. Detailed garment dimension specification ;charts were provided for future quality...the industry at large, surfaced and were addressed. 14. SUai CRMS IS. NUMHE OR PAGES 25 Apparel manufacturing, women’s shirts C RO’ 17. SECURITY

Predicting the ability to produce emerald ash borer: a comparison of riparian and upland ash forests in southern lower Michigan

Treesearch

Susan J. Crocker; Deborah G. McCullough; Nathan W. Siegert

2009-01-01

Concern for the future of ash trees in the United States has risen since the 2002 discovery of emerald ash borer (EAB) (Agrilus planipennis Fairmaire) in southeastern Michigan. The ability of ash forests in the Southern Lower Peninsula of Michigan to produce EAB was compared by physiographic class and stand size. Results showed that EAB production...

Genetic Screening Strategy for Rapid Access to Polyether Ionophore Producers and Products in Actinomycetes ▿ †

PubMed Central

Wang, Hao; Liu, Ning; Xi, Lijun; Rong, Xiaoying; Ruan, Jisheng; Huang, Ying

2011-01-01

Polyether ionophores are a unique class of polyketides with broad-spectrum activity and outstanding potency for the control of drug-resistant bacteria and parasites, and they are produced exclusively by actinomycetes. A special epoxidase gene encoding a critical tailoring enzyme involved in the biosynthesis of these compounds has been found in all five of the complete gene clusters of polyether ionophores published so far. To detect potential producer strains of these antibiotics, a pair of degenerate primers was designed according to the conserved regions of the five known polyether epoxidases. A total of 44 putative polyether epoxidase gene-positive strains were obtained by the PCR-based screening of 1,068 actinomycetes isolated from eight different habitats and 236 reference strains encompassing eight major families of Actinomycetales. The isolates spanned a wide taxonomic diversity based on 16S rRNA gene analysis, and actinomycetes isolated from acidic soils seemed to be a promising source of polyether ionophores. Four genera were detected to contain putative polyether epoxidases, including Micromonospora, which has not previously been reported to produce polyether ionophores. The designed primers also detected putative epoxidase genes from diverse known producer strains that produce polyether ionophores unrelated to the five published gene clusters. Moreover, phylogenetic and chemical analyses showed a strong correlation between the sequence of polyether epoxidases and the structure of encoded polyethers. Thirteen positive isolates were proven to be polyether ionophore producers as expected, and two new analogues were found. These results demonstrate the feasibility of using this epoxidase gene screening strategy to aid the rapid identification of known products and the discovery of unknown polyethers in actinomycetes. PMID:21421776

Genetic screening strategy for rapid access to polyether ionophore producers and products in actinomycetes.

PubMed

Wang, Hao; Liu, Ning; Xi, Lijun; Rong, Xiaoying; Ruan, Jisheng; Huang, Ying

2011-05-01

Polyether ionophores are a unique class of polyketides with broad-spectrum activity and outstanding potency for the control of drug-resistant bacteria and parasites, and they are produced exclusively by actinomycetes. A special epoxidase gene encoding a critical tailoring enzyme involved in the biosynthesis of these compounds has been found in all five of the complete gene clusters of polyether ionophores published so far. To detect potential producer strains of these antibiotics, a pair of degenerate primers was designed according to the conserved regions of the five known polyether epoxidases. A total of 44 putative polyether epoxidase gene-positive strains were obtained by the PCR-based screening of 1,068 actinomycetes isolated from eight different habitats and 236 reference strains encompassing eight major families of Actinomycetales. The isolates spanned a wide taxonomic diversity based on 16S rRNA gene analysis, and actinomycetes isolated from acidic soils seemed to be a promising source of polyether ionophores. Four genera were detected to contain putative polyether epoxidases, including Micromonospora, which has not previously been reported to produce polyether ionophores. The designed primers also detected putative epoxidase genes from diverse known producer strains that produce polyether ionophores unrelated to the five published gene clusters. Moreover, phylogenetic and chemical analyses showed a strong correlation between the sequence of polyether epoxidases and the structure of encoded polyethers. Thirteen positive isolates were proven to be polyether ionophore producers as expected, and two new analogues were found. These results demonstrate the feasibility of using this epoxidase gene screening strategy to aid the rapid identification of known products and the discovery of unknown polyethers in actinomycetes.

Drug efficiency: a new concept to guide lead optimization programs towards the selection of better clinical candidates.

