Sample records for discovery function authority

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

    PubMed

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

    2016-11-16

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

  2. Chemical Discovery

    ERIC Educational Resources Information Center

    Brown, Herbert C.

    1974-01-01

    The role of discovery in the advance of the science of chemistry and the factors that are currently operating to handicap that function are considered. Examples are drawn from the author's work with boranes. The thesis that exploratory research and discovery should be encouraged is stressed. (DT)

  3. The Ketogenic Diet and Potassium Channel Function

    DTIC Science & Technology

    2015-11-01

    1 AWARD NUMBER: W81XWH-13-1-0463 TITLE: The Ketogenic Diet and Potassium Channel Function PRINCIPAL INVESTIGATOR: Dr. Geoffrey Murphy...NUMBER The Ketogenic Diet and Potassium Channel Function 5b. GRANT NUMBER W81XWH-13-1-0463 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Geoffrey Murphy...The overall objective of this Discovery Award was to explore the hypothesis the ketogenic diet (KD) regulates neuronal excitability by influencing

  4. Using Dynamic Geometry to Expand Mathematics Teachers' Understanding of Proof

    ERIC Educational Resources Information Center

    de Villiers, Michael

    2004-01-01

    This paper gives a broad descriptive account of some activities that the author has designed using Sketchpad to develop teachers' understanding of other functions of proof than just the traditional function of 'verification'. These other functions of proof illustrated here are those of explanation, discovery and systematization (in the context of…

  5. 75 FR 14608 - Statement of Organization, Functions, and Delegations of Authority

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-26

    ... situations; (5) helps to develop and encourage innovation throughout the spectrum from scientific discovery... transparency and accountability of CDC extramural research programs; (5) provides oversight of knowledge...

  6. The discovery of the periodic table as a case of simultaneous discovery.

    PubMed

    Scerri, Eric

    2015-03-13

    The article examines the question of priority and simultaneous discovery in the context of the discovery of the periodic system. It is argued that rather than being anomalous, simultaneous discovery is the rule. Moreover, I argue that the discovery of the periodic system by at least six authors in over a period of 7 years represents one of the best examples of a multiple discovery. This notion is supported by a new view of the evolutionary development of science through a mechanism that is dubbed Sci-Gaia by analogy with Lovelock's Gaia hypothesis. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  7. The Discovery of Water Channels (Aquaporins).

    PubMed

    Brown, Dennis

    2017-01-01

    The movement of water into and out of cells is a fundamental biological process that is essential for life. Such water movement not only regulates the activity of individual cells but also is responsible for the functioning of many organ systems and for maintaining whole body water balance. It had long been suspected that water movement across biological cell membranes was in some way enhanced or facilitated by pores or channels, but the search to identify these channels was long and tedious. As is often the case in science, the secret of the water channel was eventually discovered by chance in 1992 by Peter Agre and his colleagues at the Johns Hopkins University in Baltimore, who were working on red blood cell membrane proteins. This "first" water channel was originally named CHIP28 and is now known as aquaporin 1. Agre received the Nobel Prize in Chemistry in 2003 for this discovery. There are currently 13 known aquaporins in mammals, distributed in most tissues, but many more have been identified in lower organisms and in the plant kingdom. The involvement of aquaporins in processes such as urinary concentration and body fluid homeostasis, brain function, glandular secretion, skin hydration, male fertility, hearing, vision, and most important body functions that can be imagined are now all under intense scientific scrutiny. Moreover, defects in aquaporin function have been related to various disease conditions and pathological states. This brief review will discuss their background, discovery, and function in selected bodily processes, especially focusing on hydration. © 2017 The Author(s) Published by S. Karger AG, Basel.

  8. Design of small molecule epigenetic modulators.

    PubMed

    Pachaiyappan, Boobalan; Woster, Patrick M

    2014-01-01

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

  9. ChEMBL web services: streamlining access to drug discovery data and utilities.

    PubMed

    Davies, Mark; Nowotka, Michał; Papadatos, George; Dedman, Nathan; Gaulton, Anna; Atkinson, Francis; Bellis, Louisa; Overington, John P

    2015-07-01

    ChEMBL is now a well-established resource in the fields of drug discovery and medicinal chemistry research. The ChEMBL database curates and stores standardized bioactivity, molecule, target and drug data extracted from multiple sources, including the primary medicinal chemistry literature. Programmatic access to ChEMBL data has been improved by a recent update to the ChEMBL web services (version 2.0.x, https://www.ebi.ac.uk/chembl/api/data/docs), which exposes significantly more data from the underlying database and introduces new functionality. To complement the data-focused services, a utility service (version 1.0.x, https://www.ebi.ac.uk/chembl/api/utils/docs), which provides RESTful access to commonly used cheminformatics methods, has also been concurrently developed. The ChEMBL web services can be used together or independently to build applications and data processing workflows relevant to drug discovery and chemical biology. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  10. Discovery of functional monoclonal antibodies targeting G-protein-coupled receptors and ion channels.

    PubMed

    Wilkinson, Trevor C I

    2016-06-15

    The development of recombinant antibody therapeutics is a significant area of growth in the pharmaceutical industry with almost 50 approved monoclonal antibodies on the market in the US and Europe. Despite this growth, however, certain classes of important molecular targets have remained intractable to therapeutic antibodies due to complexity of the target molecules. These complex target molecules include G-protein-coupled receptors and ion channels which represent a large potential target class for therapeutic intervention with monoclonal antibodies. Although these targets have typically been addressed by small molecule approaches, the exquisite specificity of antibodies provides a significant opportunity to provide selective modulation of these target proteins. Given this opportunity, substantial effort has been applied to address the technical challenges of targeting these complex membrane proteins with monoclonal antibodies. In this review recent progress made in the strategies for discovery of functional monoclonal antibodies for these challenging membrane protein targets is addressed. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  11. Structural and functional aspects of the nonribosomal peptide synthetase condensation domain superfamily: discovery, dissection and diversity.

    PubMed

    Bloudoff, Kristjan; Schmeing, T Martin

    2017-11-01

    Nonribosomal peptide synthetases (NRPSs) are incredible macromolecular machines that produce a wide range of biologically- and therapeutically-relevant molecules. During synthesis, peptide elongation is performed by the condensation (C) domain, as it catalyzes amide bond formation between the nascent peptide and the amino acid it adds to the chain. Since their discovery more than two decades ago, C domains have been subject to extensive biochemical, bioinformatic, mutagenic, and structural analyses. They are composed of two lobes, each with homology to chloramphenicol acetyltransferase, have two binding sites for their two peptidyl carrier protein-bound ligands, and have an active site with conserved motif HHxxxDG located between the two lobes. This review discusses some of the important insights into the structure, catalytic mechanism, specificity, and gatekeeping functions of C domains revealed since their discovery. In addition, C domains are the archetypal members of the C domain superfamily, which includes several other members that also function as NRPS domains. The other family members can replace the C domain in NRP synthesis, can work in concert with a C domain, or can fulfill diverse and novel functions. These domains include the epimerization (E) domain, the heterocyclization (Cy) domain, the ester-bond forming C domain, the fungal NRPS terminal C domain (C T ), the β-lactam ring forming C domain, and the X domain. We also discuss structural and function insight into C, E, Cy, C T and X domains, to present a holistic overview of historical and current knowledge of the C domain superfamily. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  12. BioTextQuest(+): a knowledge integration platform for literature mining and concept discovery.

    PubMed

    Papanikolaou, Nikolas; Pavlopoulos, Georgios A; Pafilis, Evangelos; Theodosiou, Theodosios; Schneider, Reinhard; Satagopam, Venkata P; Ouzounis, Christos A; Eliopoulos, Aristides G; Promponas, Vasilis J; Iliopoulos, Ioannis

    2014-11-15

    The iterative process of finding relevant information in biomedical literature and performing bioinformatics analyses might result in an endless loop for an inexperienced user, considering the exponential growth of scientific corpora and the plethora of tools designed to mine PubMed(®) and related biological databases. Herein, we describe BioTextQuest(+), a web-based interactive knowledge exploration platform with significant advances to its predecessor (BioTextQuest), aiming to bridge processes such as bioentity recognition, functional annotation, document clustering and data integration towards literature mining and concept discovery. BioTextQuest(+) enables PubMed and OMIM querying, retrieval of abstracts related to a targeted request and optimal detection of genes, proteins, molecular functions, pathways and biological processes within the retrieved documents. The front-end interface facilitates the browsing of document clustering per subject, the analysis of term co-occurrence, the generation of tag clouds containing highly represented terms per cluster and at-a-glance popup windows with information about relevant genes and proteins. Moreover, to support experimental research, BioTextQuest(+) addresses integration of its primary functionality with biological repositories and software tools able to deliver further bioinformatics services. The Google-like interface extends beyond simple use by offering a range of advanced parameterization for expert users. We demonstrate the functionality of BioTextQuest(+) through several exemplary research scenarios including author disambiguation, functional term enrichment, knowledge acquisition and concept discovery linking major human diseases, such as obesity and ageing. The service is accessible at http://bioinformatics.med.uoc.gr/biotextquest. g.pavlopoulos@gmail.com or georgios.pavlopoulos@esat.kuleuven.be Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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

    PubMed Central

    Borsook, David; Hargreaves, Richard; Becerra, Lino

    2011-01-01

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

  14. 45 CFR 2554.25 - What type of discovery is authorized and how is it conducted?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 4 2010-10-01 2010-10-01 false What type of discovery is authorized and how is it...) CORPORATION FOR NATIONAL AND COMMUNITY SERVICE PROGRAM FRAUD CIVIL REMEDIES ACT REGULATIONS Hearing Provisions § 2554.25 What type of discovery is authorized and how is it conducted? (a) The following types of...

  15. 45 CFR 2554.25 - What type of discovery is authorized and how is it conducted?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 4 2011-10-01 2011-10-01 false What type of discovery is authorized and how is it...) CORPORATION FOR NATIONAL AND COMMUNITY SERVICE PROGRAM FRAUD CIVIL REMEDIES ACT REGULATIONS Hearing Provisions § 2554.25 What type of discovery is authorized and how is it conducted? (a) The following types of...

  16. Improved accuracy of supervised CRM discovery with interpolated Markov models and cross-species comparison.

    PubMed

    Kazemian, Majid; Zhu, Qiyun; Halfon, Marc S; Sinha, Saurabh

    2011-12-01

    Despite recent advances in experimental approaches for identifying transcriptional cis-regulatory modules (CRMs, 'enhancers'), direct empirical discovery of CRMs for all genes in all cell types and environmental conditions is likely to remain an elusive goal. Effective methods for computational CRM discovery are thus a critically needed complement to empirical approaches. However, existing computational methods that search for clusters of putative binding sites are ineffective if the relevant TFs and/or their binding specificities are unknown. Here, we provide a significantly improved method for 'motif-blind' CRM discovery that does not depend on knowledge or accurate prediction of TF-binding motifs and is effective when limited knowledge of functional CRMs is available to 'supervise' the search. We propose a new statistical method, based on 'Interpolated Markov Models', for motif-blind, genome-wide CRM discovery. It captures the statistical profile of variable length words in known CRMs of a regulatory network and finds candidate CRMs that match this profile. The method also uses orthologs of the known CRMs from closely related genomes. We perform in silico evaluation of predicted CRMs by assessing whether their neighboring genes are enriched for the expected expression patterns. This assessment uses a novel statistical test that extends the widely used Hypergeometric test of gene set enrichment to account for variability in intergenic lengths. We find that the new CRM prediction method is superior to existing methods. Finally, we experimentally validate 12 new CRM predictions by examining their regulatory activity in vivo in Drosophila; 10 of the tested CRMs were found to be functional, while 6 of the top 7 predictions showed the expected activity patterns. We make our program available as downloadable source code, and as a plugin for a genome browser installed on our servers. © The Author(s) 2011. Published by Oxford University Press.

  17. 49 CFR 1313.10 - Procedures for complaints and discovery.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...) Discovery petition. A discovery petition must note on the front page “Petition for Discovery of Rail... action on a petition for discovery is taken under delegated authority, that action may be appealed to the...

  18. The future of quantum dots in drug discovery.

    PubMed

    Lin, Guimiao; Yin, Feng; Yong, Ken-Tye

    2014-09-01

    The rapid development of drug discovery today is inseparable from the interaction of advanced particle technologies and new drug synthesis protocols. Quantum dots (QDs) are regarded as a unique class of fluorescent labels, with unique optical properties such as high brightness and long-term colloidal and optical stability; these are suitable for optical imaging, drug delivery and optical tracking, fluorescence immunoassay and other medicinal applications. More importantly, QD possesses a rich surface chemistry property that is useful for incorporating various drug molecules, targeting ligands, and additional contrast agents (e.g., MRI, PET, etc.) onto the nanoparticle surface for achieving targeted and traceable drug delivery therapy at both cellular and systemic levels. In recent times, the advancement of QD technology has promoted the use of functionalized nanocrystals for in vivo applications. Such research is paving the way for drug discovery using various bioconjugated QD formulations. In this editorial, the authors highlight the current research progress and future applications of QDs in drug discovery.

  19. 22 CFR 224.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Discovery. 224.21 Section 224.21 Foreign....21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of... parties, discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery...

  20. 15 CFR 25.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 1 2013-01-01 2013-01-01 false Discovery. 25.21 Section 25.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery. (d...

  1. 15 CFR 25.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 15 Commerce and Foreign Trade 1 2012-01-01 2012-01-01 false Discovery. 25.21 Section 25.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery. (d...

  2. 15 CFR 25.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 15 Commerce and Foreign Trade 1 2014-01-01 2014-01-01 false Discovery. 25.21 Section 25.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery. (d...

  3. 5 CFR 185.122 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 5 Administrative Personnel 1 2012-01-01 2012-01-01 false Discovery. 185.122 Section 185.122... § 185.122 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of..., discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery. (d...

  4. 15 CFR 25.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 1 2011-01-01 2011-01-01 false Discovery. 25.21 Section 25.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery. (d...

  5. 22 CFR 224.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Discovery. 224.21 Section 224.21 Foreign....21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of... parties, discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery...

  6. 22 CFR 224.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Discovery. 224.21 Section 224.21 Foreign....21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of... parties, discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery...

  7. 5 CFR 185.122 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 5 Administrative Personnel 1 2011-01-01 2011-01-01 false Discovery. 185.122 Section 185.122... § 185.122 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of..., discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery. (d...

  8. 5 CFR 185.122 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Discovery. 185.122 Section 185.122... § 185.122 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of..., discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery. (d...

  9. 5 CFR 185.122 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Discovery. 185.122 Section 185.122... § 185.122 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of..., discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery. (d...

  10. 22 CFR 224.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Discovery. 224.21 Section 224.21 Foreign....21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of... parties, discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery...

  11. 15 CFR 25.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Discovery. 25.21 Section 25.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery. (d...

  12. 22 CFR 224.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Discovery. 224.21 Section 224.21 Foreign....21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of... parties, discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery...

  13. 40 CFR 27.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Discovery. 27.21 Section 27.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

  14. 40 CFR 27.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Discovery. 27.21 Section 27.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

  15. 40 CFR 27.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Discovery. 27.21 Section 27.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

  16. 40 CFR 27.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Discovery. 27.21 Section 27.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

  17. 40 CFR 27.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Discovery. 27.21 Section 27.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

  18. 14 CFR 1264.120 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false Discovery. 1264.120 Section 1264.120... PENALTIES ACT OF 1986 § 1264.120 Discovery. (a) The following types of discovery are authorized: (1..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

  19. 22 CFR 521.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 2 2013-04-01 2009-04-01 true Discovery. 521.21 Section 521.21 Foreign... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for... interpreted to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

  20. 14 CFR 1264.120 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 5 2013-01-01 2013-01-01 false Discovery. 1264.120 Section 1264.120... PENALTIES ACT OF 1986 § 1264.120 Discovery. (a) The following types of discovery are authorized: (1..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

  1. 14 CFR 1264.120 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Discovery. 1264.120 Section 1264.120... PENALTIES ACT OF 1986 § 1264.120 Discovery. (a) The following types of discovery are authorized: (1..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

  2. 22 CFR 521.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 2 2014-04-01 2014-04-01 false Discovery. 521.21 Section 521.21 Foreign... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for... interpreted to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

  3. 37 CFR 41.150 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2013-07-01 2013-07-01 false Discovery. 41.150 Section 41... COMMERCE PRACTICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Contested Cases § 41.150 Discovery. (a) Limited discovery. A party is not entitled to discovery except as authorized in this subpart. The parties may agree...

  4. 43 CFR 35.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 43 Public Lands: Interior 1 2014-10-01 2014-10-01 false Discovery. 35.21 Section 35.21 Public... AND STATEMENTS § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests...) Unless mutually agreed to by the parties, discovery is available only as ordered by the ALJ. The ALJ...

  5. 43 CFR 35.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 43 Public Lands: Interior 1 2013-10-01 2013-10-01 false Discovery. 35.21 Section 35.21 Public... AND STATEMENTS § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests...) Unless mutually agreed to by the parties, discovery is available only as ordered by the ALJ. The ALJ...

  6. 43 CFR 35.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 43 Public Lands: Interior 1 2012-10-01 2011-10-01 true Discovery. 35.21 Section 35.21 Public Lands... STATEMENTS § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for...) Unless mutually agreed to by the parties, discovery is available only as ordered by the ALJ. The ALJ...

  7. 37 CFR 41.150 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2011-07-01 2011-07-01 false Discovery. 41.150 Section 41... COMMERCE PRACTICE BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES Contested Cases § 41.150 Discovery. (a) Limited discovery. A party is not entitled to discovery except as authorized in this subpart. The...

  8. 43 CFR 35.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 43 Public Lands: Interior 1 2011-10-01 2011-10-01 false Discovery. 35.21 Section 35.21 Public... AND STATEMENTS § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests...) Unless mutually agreed to by the parties, discovery is available only as ordered by the ALJ. The ALJ...

  9. 22 CFR 521.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 2 2012-04-01 2009-04-01 true Discovery. 521.21 Section 521.21 Foreign... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for... interpreted to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

  10. 37 CFR 41.150 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2014-07-01 2014-07-01 false Discovery. 41.150 Section 41... COMMERCE PRACTICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Contested Cases § 41.150 Discovery. (a) Limited discovery. A party is not entitled to discovery except as authorized in this subpart. The parties may agree...

  11. 22 CFR 521.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 2 2011-04-01 2009-04-01 true Discovery. 521.21 Section 521.21 Foreign... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for... interpreted to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

  12. 37 CFR 41.150 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2012-07-01 2012-07-01 false Discovery. 41.150 Section 41... COMMERCE PRACTICE BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES Contested Cases § 41.150 Discovery. (a) Limited discovery. A party is not entitled to discovery except as authorized in this subpart. The...

  13. 37 CFR 41.150 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Discovery. 41.150 Section 41... COMMERCE PRACTICE BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES Contested Cases § 41.150 Discovery. (a) Limited discovery. A party is not entitled to discovery except as authorized in this subpart. The...

  14. 22 CFR 521.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 2 2010-04-01 2010-04-01 true Discovery. 521.21 Section 521.21 Foreign... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for... interpreted to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

  15. 43 CFR 35.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Discovery. 35.21 Section 35.21 Public... AND STATEMENTS § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests...) Unless mutually agreed to by the parties, discovery is available only as ordered by the ALJ. The ALJ...

  16. 14 CFR 1264.120 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Discovery. 1264.120 Section 1264.120... PENALTIES ACT OF 1986 § 1264.120 Discovery. (a) The following types of discovery are authorized: (1..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

  17. Simple animal models for amyotrophic lateral sclerosis drug discovery.

    PubMed

    Patten, Shunmoogum A; Parker, J Alex; Wen, Xiao-Yan; Drapeau, Pierre

    2016-08-01

    Simple animal models have enabled great progress in uncovering the disease mechanisms of amyotrophic lateral sclerosis (ALS) and are helping in the selection of therapeutic compounds through chemical genetic approaches. Within this article, the authors provide a concise overview of simple model organisms, C. elegans, Drosophila and zebrafish, which have been employed to study ALS and discuss their value to ALS drug discovery. In particular, the authors focus on innovative chemical screens that have established simple organisms as important models for ALS drug discovery. There are several advantages of using simple animal model organisms to accelerate drug discovery for ALS. It is the authors' particular belief that the amenability of simple animal models to various genetic manipulations, the availability of a wide range of transgenic strains for labelling motoneurons and other cell types, combined with live imaging and chemical screens should allow for new detailed studies elucidating early pathological processes in ALS and subsequent drug and target discovery.