PubMed

Braggio, Simone; Montanari, Dino; Rossi, Tino; Ratti, Emiliangelo

2010-07-01

As a result of their wide acceptance and conceptual simplicity, drug-like concepts are having a major influence on the drug discovery process, particularly in the selection of the 'optimal' absorption, distribution, metabolism, excretion and toxicity and physicochemical parameters space. While they have an undisputable value when assessing the potential of lead series or in evaluating inherent risk of a portfolio of drug candidates, they result much less useful in weighing up compounds for the selection of the best potential clinical candidate. We introduce the concept of drug efficiency as a new tool both to guide the drug discovery program teams during the lead optimization phase and to better assess the developability potential of a drug candidate.

Keep Your Voice Sound: How to Prevent and Avoid Voice Problems

MedlinePlus

... ways, your voice is as unique as your fingerprint. It’s produced in your throat by 2 bands ... Act No Fear Act Office of Inspector General USA.gov – Government Made Easy NIH…Turning Discovery Into ...

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

PubMed

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

2017-11-06

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

From machine learning to deep learning: progress in machine intelligence for rational drug discovery.

PubMed

Zhang, Lu; Tan, Jianjun; Han, Dan; Zhu, Hao

2017-11-01

Machine intelligence, which is normally presented as artificial intelligence, refers to the intelligence exhibited by computers. In the history of rational drug discovery, various machine intelligence approaches have been applied to guide traditional experiments, which are expensive and time-consuming. Over the past several decades, machine-learning tools, such as quantitative structure-activity relationship (QSAR) modeling, were developed that can identify potential biological active molecules from millions of candidate compounds quickly and cheaply. However, when drug discovery moved into the era of 'big' data, machine learning approaches evolved into deep learning approaches, which are a more powerful and efficient way to deal with the massive amounts of data generated from modern drug discovery approaches. Here, we summarize the history of machine learning and provide insight into recently developed deep learning approaches and their applications in rational drug discovery. We suggest that this evolution of machine intelligence now provides a guide for early-stage drug design and discovery in the current big data era. Copyright © 2017 Elsevier Ltd. All rights reserved.

Streptomyces artemisiae MCCB 248 isolated from Arctic fjord sediments has unique PKS and NRPS biosynthetic genes and produces potential new anticancer natural products.

PubMed

Dhaneesha, M; Benjamin Naman, C; Krishnan, K P; Sinha, Rupesh Kumar; Jayesh, P; Joseph, Valsamma; Bright Singh, I S; Gerwick, William H; Sajeevan, T P

2017-05-01

After screening marine actinomycetes isolated from sediment samples collected from the Arctic fjord Kongsfjorden for potential anticancer activity, an isolate identified as Streptomyces artemisiae MCCB 248 exhibited promising results against the NCI-H460 human lung cancer cell line. H460 cells treated with the ethyl acetate extract of strain MCCB 248 and stained with Hoechst 33342 showed clear signs of apoptosis, including shrinkage of the cell nucleus, DNA fragmentation and chromatin condensation. Further to this treated cells showed indications of early apoptotic cell death, including a significant proportion of Annexin V positive staining and evidence of DNA damage as observed in the TUNEL assay. Amplified PKS 1 and NRPS genes involved in secondary metabolite production showed only 82% similarity to known biosynthetic genes of Streptomyces, indicating the likely production of a novel secondary metabolite in this extract. Additionally, chemical dereplication efforts using LC-MS/MS molecular networking suggested the presence of a series of undescribed tetraene polyols. Taken together, these results revealed that this Arctic S. artemisiae strain MCCB 248 is a promising candidate for natural products drug discovery and genome mining for potential anticancer agents.

Vaccines 'on demand': science fiction or a future reality.

PubMed

Ulmer, Jeffrey B; Mansoura, Monique K; Geall, Andrew J

2015-02-01

Self-amplifying mRNA vaccines are being developed as a platform technology with potential to be used for a broad range of targets. The synthetic production methods for their manufacture, combined with the modern tools of bioinformatics and synthetic biology, enable these vaccines to be produced rapidly from an electronic gene sequence. Preclinical proof of concept has so far been achieved for influenza, respiratory syncytial virus, rabies, Ebola, cytomegalovirus, human immunodeficiency virus and malaria. This editorial highlights the key milestones in the discovery and development of self-amplifying mRNA vaccines, and reviews how they might be used as a rapid response platform. The paper points out how future improvements in RNA vector design and non-viral delivery may lead to decreases in effective dose and increases in production capacity. The prospects for non-viral delivery of self-amplifying mRNA vaccines are very promising. Like other types of nucleic acid vaccines, these vaccines have the potential to draw on the positive attributes of live-attenuated vaccines while obviating many potential safety limitations. Hence, this approach could enable the concept of vaccines on demand as a rapid response to a real threat rather than the deployment of strategic stockpiles based on epidemiological predictions for possible threats.