  18. Have artificial neural networks met expectations in drug discovery as implemented in QSAR framework?

    PubMed

    Dobchev, Dimitar; Karelson, Mati

    2016-07-01

    Artificial neural networks (ANNs) are highly adaptive nonlinear optimization algorithms that have been applied in many diverse scientific endeavors, ranging from economics, engineering, physics, and chemistry to medical science. Notably, in the past two decades, ANNs have been used widely in the process of drug discovery. In this review, the authors discuss advantages and disadvantages of ANNs in drug discovery as incorporated into the quantitative structure-activity relationships (QSAR) framework. Furthermore, the authors examine the recent studies, which span over a broad area with various diseases in drug discovery. In addition, the authors attempt to answer the question about the expectations of the ANNs in drug discovery and discuss the trends in this field. The old pitfalls of overtraining and interpretability are still present with ANNs. However, despite these pitfalls, the authors believe that ANNs have likely met many of the expectations of researchers and are still considered as excellent tools for nonlinear data modeling in QSAR. It is likely that ANNs will continue to be used in drug development in the future.

  19. 31 CFR 16.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance: Treasury 1 2012-07-01 2012-07-01 false Discovery. 16.21 Section 16.21 Money... FRAUD CIVIL REMEDIES ACT OF 1986 § 16.21 Discovery. (a) The following types of discovery are authorized... to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

  20. 31 CFR 16.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance: Treasury 1 2013-07-01 2013-07-01 false Discovery. 16.21 Section 16.21 Money... FRAUD CIVIL REMEDIES ACT OF 1986 § 16.21 Discovery. (a) The following types of discovery are authorized... to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

  1. 31 CFR 16.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance: Treasury 1 2014-07-01 2014-07-01 false Discovery. 16.21 Section 16.21 Money... FRAUD CIVIL REMEDIES ACT OF 1986 § 16.21 Discovery. (a) The following types of discovery are authorized... to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

  2. 14 CFR § 1264.120 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 5 2014-01-01 2014-01-01 false Discovery. § 1264.120 Section § 1264.120... PENALTIES ACT OF 1986 § 1264.120 Discovery. (a) The following types of discovery are authorized: (1..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

  3. 31 CFR 16.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance: Treasury 1 2011-07-01 2011-07-01 false Discovery. 16.21 Section 16.21 Money... FRAUD CIVIL REMEDIES ACT OF 1986 § 16.21 Discovery. (a) The following types of discovery are authorized... to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

  4. 31 CFR 16.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Discovery. 16.21 Section 16.21 Money... FRAUD CIVIL REMEDIES ACT OF 1986 § 16.21 Discovery. (a) The following types of discovery are authorized... to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

  5. New displays and new emotions: a commentary on Rozin and Cohen (2003).

    PubMed

    Keltner, Dacher; Shiota, Michelle N

    2003-03-01

    In this article, the authors elaborate on 3 ideas advanced in P. Rozin and A. B. Cohen's (2003) innovative study of facial expression. Taking a cue from their discovery of new expressive behaviors (e.g., the narrowed eyebrows), the authors review recent studies showing that emotions are conveyed in more channels than usually studied, including posture, gaze patterns, voice, and touch. Building on their claim that confusion has a distinct display, the authors review evidence showing distinct displays for 3 self-conscious emotions (embarrassment, shame, and pride), 5 positive emotions (amusement, desire, happiness, love, interest), and sympathy and compassion. Finally, the authors offer a functional definition of emotion to integrate these findings on "new" displays and emotions.

  6. The impact of assay technology as applied to safety assessment in reducing compound attrition in drug discovery.

    PubMed

    Thomas, Craig E; Will, Yvonne

    2012-02-01

    Attrition in the drug industry due to safety findings remains high and requires a shift in the current safety testing paradigm. Many companies are now positioning safety assessment at each stage of the drug development process, including discovery, where an early perspective on potential safety issues is sought, often at chemical scaffold level, using a variety of emerging technologies. Given the lengthy development time frames of drugs in the pharmaceutical industry, the authors believe that the impact of new technologies on attrition is best measured as a function of the quality and timeliness of candidate compounds entering development. The authors provide an overview of in silico and in vitro models, as well as more complex approaches such as 'omics,' and where they are best positioned within the drug discovery process. It is important to take away that not all technologies should be applied to all projects. Technologies vary widely in their validation state, throughput and cost. A thoughtful combination of validated and emerging technologies is crucial in identifying the most promising candidates to move to proof-of-concept testing in humans. In spite of the challenges inherent in applying new technologies to drug discovery, the successes and recognition that we cannot continue to rely on safety assessment practices used for decades have led to rather dramatic strategy shifts and fostered partnerships across government agencies and industry. We are optimistic that these efforts will ultimately benefit patients by delivering effective and safe medications in a timely fashion.

  7. The center for causal discovery of biomedical knowledge from big data.

    PubMed

    Cooper, Gregory F; Bahar, Ivet; Becich, Michael J; Benos, Panayiotis V; Berg, Jeremy; Espino, Jeremy U; Glymour, Clark; Jacobson, Rebecca Crowley; Kienholz, Michelle; Lee, Adrian V; Lu, Xinghua; Scheines, Richard

    2015-11-01

    The Big Data to Knowledge (BD2K) Center for Causal Discovery is developing and disseminating an integrated set of open source tools that support causal modeling and discovery of biomedical knowledge from large and complex biomedical datasets. The Center integrates teams of biomedical and data scientists focused on the refinement of existing and the development of new constraint-based and Bayesian algorithms based on causal Bayesian networks, the optimization of software for efficient operation in a supercomputing environment, and the testing of algorithms and software developed using real data from 3 representative driving biomedical projects: cancer driver mutations, lung disease, and the functional connectome of the human brain. Associated training activities provide both biomedical and data scientists with the knowledge and skills needed to apply and extend these tools. Collaborative activities with the BD2K Consortium further advance causal discovery tools and integrate tools and resources developed by other centers. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association.All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Molecular dynamics simulations and novel drug discovery.

    PubMed

    Liu, Xuewei; Shi, Danfeng; Zhou, Shuangyan; Liu, Hongli; Liu, Huanxiang; Yao, Xiaojun

    2018-01-01

    Molecular dynamics (MD) simulations can provide not only plentiful dynamical structural information on biomacromolecules but also a wealth of energetic information about protein and ligand interactions. Such information is very important to understanding the structure-function relationship of the target and the essence of protein-ligand interactions and to guiding the drug discovery and design process. Thus, MD simulations have been applied widely and successfully in each step of modern drug discovery. Areas covered: In this review, the authors review the applications of MD simulations in novel drug discovery, including the pathogenic mechanisms of amyloidosis diseases, virtual screening and the interaction mechanisms between drugs and targets. Expert opinion: MD simulations have been used widely in investigating the pathogenic mechanisms of diseases caused by protein misfolding, in virtual screening, and in investigating drug resistance mechanisms caused by mutations of the target. These issues are very difficult to solve by experimental methods alone. Thus, in the future, MD simulations will have wider application with the further improvement of computational capacity and the development of better sampling methods and more accurate force fields together with more efficient analysis methods.

  9. No wisdom in the crowd: genome annotation in the era of big data - current status and future prospects.

    PubMed

    Danchin, Antoine; Ouzounis, Christos; Tokuyasu, Taku; Zucker, Jean-Daniel

    2018-07-01

    Science and engineering rely on the accumulation and dissemination of knowledge to make discoveries and create new designs. Discovery-driven genome research rests on knowledge passed on via gene annotations. In response to the deluge of sequencing big data, standard annotation practice employs automated procedures that rely on majority rules. We argue this hinders progress through the generation and propagation of errors, leading investigators into blind alleys. More subtly, this inductive process discourages the discovery of novelty, which remains essential in biological research and reflects the nature of biology itself. Annotation systems, rather than being repositories of facts, should be tools that support multiple modes of inference. By combining deduction, induction and abduction, investigators can generate hypotheses when accurate knowledge is extracted from model databases. A key stance is to depart from 'the sequence tells the structure tells the function' fallacy, placing function first. We illustrate our approach with examples of critical or unexpected pathways, using MicroScope to demonstrate how tools can be implemented following the principles we advocate. We end with a challenge to the reader. © 2018 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.

  10. 49 CFR 31.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 1 2013-10-01 2013-10-01 false Discovery. 31.21 Section 31.21 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

  11. 49 CFR 31.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 1 2012-10-01 2012-10-01 false Discovery. 31.21 Section 31.21 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

  12. 49 CFR 31.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 1 2011-10-01 2011-10-01 false Discovery. 31.21 Section 31.21 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

  13. 49 CFR 31.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 1 2014-10-01 2014-10-01 false Discovery. 31.21 Section 31.21 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

  14. The discovery of the prokaryotic cytoskeleton: 25th anniversary.

    PubMed

    Erickson, Harold P

    2017-02-01

    The year 2017 marks the 25th anniversary of the discovery of homologues of tubulin and actin in prokaryotes. Before 1992, it was largely accepted that tubulin and actin were unique to eukaryotes. Then three laboratories independently discovered that FtsZ, a protein already known as a key player in bacterial cytokinesis, had the "tubulin signature sequence" present in all α-, β-, and γ-tubulins. That same year, three candidates for bacterial actins were discovered in silico. X-ray crystal structures have since confirmed multiple bacterial proteins to be homologues of eukaryotic tubulin and actin. Tubulin and actin were apparently derived from bacterial precursors that had already evolved a wide range of cytoskeletal functions. © 2017 Erickson. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  15. 45 CFR 79.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Discovery. 79.21 Section 79.21 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PROGRAM FRAUD CIVIL REMEDIES § 79.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  16. 46 CFR 550.502 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 9 2011-10-01 2011-10-01 false Discovery. 550.502 Section 550.502 Shipping FEDERAL... Proceedings § 550.502 Discovery. The Commission may authorize a party to a proceeding to use depositions, written interrogatories, and discovery procedures that, to the extent practicable, are in conformity with...

  17. 46 CFR 550.502 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 9 2014-10-01 2014-10-01 false Discovery. 550.502 Section 550.502 Shipping FEDERAL... Proceedings § 550.502 Discovery. The Commission may authorize a party to a proceeding to use depositions, written interrogatories, and discovery procedures that, to the extent practicable, are in conformity with...

  18. 22 CFR 35.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Discovery. 35.21 Section 35.21 Foreign Relations DEPARTMENT OF STATE CLAIMS AND STOLEN PROPERTY PROGRAM FRAUD CIVIL REMEDIES § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  19. 10 CFR 1013.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 4 2012-01-01 2012-01-01 false Discovery. 1013.21 Section 1013.21 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) PROGRAM FRAUD CIVIL REMEDIES AND PROCEDURES § 1013.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

  20. 45 CFR 79.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 1 2014-10-01 2014-10-01 false Discovery. 79.21 Section 79.21 Public Welfare Department of Health and Human Services GENERAL ADMINISTRATION PROGRAM FRAUD CIVIL REMEDIES § 79.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  1. 28 CFR 71.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Discovery. 71.21 Section 71.21 Judicial... REMEDIES ACT OF 1986 Implementation for Actions Initiated by the Department of Justice § 71.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  2. 10 CFR 1013.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 4 2013-01-01 2013-01-01 false Discovery. 1013.21 Section 1013.21 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) PROGRAM FRAUD CIVIL REMEDIES AND PROCEDURES § 1013.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

  3. 22 CFR 35.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Discovery. 35.21 Section 35.21 Foreign Relations DEPARTMENT OF STATE CLAIMS AND STOLEN PROPERTY PROGRAM FRAUD CIVIL REMEDIES § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  4. 10 CFR 1013.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Discovery. 1013.21 Section 1013.21 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) PROGRAM FRAUD CIVIL REMEDIES AND PROCEDURES § 1013.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

  5. 45 CFR 79.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 1 2013-10-01 2013-10-01 false Discovery. 79.21 Section 79.21 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PROGRAM FRAUD CIVIL REMEDIES § 79.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  6. 28 CFR 71.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Discovery. 71.21 Section 71.21 Judicial... REMEDIES ACT OF 1986 Implementation for Actions Initiated by the Department of Justice § 71.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  7. 10 CFR 1013.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 4 2014-01-01 2014-01-01 false Discovery. 1013.21 Section 1013.21 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) PROGRAM FRAUD CIVIL REMEDIES AND PROCEDURES § 1013.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

  8. 7 CFR 1.322 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 1 2013-01-01 2013-01-01 false Discovery. 1.322 Section 1.322 Agriculture Office of... Under the Program Fraud Civil Remedies Act of 1986 § 1.322 Discovery. (a) The following types of discovery are authorized: (1) Requests for production, inspection and photocopying of documents; (2...

  9. 45 CFR 79.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 1 2011-10-01 2011-10-01 false Discovery. 79.21 Section 79.21 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PROGRAM FRAUD CIVIL REMEDIES § 79.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  10. 7 CFR 1.322 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 1 2014-01-01 2014-01-01 false Discovery. 1.322 Section 1.322 Agriculture Office of... Under the Program Fraud Civil Remedies Act of 1986 § 1.322 Discovery. (a) The following types of discovery are authorized: (1) Requests for production, inspection and photocopying of documents; (2...

  11. 45 CFR 79.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 1 2012-10-01 2012-10-01 false Discovery. 79.21 Section 79.21 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PROGRAM FRAUD CIVIL REMEDIES § 79.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  12. 28 CFR 71.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Discovery. 71.21 Section 71.21 Judicial... REMEDIES ACT OF 1986 Implementation for Actions Initiated by the Department of Justice § 71.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  13. 7 CFR 1.322 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 1 2011-01-01 2011-01-01 false Discovery. 1.322 Section 1.322 Agriculture Office of... Under the Program Fraud Civil Remedies Act of 1986 § 1.322 Discovery. (a) The following types of discovery are authorized: (1) Requests for production, inspection and photocopying of documents; (2...

  14. 22 CFR 35.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Discovery. 35.21 Section 35.21 Foreign Relations DEPARTMENT OF STATE CLAIMS AND STOLEN PROPERTY PROGRAM FRAUD CIVIL REMEDIES § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  15. 46 CFR 550.502 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 9 2012-10-01 2012-10-01 false Discovery. 550.502 Section 550.502 Shipping FEDERAL... Proceedings § 550.502 Discovery. The Commission may authorize a party to a proceeding to use depositions, written interrogatories, and discovery procedures that, to the extent practicable, are in conformity with...

  16. 7 CFR 1.322 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 1 2012-01-01 2012-01-01 false Discovery. 1.322 Section 1.322 Agriculture Office of... Under the Program Fraud Civil Remedies Act of 1986 § 1.322 Discovery. (a) The following types of discovery are authorized: (1) Requests for production, inspection and photocopying of documents; (2...

  17. 28 CFR 71.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Discovery. 71.21 Section 71.21 Judicial... REMEDIES ACT OF 1986 Implementation for Actions Initiated by the Department of Justice § 71.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  18. 22 CFR 35.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Discovery. 35.21 Section 35.21 Foreign Relations DEPARTMENT OF STATE CLAIMS AND STOLEN PROPERTY PROGRAM FRAUD CIVIL REMEDIES § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  19. 46 CFR 550.502 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 9 2013-10-01 2013-10-01 false Discovery. 550.502 Section 550.502 Shipping FEDERAL... Proceedings § 550.502 Discovery. The Commission may authorize a party to a proceeding to use depositions, written interrogatories, and discovery procedures that, to the extent practicable, are in conformity with...

  20. 49 CFR 821.55 - Complaint, answer to complaint, motions and discovery.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... and upon just and reasonable terms. (d) Discovery. Discovery is authorized in proceedings governed by...) NATIONAL TRANSPORTATION SAFETY BOARD RULES OF PRACTICE IN AIR SAFETY PROCEEDINGS Special Rules Applicable... to complaint, motions and discovery. (a) Complaint. In proceedings governed by this subpart, the...

  1. 46 CFR 550.502 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 9 2010-10-01 2010-10-01 false Discovery. 550.502 Section 550.502 Shipping FEDERAL... Proceedings § 550.502 Discovery. The Commission may authorize a party to a proceeding to use depositions, written interrogatories, and discovery procedures that, to the extent practicable, are in conformity with...

  2. 22 CFR 35.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Discovery. 35.21 Section 35.21 Foreign Relations DEPARTMENT OF STATE CLAIMS AND STOLEN PROPERTY PROGRAM FRAUD CIVIL REMEDIES § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  3. 10 CFR 1013.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Discovery. 1013.21 Section 1013.21 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) PROGRAM FRAUD CIVIL REMEDIES AND PROCEDURES § 1013.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

  4. 7 CFR 1.322 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Discovery. 1.322 Section 1.322 Agriculture Office of... Under the Program Fraud Civil Remedies Act of 1986 § 1.322 Discovery. (a) The following types of discovery are authorized: (1) Requests for production, inspection and photocopying of documents; (2...

  5. 28 CFR 71.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Discovery. 71.21 Section 71.21 Judicial... REMEDIES ACT OF 1986 Implementation for Actions Initiated by the Department of Justice § 71.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

  6. [The methods of Western medicine in on ancient medicine].

    PubMed

    Ban, Deokjin

    2010-06-30

    The treatise On Ancient Medicine attests that questions of method were being debated both in medicine and in philosophy and is important evidence of cross-discipline methodological controversy. The treatise On Ancient Medicine is the first attempt in the history of Greek thought to provide a detailed account of the development of a science from a starting point in observation and experience. The author of it criticizes philosophical physicians who attempt to systematized medicine by reducing it to the interaction of one or more of the opposites hot, cold, wet, and dry, factors. He regards the theory of his opponents as hypothesis(hypothesis). Medicine has long been in possession of both an archē and a hodos, a principle and a method, which have enabled it to make discoveries over a long period of time. As far as method is concerned, the traditional science of medicine attained the knowledge of the visible by starting from observation and experience, but it recommended the use of reasoning and analogies with familiar objects as a means of learning about the invisible. It also utilized inference from the visible to the visible(epilogismos) and inference from the visible to the invisible(analogismos). The use of analogy as a means of learning about the obscure was also part of the common heritage of early philosophy and medicine. But the author's use of the analogical method distinguishes it from Empedocles' well-known analogy comparisons of the eye to a lantern and the process of respiration to the operations of a clepsydra. According to the author, traditional science of medicine used functional analogy like wine example and cheese example to know the function of humors within the body and utilized structured analogy like a tube example and a cupping instrument example to acknowledge an organ or structure within the body. But the author didn't distinguish between the claim that medicine has a systematic method of making discoveries and very different claim that it has a systematic method of treatment. The reason for this is that he thought that discoveries are the end point of the method of investigation and the starting point of the procedures used in treatment.

  7. 78 FR 37261 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-20

    ... Change Relating to Amendments to the Discovery Guide Used in Customer Arbitration Proceedings June 13... Discovery Guide (``Guide'') used in customer arbitration proceedings to provide general guidance on electronic discovery (``e-discovery'') issues and product cases and to clarify the existing provision...

  8. 34 CFR 33.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 1 2013-07-01 2013-07-01 false Discovery. 33.21 Section 33.21 Education Office of the Secretary, Department of Education PROGRAM FRAUD CIVIL REMEDIES ACT § 33.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying...

  9. 34 CFR 33.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 1 2012-07-01 2012-07-01 false Discovery. 33.21 Section 33.21 Education Office of the Secretary, Department of Education PROGRAM FRAUD CIVIL REMEDIES ACT § 33.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying...

  10. 29 CFR 22.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 1 2012-07-01 2012-07-01 false Discovery. 22.21 Section 22.21 Labor Office of the Secretary of Labor PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 22.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  11. 20 CFR 355.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 20 Employees' Benefits 1 2014-04-01 2012-04-01 true Discovery. 355.21 Section 355.21 Employees... UNDER THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 355.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  12. 34 CFR 33.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 1 2014-07-01 2014-07-01 false Discovery. 33.21 Section 33.21 Education Office of the Secretary, Department of Education PROGRAM FRAUD CIVIL REMEDIES ACT § 33.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying...

  13. 6 CFR 13.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 6 Domestic Security 1 2014-01-01 2014-01-01 false Discovery. 13.21 Section 13.21 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY PROGRAM FRAUD CIVIL REMEDIES § 13.21 Discovery. (a) In general. (1) The following types of discovery are authorized: (i) Requests for production of...