Retrospective analysis of natural products provides insights for future discovery trends

PubMed Central

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

2017-01-01

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

Using glycome databases for drug discovery.

PubMed

Aoki-Kinoshita, Kiyoko F

2008-08-01

The glycomics field has made great advancements in the last decade due to technologies for their synthesis and analysis including carbohydrate microarrays. Accordingly, databases for glycomics research have also emerged and been made publicly available by many major institutions worldwide. This review introduces these and other useful databases on which new methods for drug discovery can be developed. The scope of this review covers current documented and accessible databases and resources pertaining to glycomics. These were selected with the expectation that they may be useful for drug discovery research. There is a plethora of glycomics databases that have much potential for drug discovery. This may seem daunting at first but this review helps to put some of these resources into perspective. Additionally, some thoughts on how to integrate these resources to allow more efficient research are presented.

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

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

Wang, Hui; Shi, Tujin; Qian, Wei-Jun

2015-12-04

Mass spectrometry-based proteomics has become an indispensable tool in biomedical research with broad applications ranging from fundamental biology, systems biology, and biomarker discovery. Recent advances in LC-MS have made it become a major technology in clinical applications, especially in cancer biomarker discovery and verification. To overcome the challenges associated with the analysis of clinical samples, such as extremely wide dynamic range of protein concentrations in biofluids and the need to perform high throughput and accurate quantification, significant efforts have been devoted to improve the overall performance of LC-MS bases clinical proteomics. In this review, we summarize the recent advances inmore » LC-MS in the aspect of cancer biomarker discovery and quantification, and discuss its potentials, limitations, and future perspectives.« less

Mechanisms of fatty acid synthesis in marine fungus-like protists.

PubMed

Xie, Yunxuan; Wang, Guangyi

2015-10-01

Thraustochytrids are unicellular fungus-like protists and are well known for their ability to produce interesting nutraceutical compounds. Significant efforts have been made to improve their efficient production of important fatty acids (FAs), mostly by optimizing fermentation conditions and selecting highly productive thraustochytrid strains. Furthermore, noticeable improvements have been made in understanding the mechanism of FA biosynthesis, allowing for a better understanding of how thraustochytrids assemble these unique metabolites and how their biosynthesis is coupled with other related pathways. This review summarizes recent achievements on two major FA biosynthesis pathways, the standard pathway and the polyketide synthase pathway, and detail features of individual enzymes involved in FA biosynthesis, biotechnological advances in pathway engineering and enzyme characterization, and the discovery of other pathways that affect the efficiency of FA accumulation. Perspectives of biotechnological potential application of thraustochytrids are also discussed.

Atypical Dopamine Uptake Inhibitors that Provide Clues About Cocaine's Mechanism at the Dopamine Transporter

NASA Astrophysics Data System (ADS)

Hauck Newman, Amy; Katz, Jonathan L.

The dopamine transporter (DAT) has been a primary target for cocaine abuse/addiction medication discovery. However predicted addiction liability and limited clinical evaluation has provided a formidable challenge for development of these agents for human use. The unique and atypical pharmacological profile of the benztropine (BZT) class of dopamine uptake inhibitors, in preclinical models of cocaine effects and abuse, has encouraged further development of these agents. Moreover, in vivo studies have challenged the original DAT hypothesis and demonstrated that DAT occupancy and subsequent increases in dopamine produced by BZT analogues are significantly delayed and long lasting, as compared to cocaine. These important and distinctive elements are critical to the lack of abuse liability among BZT analogues, and improve their potential for development as treatments for cocaine abuse and possibly other neuropsychiatric disorders.

The future of spectroscopic life detection on exoplanets

PubMed Central

Seager, Sara

2014-01-01

The discovery and characterization of exoplanets have the potential to offer the world one of the most impactful findings ever in the history of astronomy—the identification of life beyond Earth. Life can be inferred by the presence of atmospheric biosignature gases—gases produced by life that can accumulate to detectable levels in an exoplanet atmosphere. Detection will be made by remote sensing by sophisticated space telescopes. The conviction that biosignature gases will actually be detected in the future is moderated by lessons learned from the dozens of exoplanet atmospheres studied in last decade, namely the difficulty in robustly identifying molecules, the possible interference of clouds, and the permanent limitations from a spectrum of spatially unresolved and globally mixed gases without direct surface observations. The vision for the path to assess the presence of life beyond Earth is being established. PMID:25092345

Production of Biomass-Based Automotive Lubricants by Reductive Etherification.