  14. 29 CFR 22.21 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 1 2014-07-01 2013-07-01 true Discovery. 22.21 Section 22.21 Labor Office of the Secretary of Labor PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 22.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  15. 6 CFR 13.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 6 Domestic Security 1 2011-01-01 2011-01-01 false Discovery. 13.21 Section 13.21 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY PROGRAM FRAUD CIVIL REMEDIES § 13.21 Discovery. (a) In general. (1) The following types of discovery are authorized: (i) Requests for production of...

  16. 20 CFR 355.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 1 2011-04-01 2011-04-01 false Discovery. 355.21 Section 355.21 Employees... UNDER THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 355.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  17. 41 CFR 105-70.021 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 41 Public Contracts and Property Management 3 2013-07-01 2013-07-01 false Discovery. 105-70.021...-IMPLEMENTATION OF THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 105-70.021 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  18. 12 CFR 308.520 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 5 2013-01-01 2013-01-01 false Discovery. 308.520 Section 308.520 Banks and... PROCEDURE Program Fraud Civil Remedies and Procedures § 308.520 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  19. 12 CFR 308.520 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 5 2012-01-01 2012-01-01 false Discovery. 308.520 Section 308.520 Banks and... PROCEDURE Program Fraud Civil Remedies and Procedures § 308.520 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  20. 6 CFR 13.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 6 Domestic Security 1 2012-01-01 2012-01-01 false Discovery. 13.21 Section 13.21 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY PROGRAM FRAUD CIVIL REMEDIES § 13.21 Discovery. (a) In general. (1) The following types of discovery are authorized: (i) Requests for production of...

  1. 29 CFR 22.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 1 2013-07-01 2013-07-01 false Discovery. 22.21 Section 22.21 Labor Office of the Secretary of Labor PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 22.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  2. 34 CFR 33.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 1 2011-07-01 2011-07-01 false Discovery. 33.21 Section 33.21 Education Office of the Secretary, Department of Education PROGRAM FRAUD CIVIL REMEDIES ACT § 33.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying...

  3. 20 CFR 355.21 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 20 Employees' Benefits 1 2012-04-01 2012-04-01 false Discovery. 355.21 Section 355.21 Employees... UNDER THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 355.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  4. 12 CFR 308.520 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 5 2014-01-01 2014-01-01 false Discovery. 308.520 Section 308.520 Banks and... PROCEDURE Program Fraud Civil Remedies and Procedures § 308.520 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  5. 41 CFR 105-70.021 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 41 Public Contracts and Property Management 3 2011-01-01 2011-01-01 false Discovery. 105-70.021...-IMPLEMENTATION OF THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 105-70.021 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  6. 41 CFR 105-70.021 - Discovery.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 41 Public Contracts and Property Management 3 2014-01-01 2014-01-01 false Discovery. 105-70.021...-IMPLEMENTATION OF THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 105-70.021 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  7. 6 CFR 13.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 6 Domestic Security 1 2013-01-01 2013-01-01 false Discovery. 13.21 Section 13.21 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY PROGRAM FRAUD CIVIL REMEDIES § 13.21 Discovery. (a) In general. (1) The following types of discovery are authorized: (i) Requests for production of...

  8. 41 CFR 105-70.021 - Discovery.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 41 Public Contracts and Property Management 3 2012-01-01 2012-01-01 false Discovery. 105-70.021...-IMPLEMENTATION OF THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 105-70.021 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  9. 29 CFR 22.21 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 1 2011-07-01 2011-07-01 false Discovery. 22.21 Section 22.21 Labor Office of the Secretary of Labor PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 22.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  10. 20 CFR 355.21 - Discovery.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 20 Employees' Benefits 1 2013-04-01 2012-04-01 true Discovery. 355.21 Section 355.21 Employees... UNDER THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 355.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  11. 12 CFR 308.520 - Discovery.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 4 2011-01-01 2011-01-01 false Discovery. 308.520 Section 308.520 Banks and... PROCEDURE Program Fraud Civil Remedies and Procedures § 308.520 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  12. 20 CFR 355.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false Discovery. 355.21 Section 355.21 Employees... UNDER THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 355.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  13. 34 CFR 33.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false Discovery. 33.21 Section 33.21 Education Office of the Secretary, Department of Education PROGRAM FRAUD CIVIL REMEDIES ACT § 33.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying...

  14. 45 CFR 160.516 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Discovery. 160.516 Section 160.516 Public Welfare... ADMINISTRATIVE REQUIREMENTS Procedures for Hearings § 160.516 Discovery. (a) A party may make a request to... forms of discovery, other than those permitted under paragraph (a) of this section, are not authorized...

  15. 12 CFR 308.520 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Discovery. 308.520 Section 308.520 Banks and... PROCEDURE Program Fraud Civil Remedies and Procedures § 308.520 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  16. 29 CFR 22.21 - Discovery.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 1 2010-07-01 2010-07-01 true Discovery. 22.21 Section 22.21 Labor Office of the Secretary of Labor PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 22.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

  17. The varied functions of aluminium-activated malate transporters-much more than aluminium resistance.

    PubMed

    Palmer, Antony J; Baker, Alison; Muench, Stephen P

    2016-06-15

    The ALMT (aluminium-activated malate transporter) family comprises a functionally diverse but structurally similar group of ion channels. They are found ubiquitously in plant species, expressed throughout different tissues, and located in either the plasma membrane or tonoplast. The first family member identified was TaALMT1, discovered in wheat root tips, which was found to be involved in aluminium resistance by means of malate exudation into the soil. However, since this discovery other family members have been shown to have many other functions such as roles in stomatal opening, general anionic homoeostasis, and in economically valuable traits such as fruit flavour. Recent evidence has also shown that ALMT proteins can act as key molecular actors in GABA (γ-aminobutyric acid) signalling, the first evidence that GABA can act as a signal transducer in plants. © 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  18. 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.

  19. Bioinformatics in translational drug discovery.

    PubMed

    Wooller, Sarah K; Benstead-Hume, Graeme; Chen, Xiangrong; Ali, Yusuf; Pearl, Frances M G

    2017-08-31

    Bioinformatics approaches are becoming ever more essential in translational drug discovery both in academia and within the pharmaceutical industry. Computational exploitation of the increasing volumes of data generated during all phases of drug discovery is enabling key challenges of the process to be addressed. Here, we highlight some of the areas in which bioinformatics resources and methods are being developed to support the drug discovery pipeline. These include the creation of large data warehouses, bioinformatics algorithms to analyse 'big data' that identify novel drug targets and/or biomarkers, programs to assess the tractability of targets, and prediction of repositioning opportunities that use licensed drugs to treat additional indications. © 2017 The Author(s).

  20. New Discoveries about Dinosaurs: Separating the Facts from the News.

    ERIC Educational Resources Information Center

    Padian, Kevin

    1988-01-01

    Reviews discoveries and reports of dinosaurs to help put them into paleontological perspective. Proposes that discoveries not be announced from the field, but submitted to professional evaluation and peer review before release to the public. (Author/RT)

  1. The cybernetics of TNF: Old views and newer ones.

    PubMed

    Wallach, David

    2016-02-01

    The proinflammatory cytokine tumor necrosis factor (TNF) orchestrates complex multicellular processes through a wide variety of changes that it induces in cell functions. At various stages of the study of TNF, attention has been drawn to one of three different modes of its action. The work that led to the discovery of this cytokine addressed situations in which it inflicts massive damage to tissues through a mode of action that appeared to be unrestricted. In the years that followed, attention was drawn to the existence of negative feedback mechanisms that do restrict TNF formation and function, and of reciprocal mechanisms for negatively regulating TNF-induced gene activation and of cell death. Most recently, the discovery of the critical role of TNF in chronic inflammatory diseases directed attention to the ability of TNF also to act with no apparent time restriction. Major gaps still remain in our knowledge of the cellular and molecular basis for these three modes of TNF action. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. Simulation with quantum mechanics/molecular mechanics for drug discovery.

    PubMed

    Barbault, Florent; Maurel, François

    2015-10-01

    Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

  3. Simulation with quantum mechanics/molecular mechanics for drug discovery.

    PubMed

    Barbault, Florent; Maurel, François

    2015-08-08

    Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. Areas covered: In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. Expert opinion: QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

  4. Anticoagulant factor V: factors affecting the integration of novel scientific discoveries into the broader framework.

    PubMed

    LaBonte, Michelle L

    2014-09-01

    Since its initial discovery in the 1940s, factor V has long been viewed as an important procoagulant protein in the coagulation cascade. However, in the later part of the 20th century, two different scientists proposed novel anticoagulant roles for factor V. Philip Majerus proposed the first anticoagulant function for factor V in 1983, yet ultimately it was not widely accepted by the broader scientific community. In contrast, Björn Dahlbäck proposed a different anticoagulant role for factor V in 1994. While this role was initially contested, it was ultimately accepted and integrated into the scientific framework. In this paper, I present a detailed historical account of these two anticoagulant discoveries and propose three key reasons why Dahlbäck's anticoagulant role for factor V was accepted whereas Majerus' proposed role was largely overlooked. Perhaps most importantly, Dahlbäck's proposed anticoagulant role was of great clinical interest because the discovery involved the study of an important subset of patients with thrombophilia. Soon after Dahlbäck's 1994 work, this patient population was shown to possess the factor V Leiden mutation. Also key in the ultimate acceptance of the second proposed anticoagulant role was the persistence of the scientist who made the discovery and the interest in and ability of others to replicate and reinforce this work. This analysis of two different yet similar discoveries sheds light on factors that play an important role in how new discoveries are incorporated into the existing scientific framework. Copyright © 2014 The Author. Published by Elsevier Ltd.. All rights reserved.

  5. Use of Computational Functional Genomics in Drug Discovery and Repurposing for Analgesic Indications.

    PubMed

    Lötsch, Jörn; Kringel, Dario

    2018-06-01

    The novel research area of functional genomics investigates biochemical, cellular, or physiological properties of gene products with the goal of understanding the relationship between the genome and the phenotype. These developments have made analgesic drug research a data-rich discipline mastered only by making use of parallel developments in computer science, including the establishment of knowledge bases, mining methods for big data, machine-learning, and artificial intelligence, (Table ) which will be exemplarily introduced in the following. © 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  6. Structure-based discovery and binding site analysis of histamine receptor ligands.

    PubMed

    Kiss, Róbert; Keserű, György M

    2016-12-01

    The application of structure-based drug discovery in histamine receptor projects was previously hampered by the lack of experimental structures. The publication of the first X-ray structure of the histamine H1 receptor has been followed by several successful virtual screens and binding site analysis studies of H1-antihistamines. This structure together with several other recently solved aminergic G-protein coupled receptors (GPCRs) enabled the development of more realistic homology models for H2, H3 and H4 receptors. Areas covered: In this paper, the authors review the development of histamine receptor models and their application in drug discovery. Expert opinion: In the authors' opinion, the application of atomistic histamine receptor models has played a significant role in understanding key ligand-receptor interactions as well as in the discovery of novel chemical starting points. The recently solved H1 receptor structure is a major milestone in structure-based drug discovery; however, our analysis also demonstrates that for building H3 and H4 receptor homology models, other GPCRs may be more suitable as templates. For these receptors, the authors envisage that the development of higher quality homology models will significantly contribute to the discovery and optimization of novel H3 and H4 ligands.

  7. 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'.

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

    ERIC Educational Resources Information Center

    Fawley, Nancy; Krysak, Nikki

    2014-01-01

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

  9. 16 CFR 3.31 - General discovery provisions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Administrative Law Judge may authorize for good cause additional discovery of materials in the possession...-testifying Commission employees, unless the Administrative Law Judge determines there is good cause to... discovery if the requesting party shows good cause, considering the limitations of paragraph (c)(2). The...

  10. 16 CFR 3.31 - General discovery provisions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Administrative Law Judge may authorize for good cause additional discovery of materials in the possession...-testifying Commission employees, unless the Administrative Law Judge determines there is good cause to... discovery if the requesting party shows good cause, considering the limitations of paragraph (c)(2). The...

  11. A resurgence in field research is essential to better understand the diversity, ecology, and evolution of microbial eukaryotes.

    PubMed

    Heger, Thierry J; Edgcomb, Virginia P; Kim, Eunsoo; Lukeš, Julius; Leander, Brian S; Yubuki, Naoji

    2014-01-01

    The discovery and characterization of protist communities from diverse environments are crucial for understanding the overall evolutionary history of life on earth. However, major questions about the diversity, ecology, and evolutionary history of protists remain unanswered, notably because data obtained from natural protist communities, especially of heterotrophic species, remain limited. In this review, we discuss the challenges associated with "field protistology", defined here as the exploration, characterization, and interpretation of microbial eukaryotic diversity within the context of natural environments or field experiments, and provide suggestions to help fill this important gap in knowledge. We also argue that increased efforts in field studies that combine molecular and microscopical methods offer the most promising path toward (1) the discovery of new lineages that expand the tree of eukaryotes; (2) the recognition of novel evolutionary patterns and processes; (3) the untangling of ecological interactions and functions, and their roles in larger ecosystem processes; and (4) the evaluation of protist adaptations to a changing climate. © 2013 The Author(s) Journal of Eukaryotic Microbiology © 2013 International Society of Protistologists.

  12. A system to build distributed multivariate models and manage disparate data sharing policies: implementation in the scalable national network for effectiveness research.

    PubMed

    Meeker, Daniella; Jiang, Xiaoqian; Matheny, Michael E; Farcas, Claudiu; D'Arcy, Michel; Pearlman, Laura; Nookala, Lavanya; Day, Michele E; Kim, Katherine K; Kim, Hyeoneui; Boxwala, Aziz; El-Kareh, Robert; Kuo, Grace M; Resnic, Frederic S; Kesselman, Carl; Ohno-Machado, Lucila

    2015-11-01

    Centralized and federated models for sharing data in research networks currently exist. To build multivariate data analysis for centralized networks, transfer of patient-level data to a central computation resource is necessary. The authors implemented distributed multivariate models for federated networks in which patient-level data is kept at each site and data exchange policies are managed in a study-centric manner. The objective was to implement infrastructure that supports the functionality of some existing research networks (e.g., cohort discovery, workflow management, and estimation of multivariate analytic models on centralized data) while adding additional important new features, such as algorithms for distributed iterative multivariate models, a graphical interface for multivariate model specification, synchronous and asynchronous response to network queries, investigator-initiated studies, and study-based control of staff, protocols, and data sharing policies. Based on the requirements gathered from statisticians, administrators, and investigators from multiple institutions, the authors developed infrastructure and tools to support multisite comparative effectiveness studies using web services for multivariate statistical estimation in the SCANNER federated network. The authors implemented massively parallel (map-reduce) computation methods and a new policy management system to enable each study initiated by network participants to define the ways in which data may be processed, managed, queried, and shared. The authors illustrated the use of these systems among institutions with highly different policies and operating under different state laws. Federated research networks need not limit distributed query functionality to count queries, cohort discovery, or independently estimated analytic models. Multivariate analyses can be efficiently and securely conducted without patient-level data transport, allowing institutions with strict local data storage requirements to participate in sophisticated analyses based on federated research networks. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association.

  13. Mathematical Modeling and Analysis of Mass Spectrometry Data in Workflows for the Discovery of Biomarkets in Breast Cancer

    DTIC Science & Technology

    2008-07-01

    Mass Spectrometry Data in Workflows for the Discovery of Biomarkets in Breast Cancer PRINCIPAL INVESTIGATOR: Vladimir Fokin, Ph.D... Biomarkets in Breast Cancer 5b. GRANT NUMBER W81XWH-07-1-0447 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Vladimir Fokin, Ph.D

  14. 78 FR 57916 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-20

    ... Relating to Amendments to the Discovery Guide Used in Customer Arbitration Proceedings, as Modified by... update the Discovery Guide (``Guide'') used in customer arbitration proceedings.\\1\\ According to FINRA, the Guide supplements the discovery rules contained in the FINRA Code of Arbitration Procedure for...

  15. Physicists and Astronomy--Will You Join the Dance?

    ERIC Educational Resources Information Center

    Harwit, Martin

    1981-01-01

    Focuses on past achievements of physicists beginning with the discovery of gaseous nebulae and listing seven commonly found characteristics of this and other observational discoveries which can foster further discovery. Suggests how theory is related to observation and where physicists make their greatest contributions to astronomy. (Author/JN)

  16. Psychological and Physiological Mechanisms by Which Discovery and Didactic Methods Work.

    ERIC Educational Resources Information Center

    Keegan, Mark

    1995-01-01

    Describes physiological, affective, and cognitive mechanisms by which didactic and discovery methods appear to work, as revealed by research literature. The optimal instructional method depends on the instructional objective, the educator's skills, and the nature of the students. Suggests more use of discovery methods. (69 references) (Author/MKR)

  17. 76 FR 56848 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Granting...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-14

    ... Rule Change To Amend FINRA Rule 9251 to Explicitly Protect From Discovery Those Documents That Federal... explicitly protect from discovery those documents that federal law prohibits FINRA from disclosing. The... the discovery phase of a disciplinary proceeding. The rule also explicitly shields certain types of...

  18. The EcoCyc database: reflecting new knowledge about Escherichia coli K-12.

    PubMed

    Keseler, Ingrid M; Mackie, Amanda; Santos-Zavaleta, Alberto; Billington, Richard; Bonavides-Martínez, César; Caspi, Ron; Fulcher, Carol; Gama-Castro, Socorro; Kothari, Anamika; Krummenacker, Markus; Latendresse, Mario; Muñiz-Rascado, Luis; Ong, Quang; Paley, Suzanne; Peralta-Gil, Martin; Subhraveti, Pallavi; Velázquez-Ramírez, David A; Weaver, Daniel; Collado-Vides, Julio; Paulsen, Ian; Karp, Peter D

    2017-01-04

    EcoCyc (EcoCyc.org) is a freely accessible, comprehensive database that collects and summarizes experimental data for Escherichia coli K-12, the best-studied bacterial model organism. New experimental discoveries about gene products, their function and regulation, new metabolic pathways, enzymes and cofactors are regularly added to EcoCyc. New SmartTable tools allow users to browse collections of related EcoCyc content. SmartTables can also serve as repositories for user- or curator-generated lists. EcoCyc now supports running and modifying E. coli metabolic models directly on the EcoCyc website. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  19. 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...

  20. The Europa Ocean Discovery mission

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

    Edwards, B.C.; Chyba, C.F.; Abshire, J.B.

    1997-06-01

    Since it was first proposed that tidal heating of Europa by Jupiter might lead to liquid water oceans below Europa`s ice cover, there has been speculation over the possible exobiological implications of such an ocean. Liquid water is the essential ingredient for life as it is known, and the existence of a second water ocean in the Solar System would be of paramount importance for seeking the origin and existence of life beyond Earth. The authors present here a Discovery-class mission concept (Europa Ocean Discovery) to determine the existence of a liquid water ocean on Europa and to characterize Europa`smore » surface structure. The technical goal of the Europa Ocean Discovery mission is to study Europa with an orbiting spacecraft. This goal is challenging but entirely feasible within the Discovery envelope. There are four key challenges: entering Europan orbit, generating power, surviving long enough in the radiation environment to return valuable science, and complete the mission within the Discovery program`s launch vehicle and budget constraints. The authors will present here a viable mission that meets these challenges.« less

  1. Illuminating Neural Circuits: From Molecules to MRI.

    PubMed

    Lee, Jin Hyung; Kreitzer, Anatol C; Singer, Annabelle C; Schiff, Nicholas D

    2017-11-08

    Neurological disease drives symptoms through pathological changes to circuit functions. Therefore, understanding circuit mechanisms that drive behavioral dysfunction is of critical importance for quantitative diagnosis and systematic treatment of neurological disease. Here, we describe key technologies that enable measurement and manipulation of neural activity and neural circuits. Applying these approaches led to the discovery of circuit mechanisms underlying pathological motor behavior, arousal regulation, and protein accumulation. Finally, we discuss how optogenetic functional magnetic resonance imaging reveals global scale circuit mechanisms, and how circuit manipulations could lead to new treatments of neurological diseases. Copyright © 2017 the authors 0270-6474/17/3710817-09$15.00/0.