PubMed

Jadhav, Deepak; Grippo, Adam M; Shylesh, Sankaranarayanapillai; Gokhale, Amit A; Redshaw, John; Bell, Alexis T

2017-06-09

Growing concern with the effects of CO 2 emissions due to the combustion of petroleum-based transportation fuels has motivated the search for means to increase engine efficiency. The discovery of ethers with low viscosity presents an important opportunity to improve engine efficiency and fuel economy. We show here a strategy for the catalytic synthesis of such ethers by reductive etherification/O-alkylation of alcohols using building blocks that can be sourced from biomass. We find that long-chain branched ethers have several properties that make them superior lubricants to the mineral oil and synthetic base oils used today. These ethers provide a class of potentially renewable alternatives to conventional lubricants produced from petroleum and may contribute to the reduction of greenhouse gases associated with vehicle emissions. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Unraveling Nutritional Regulation of Tacrolimus Biosynthesis in Streptomyces tsukubaensis through omic Approaches.

PubMed

Ordóñez-Robles, María; Santos-Beneit, Fernando; Martín, Juan F

2018-05-01

Streptomyces tsukubaensis stands out among actinomycetes by its ability to produce the immunosuppressant tacrolimus. Discovered about 30 years ago, this macrolide is widely used as immunosuppressant in current clinics. Other potential applications for the treatment of cancer and as neuroprotective agent have been proposed in the last years. In this review we introduce the discovery of S. tsukubaensis and tacrolimus, its biosynthetic pathway and gene cluster ( fkb ) regulation. We have focused this work on the omic studies performed in this species in order to understand tacrolimus production. Transcriptomics, proteomics and metabolomics have improved our knowledge about the fkb transcriptional regulation and have given important clues about nutritional regulation of tacrolimus production that can be applied to improve production yields. Finally, we address some points of S. tsukubaensis biology that deserve more attention.

Natural and engineered biosynthesis of fluorinated natural products.

PubMed

Walker, Mark C; Chang, Michelle C Y

2014-09-21

Both natural products and synthetic organofluorines play important roles in the discovery and design of pharmaceuticals. The combination of these two classes of molecules has the potential to be useful in the ongoing search for new bioactive compounds but our ability to produce site-selectively fluorinated natural products remains limited by challenges in compatibility between their high structural complexity and current methods for fluorination. Living systems provide an alternative route to chemical fluorination and could enable the production of organofluorine natural products through synthetic biology approaches. While the identification of biogenic organofluorines has been limited, the study of the native organisms and enzymes that utilize these compounds can help to guide efforts to engineer the incorporation of this unusual element into complex pharmacologically active natural products. This review covers recent advances in understanding both natural and engineered production of organofluorine natural products.

Exploration limited since '70s in Libya's Sirte basin

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

Thomas, D.

1995-03-13

Esso Standard made the first Libyan oil discovery in the western Ghadames basin in 1957. The Atshan-2 well tested oil from Devonian sandstones, and the play was a continuation of the Paleozoic trend found productive in the neighboring Edjeleh region of eastern Algeria. Exploration in the Sirte basin began in earnest in 1958. Within the next 10 years, 16 major oil fields had been discovered, each with recoverable reserves greater than 500 million bbl of oil. Libya currently produces under OPEC quota approximately 1.4 million b/d of oil, with discovered in-place reserves of 130 billion bbl of oil. The papermore » describes the structural framework, sedimentary basins of Libya, the Sirte basin, petroleum geology, play types, source rocks, generation and migration of hydrocarbons, oil reserves, potential, and acreage availability.« less

Interleukin-8: an expanding universe beyond neutrophil chemotaxis and activation.

PubMed

Mukaida, N

2000-12-01

Since the discovery 13 years ago of interleukin (IL)-8 as a potent neutrophil chemotactic factor, accumulating evidence has established it as a crucial mediator in neutrophil-dependent acute inflammation. Numerous observations have demonstrated that various types of cells can produce a large amount of IL-8, either in response to various stimuli or constitutively, after malignant transformation. Recent studies of IL-8-mediated signaling have revealed that IL-8 activates a wide range of signaling molecules in a coordinate manner. IL-8 has been proven to have diverse actions on various types of leukocytic and nonleukocytic cells besides neutrophils. The author reviews recent progress in IL-8 signal transduction and biological actions on nonneutrophilic leukocytes, including T lymphocytes, monocytes, and hematopoietic progenitor cells. Potential involvement of IL-8 in viral infections and tumor progression is also discussed.