  2. From basic to clinical neuropharmacology: targetophilia or pharmacodynamics?

    PubMed

    Green, A Richard; Aronson, Jeffrey K

    2012-06-01

    Historically, much drug discovery and development in psychopharmacology tended to be empirical. However, over the last 20 years it has primarily been target oriented, with synthesis and selection of compounds designed to act at a specific neurochemical site. Such compounds are then examined in functional animal models of disease. There is little evidence that this approach (which we call 'targetophilia') has enhanced the discovery process and some indications that it may have retarded it. A major problem is the weakness of many animal models in mimicking the disease and the lack of appropriate biochemical markers of drug action in animals and patients. In this review we argue that preclinical studies should be conducted as if they were clinical studies in design, analysis, and reporting, and that clinical pharmacologists should be involved at the earliest stages, to help ensure that animal models reflect as closely as possible the clinical disease. In addition, their familiarity with pharmacokinetic-pharmacodynamic integration (PK-PD) would help ensure that appropriate dosing and drug measurement techniques are applied to the discovery process, thereby producing results with relevance to therapeutics. Better integration of experimental and clinical pharmacologists early in the discovery process would allow observations in animals and patients to be quickly exchanged between the two disciplines. This non-linear approach to discovery used to be the way research proceeded, and it resulted in productivity that has never been bettered. It also follows that occasionally 'look-see' studies, a proven technique for drug discovery, deserve to be reintroduced. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

  3. Biophysical stimulation for in vitro engineering of functional cardiac tissues.

    PubMed

    Korolj, Anastasia; Wang, Erika Yan; Civitarese, Robert A; Radisic, Milica

    2017-07-01

    Engineering functional cardiac tissues remains an ongoing significant challenge due to the complexity of the native environment. However, our growing understanding of key parameters of the in vivo cardiac microenvironment and our ability to replicate those parameters in vitro are resulting in the development of increasingly sophisticated models of engineered cardiac tissues (ECT). This review examines some of the most relevant parameters that may be applied in culture leading to higher fidelity cardiac tissue models. These include the biochemical composition of culture media and cardiac lineage specification, co-culture conditions, electrical and mechanical stimulation, and the application of hydrogels, various biomaterials, and scaffolds. The review will also summarize some of the recent functional human tissue models that have been developed for in vivo and in vitro applications. Ultimately, the creation of sophisticated ECT that replicate native structure and function will be instrumental in advancing cell-based therapeutics and in providing advanced models for drug discovery and testing. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  4. 76 FR 2808 - Procedures for the Handling of Retaliation Complaints Under the Employee Protection Provisions of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-18

    ... has broad authority to limit discovery. The preamble noted, for example, that an ALJ may limit the... also noted that an ALJ may exercise discretion to limit discovery unless the complainant agrees to...; and that if a complainant seeks excessive or burdensome discovery under the ALJ's rules and procedures...

  5. Preference vs. Authority: A Comparison of Student Searching in a Subject-Specific Indexing and Abstracting Database and a Customized Discovery Layer

    ERIC Educational Resources Information Center

    Dahlen, Sarah P. C.; Hanson, Kathlene

    2017-01-01

    Discovery layers provide a simplified interface for searching library resources. Libraries with limited finances make decisions about retaining indexing and abstracting databases when similar information is available in discovery layers. These decisions should be informed by student success at finding quality information as well as satisfaction…

  6. Promise Fulfilled? An EBSCO Discovery Service Usability Study

    ERIC Educational Resources Information Center

    Williams, Sarah C.; Foster, Anita K.

    2011-01-01

    Discovery tools are the next phase of library search systems. Illinois State University's Milner Library implemented EBSCO Discovery Service in August 2010. The authors conducted usability studies on the system in the fall of 2010. The aims of the study were twofold: first, to determine how Milner users set about using the system in order to…

  7. 48 CFR 970.5227-11 - Patent rights-management and operating contracts, for-profit contractor, non-technology transfer.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... patent waiver regulations at 10 CFR part 784. (3) Invention means any invention or discovery which is or... Contracting Officer or authorized representative deems reasonably pertinent to the discovery or identification... Energy Act of 1954, as amended, may be asserted with respect to any invention or discovery made or...

  8. 48 CFR 970.5227-11 - Patent rights-management and operating contracts, for-profit contractor, non-technology transfer.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... patent waiver regulations at 10 CFR part 784. (3) Invention means any invention or discovery which is or... Contracting Officer or authorized representative deems reasonably pertinent to the discovery or identification... Energy Act of 1954, as amended, may be asserted with respect to any invention or discovery made or...

  9. 48 CFR 970.5227-11 - Patent rights-management and operating contracts, for-profit contractor, non-technology transfer.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... patent waiver regulations at 10 CFR part 784. (3) Invention means any invention or discovery which is or... Contracting Officer or authorized representative deems reasonably pertinent to the discovery or identification... Energy Act of 1954, as amended, may be asserted with respect to any invention or discovery made or...

  10. 48 CFR 970.5227-11 - Patent rights-management and operating contracts, for-profit contractor, non-technology transfer.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... patent waiver regulations at 10 CFR part 784. (3) Invention means any invention or discovery which is or... Contracting Officer or authorized representative deems reasonably pertinent to the discovery or identification... Energy Act of 1954, as amended, may be asserted with respect to any invention or discovery made or...

  11. Use of eQTL Analysis for the Discovery of Target Genes Identified by GWAS

    DTIC Science & Technology

    2014-04-01

    technology. Cases having a RIN number of 7.0 or greater were considered good quality. Once completed, the optimum set of 500 samples were then selected for...AD_________________ Award Number: W81XWH-11-1-0261 TITLE: Use of eQTL Analysis for the Discovery...Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and

  12. Modern approaches to accelerate discovery of new antischistosomal drugs.

    PubMed

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

    2016-06-01

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

  13. Anniversary of the discovery/isolation of the yeast centromere by Clarke and Carbon.

    PubMed

    Bloom, Kerry

    2015-05-01

    The first centromere was isolated 35 years ago by Louise Clarke and John Carbon from budding yeast. They embarked on their journey with rudimentary molecular tools (by today's standards) and little knowledge of the structure of a chromosome, much less the nature of a centromere. Their discovery opened up a new field, as centromeres have now been isolated from fungi and numerous plants and animals, including mammals. Budding yeast and several other fungi have small centromeres with short, well-defined sequences, known as point centromeres, whereas regional centromeres span several kilobases up to megabases and do not seem to have DNA sequence specificity. Centromeres are at the heart of artificial chromosomes, and we have seen the birth of synthetic centromeres in budding and fission yeast and mammals. The diversity in centromeres throughout phylogeny belie conserved functions that are only beginning to be understood. © 2015 Bloom. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  14. Target-Pathogen: a structural bioinformatic approach to prioritize drug targets in pathogens.

    PubMed

    Sosa, Ezequiel J; Burguener, Germán; Lanzarotti, Esteban; Defelipe, Lucas; Radusky, Leandro; Pardo, Agustín M; Marti, Marcelo; Turjanski, Adrián G; Fernández Do Porto, Darío

    2018-01-04

    Available genomic data for pathogens has created new opportunities for drug discovery and development to fight them, including new resistant and multiresistant strains. In particular structural data must be integrated with both, gene information and experimental results. In this sense, there is a lack of an online resource that allows genome wide-based data consolidation from diverse sources together with thorough bioinformatic analysis that allows easy filtering and scoring for fast target selection for drug discovery. Here, we present Target-Pathogen database (http://target.sbg.qb.fcen.uba.ar/patho), designed and developed as an online resource that allows the integration and weighting of protein information such as: function, metabolic role, off-targeting, structural properties including druggability, essentiality and omic experiments, to facilitate the identification and prioritization of candidate drug targets in pathogens. We include in the database 10 genomes of some of the most relevant microorganisms for human health (Mycobacterium tuberculosis, Mycobacterium leprae, Klebsiella pneumoniae, Plasmodium vivax, Toxoplasma gondii, Leishmania major, Wolbachia bancrofti, Trypanosoma brucei, Shigella dysenteriae and Schistosoma Smanosoni) and show its applicability. New genomes can be uploaded upon request. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  15. Dual Catalytic Activity of a Cytochrome P450 Controls Bifurcation at a Metabolic Branch Point of Alkaloid Biosynthesis in Rauwolfia serpentina.

    PubMed

    Dang, Thu-Thuy T; Franke, Jakob; Tatsis, Evangelos; O'Connor, Sarah E

    2017-08-01

    Plants create tremendous chemical diversity from a single biosynthetic intermediate. In plant-derived ajmalan alkaloid pathways, the biosynthetic intermediate vomilenine can be transformed into the anti-arrhythmic compound ajmaline, or alternatively, can isomerize to form perakine, an alkaloid with a structurally distinct scaffold. Here we report the discovery and characterization of vinorine hydroxylase, a cytochrome P450 enzyme that hydroxylates vinorine to form vomilenine, which was found to exist as a mixture of rapidly interconverting epimers. Surprisingly, this cytochrome P450 also catalyzes the non-oxidative isomerization of the ajmaline precursor vomilenine to perakine. This unusual dual catalytic activity of vinorine hydroxylase thereby provides a control mechanism for the bifurcation of these alkaloid pathway branches. This discovery highlights the unusual catalytic functionality that has evolved in plant pathways. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  16. Epigenome-wide association studies for cancer biomarker discovery in circulating cell-free DNA: technical advances and challenges.

    PubMed

    Tanić, Miljana; Beck, Stephan

    2017-02-01

    Since introducing the concept of epigenome-wide association studies (EWAS) in 2011, there has been a vast increase in the number of published EWAS studies in common diseases, including in cancer. These studies have increased our understanding of epigenetic events underlying carcinogenesis and have enabled the discovery of cancer-specific methylation biomarkers. In this mini-review, we have focused on the state of the art in EWAS applied to cell-free circulating DNA for epigenetic biomarker discovery in cancer and discussed associated technical advances and challenges, and our expectations for the future of the field. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  17. Graph theory analysis of complex brain networks: new concepts in brain mapping applied to neurosurgery.

    PubMed

    Hart, Michael G; Ypma, Rolf J F; Romero-Garcia, Rafael; Price, Stephen J; Suckling, John

    2016-06-01

    Neuroanatomy has entered a new era, culminating in the search for the connectome, otherwise known as the brain's wiring diagram. While this approach has led to landmark discoveries in neuroscience, potential neurosurgical applications and collaborations have been lagging. In this article, the authors describe the ideas and concepts behind the connectome and its analysis with graph theory. Following this they then describe how to form a connectome using resting state functional MRI data as an example. Next they highlight selected insights into healthy brain function that have been derived from connectome analysis and illustrate how studies into normal development, cognitive function, and the effects of synthetic lesioning can be relevant to neurosurgery. Finally, they provide a précis of early applications of the connectome and related techniques to traumatic brain injury, functional neurosurgery, and neurooncology.