Metazoan tRNA introns generate stable circular RNAs in vivo

PubMed Central

Lu, Zhipeng; Filonov, Grigory S.; Noto, John J.; Schmidt, Casey A.; Hatkevich, Talia L.; Wen, Ying; Jaffrey, Samie R.; Matera, A. Gregory

2015-01-01

We report the discovery of a class of abundant circular noncoding RNAs that are produced during metazoan tRNA splicing. These transcripts, termed tRNA intronic circular (tric)RNAs, are conserved features of animal transcriptomes. Biogenesis of tricRNAs requires anciently conserved tRNA sequence motifs and processing enzymes, and their expression is regulated in an age-dependent and tissue-specific manner. Furthermore, we exploited this biogenesis pathway to develop an in vivo expression system for generating “designer” circular RNAs in human cells. Reporter constructs expressing RNA aptamers such as Spinach and Broccoli can be used to follow the transcription and subcellular localization of tricRNAs in living cells. Owing to the superior stability of circular vs. linear RNA isoforms, this expression system has a wide range of potential applications, from basic research to pharmaceutical science. PMID:26194134

The future of spectroscopic life detection on exoplanets.

PubMed

Seager, Sara

2014-09-02

The discovery and characterization of exoplanets have the potential to offer the world one of the most impactful findings ever in the history of astronomy--the identification of life beyond Earth. Life can be inferred by the presence of atmospheric biosignature gases--gases produced by life that can accumulate to detectable levels in an exoplanet atmosphere. Detection will be made by remote sensing by sophisticated space telescopes. The conviction that biosignature gases will actually be detected in the future is moderated by lessons learned from the dozens of exoplanet atmospheres studied in last decade, namely the difficulty in robustly identifying molecules, the possible interference of clouds, and the permanent limitations from a spectrum of spatially unresolved and globally mixed gases without direct surface observations. The vision for the path to assess the presence of life beyond Earth is being established.

Bioligninolysis: recent updates for biotechnological solution.

PubMed

Paliwal, Rashmi; Rawat, A P; Rawat, Monica; Rai, J P N

2012-08-01

Bioligninolysis involves living organisms and/or their products in degradation of lignin, which is highly resistant, plant-originated polymer having three-dimensional network of dimethoxylated (syringyl), monomethoxylated (guaiacyl), and non-methoxylated (p-hydroxyphenyl) phenylpropanoid and acetylated units. As a major repository of aromatic chemical structures on earth, lignin bears paramount significance for its removal owing to potential application of bioligninolytic systems in industrial production. Early reports illustrating the discovery and cloning of ligninolytic biocatalysts in fungi was truly a landmark in the field of enzymatic delignification. However, the enzymology for bacterial delignification is hitherto poorly understood. Moreover, the lignin-degrading bacterial genes are still unknown and need further exploration. This review deals with the current knowledge about ligninolytic enzyme families produced by fungi and bacteria, their mechanisms of action, and genetic regulation and reservations, which render them attractive candidates in biotechnological applications.

Chemical and UV Mutagenesis.

PubMed

Bose, Jeffrey L

2016-01-01

The ability to create mutations is an important step towards understanding bacterial physiology and virulence. While targeted approaches are invaluable, the ability to produce genome-wide random mutations can lead to crucial discoveries. Transposon mutagenesis is a useful approach, but many interesting mutations can be missed by these insertions that interrupt coding and noncoding sequences due to the integration of an entire transposon. Chemical mutagenesis and UV-based random mutagenesis are alternate approaches to isolate mutations of interest with the potential of only single nucleotide changes. Once a standard method, difficulty in identifying mutation sites had decreased the popularity of this technique. However, thanks to the recent emergence of economical whole-genome sequencing, this approach to making mutations can once again become a viable option. Therefore, this chapter provides an overview protocol for random mutagenesis using UV light or DNA-damaging chemicals.

[Quinquina and man].

PubMed

Seigneuric, C; Camara, B; Delmont, J; Busato, F; Payen, J L; Armengaud, M; Marchou, B

2008-10-01

Many great discoveries have been made by chance but some have been the result of human perseverance and ingenuity. A sterling example of the second case is quinquina that was discovered in Peru and is now produced in Java. Quinquina has gone through centuries without losing its medical efficacy that efficacy allowed the exploration and colonization of Africa and played a key role in the ability to conduct overseas military campaigns. Because of its strategic importance, it was a coveted resource. It led to the discovery of homeopathy and dyes, allowed the development of organic chemistry, and has been used to make alcoholic bitters and soft drinks.