  18. Potentials of single-cell biology in identification and validation of disease biomarkers.

    PubMed

    Niu, Furong; Wang, Diane C; Lu, Jiapei; Wu, Wei; Wang, Xiangdong

    2016-09-01

    Single-cell biology is considered a new approach to identify and validate disease-specific biomarkers. However, the concern raised by clinicians is how to apply single-cell measurements for clinical practice, translate the message of single-cell systems biology into clinical phenotype or explain alterations of single-cell gene sequencing and function in patient response to therapies. This study is to address the importance and necessity of single-cell gene sequencing in the identification and development of disease-specific biomarkers, the definition and significance of single-cell biology and single-cell systems biology in the understanding of single-cell full picture, the development and establishment of whole-cell models in the validation of targeted biological function and the figure and meaning of single-molecule imaging in single cell to trace intra-single-cell molecule expression, signal, interaction and location. We headline the important role of single-cell biology in the discovery and development of disease-specific biomarkers with a special emphasis on understanding single-cell biological functions, e.g. mechanical phenotypes, single-cell biology, heterogeneity and organization of genome function. We have reason to believe that such multi-dimensional, multi-layer, multi-crossing and stereoscopic single-cell biology definitely benefits the discovery and development of disease-specific biomarkers. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  19. Patient-derived tumour xenografts for breast cancer drug discovery.

    PubMed

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

    2016-12-01

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

  20. Biomarker discovery and development in pediatric critical care medicine

    PubMed Central

    Kaplan, Jennifer M.; Wong, Hector R.

    2010-01-01

    Objective To frame the general process of biomarker discovery and development, and to describe a proposal for the development of a multi-biomarker based risk model for pediatric septic shock. Data Source Narrative literature review and author generated data. Main Results Biomarkers can be grouped into four broad classes, based on the intended function: diagnostic, monitoring, surrogate, and stratification. Biomarker discovery and development requires a rigorous process, which is frequently not well followed in the critical care medicine literature. Very few biomarkers have successfully transitioned from the candidate stage to the true biomarker stage. There is great interest in developing diagnostic and stratification biomarkers for sepsis. Procalcitonin is currently the most promising diagnostic biomarker for sepsis. Recent evidence suggests that interleukin-8 can be used to stratify children with septic shock having a high likelihood of survival with standard care. Currently, there is a multi-institutional effort to develop a multi-biomarker based sepsis risk model intended to predict outcome and illness severity for individual children with septic shock. Conclusions Biomarker discovery and development is an important portion of the pediatric critical care medicine translational research agenda. This effort will require collaboration across multiple institutions and investigators. Rigorous conduct of biomarker-focused research holds the promise of transforming our ability to care for individual patients and our ability to conduct clinical trials in a more effective manner. PMID:20473243

  1. Ovarian Stem Cell Nests in Reproduction and Ovarian Aging.

    PubMed

    Ye, Haifeng; Zheng, Tuochen; Li, Wei; Li, Xiaoyan; Fu, Xinxin; Huang, Yaoqi; Hu, Chuan; Li, Jia; Huang, Jian; Liu, Zhengyv; Zheng, Liping; Zheng, Yuehui

    2017-01-01

    The fixed primordial follicles pool theory, which monopolized reproductive medicine for more than one hundred years, has been broken by the discovery, successful isolation and establishment of ovarian stem cells. It has brought more hope than ever of increasing the size of primordial follicle pool, improving ovarian function and delaying ovarian consenescence. Traditional view holds that stem cell aging contributes to the senility of body and organs. However, in the process of ovarian aging, the main factor leading to the decline of the reproductive function is the aging and degradation of ovarian stem cell nests, rather than the senescence of ovarian germ cells themselves. Recent studies have found that the immune system and circulatory system are involved in the formation of ovarian germline stem cell niches, as well as regulating the proliferation and differentiation of ovarian germline stem cells through cellular and hormonal signals. Therefore, we can improve ovarian function and delay ovarian aging by improving the immune system and circulatory system, which will provide an updated program for the treatment of premature ovarian failure (POF) and infertility. © 2017 The Author(s). Published by S. Karger AG, Basel.

  2. Animal coloration research: why it matters.

    PubMed

    Caro, Tim; Stoddard, Mary Caswell; Stuart-Fox, Devi

    2017-07-05

    While basic research on animal coloration is the theme of this special edition, here we highlight its applied significance for industry, innovation and society. Both the nanophotonic structures producing stunning optical effects and the colour perception mechanisms in animals are extremely diverse, having been honed over millions of years of evolution for many different purposes. Consequently, there is a wealth of opportunity for biomimetic and bioinspired applications of animal coloration research, spanning colour production, perception and function. Fundamental research on the production and perception of animal coloration is contributing to breakthroughs in the design of new materials (cosmetics, textiles, paints, optical coatings, security labels) and new technologies (cameras, sensors, optical devices, robots, biomedical implants). In addition, discoveries about the function of animal colour are influencing sport, fashion, the military and conservation. Understanding and applying knowledge of animal coloration is now a multidisciplinary exercise. Our goal here is to provide a catalyst for new ideas and collaborations between biologists studying animal coloration and researchers in other disciplines.This article is part of the themed issue 'Animal coloration: production, perception, function and application'. © 2017 The Author(s).

  3. [Physiology and disease of the endocrine function of the pancreas (author's transl)].

    PubMed

    Stubbe, P

    1980-12-01

    Qualitative and quantitative immunocytochemistry, electronmicroscopy and radio-immuno-assays led to the discovery of 5 pancreatic polypeptide hormones under physiological conditions. The active endocrine cells and the produced hormones are termed A, B, D, D1, and PP cell and glucagon, insulin, somatostatin, vasoactive intestinal polypeptide (VIP) and pancreatic polypeptide (PP) respectively. Beside the physiology of secretion and action a survey of pathological conditions in the paediatric age group is given. Insulin is the most important of pancreatic hormones in childhood. Therefore diagnosis and treatment of hyperinsulinism are described in extension.

  4. RNA interference for functional genomics and improvement of cotton (Gossypium species)

    USDA-ARS?s Scientific Manuscript database

    RNA interference (RNAi), is a powerful new technology in the discovery of genetic sequence functions, and has become a valuable tool for functional genomics of cotton (Gossypium ssp.). The rapid adoption of RNAi has replaced previous antisense technology. RNAi has aided in the discovery of function ...

  5. A Discovery Experiment: Carbon Dioxide Soap Bubble Dynamics.

    ERIC Educational Resources Information Center

    Millikan, Roger C.

    1978-01-01

    The observation of soap bubbles in a beaker of carbon dioxide gas helps students to feel the pleasure that comes from understanding nature, from applying that understanding to real problems, and from making unexpected discoveries that yield to analysis. (Author/BB)

  6. BLSSpeller: exhaustive comparative discovery of conserved cis-regulatory elements.

    PubMed

    De Witte, Dieter; Van de Velde, Jan; Decap, Dries; Van Bel, Michiel; Audenaert, Pieter; Demeester, Piet; Dhoedt, Bart; Vandepoele, Klaas; Fostier, Jan

    2015-12-01

    The accurate discovery and annotation of regulatory elements remains a challenging problem. The growing number of sequenced genomes creates new opportunities for comparative approaches to motif discovery. Putative binding sites are then considered to be functional if they are conserved in orthologous promoter sequences of multiple related species. Existing methods for comparative motif discovery usually rely on pregenerated multiple sequence alignments, which are difficult to obtain for more diverged species such as plants. As a consequence, misaligned regulatory elements often remain undetected. We present a novel algorithm that supports both alignment-free and alignment-based motif discovery in the promoter sequences of related species. Putative motifs are exhaustively enumerated as words over the IUPAC alphabet and screened for conservation using the branch length score. Additionally, a confidence score is established in a genome-wide fashion. In order to take advantage of a cloud computing infrastructure, the MapReduce programming model is adopted. The method is applied to four monocotyledon plant species and it is shown that high-scoring motifs are significantly enriched for open chromatin regions in Oryza sativa and for transcription factor binding sites inferred through protein-binding microarrays in O.sativa and Zea mays. Furthermore, the method is shown to recover experimentally profiled ga2ox1-like KN1 binding sites in Z.mays. BLSSpeller was written in Java. Source code and manual are available at http://bioinformatics.intec.ugent.be/blsspeller Klaas.Vandepoele@psb.vib-ugent.be or jan.fostier@intec.ugent.be. Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

  7. The future of crystallography in drug discovery

    PubMed Central

    Zheng, Heping; Hou, Jing; Zimmerman, Matthew D; Wlodawer, Alexander; Minor, Wladek

    2014-01-01

    Introduction X-ray crystallography plays an important role in structure-based drug design (SBDD), and accurate analysis of crystal structures of target macromolecules and macromolecule–ligand complexes is critical at all stages. However, whereas there has been significant progress in improving methods of structural biology, particularly in X-ray crystallography, corresponding progress in the development of computational methods (such as in silico high-throughput screening) is still on the horizon. Crystal structures can be overinterpreted and thus bias hypotheses and follow-up experiments. As in any experimental science, the models of macromolecular structures derived from X-ray diffraction data have their limitations, which need to be critically evaluated and well understood for structure-based drug discovery. Areas covered This review describes how the validity, accuracy and precision of a protein or nucleic acid structure determined by X-ray crystallography can be evaluated from three different perspectives: i) the nature of the diffraction experiment; ii) the interpretation of an electron density map; and iii) the interpretation of the structural model in terms of function and mechanism. The strategies to optimally exploit a macromolecular structure are also discussed in the context of ‘Big Data’ analysis, biochemical experimental design and structure-based drug discovery. Expert opinion Although X-ray crystallography is one of the most detailed ‘microscopes’ available today for examining macromolecular structures, the authors would like to re-emphasize that such structures are only simplified models of the target macromolecules. The authors also wish to reinforce the idea that a structure should not be thought of as a set of precise coordinates but rather as a framework for generating hypotheses to be explored. Numerous biochemical and biophysical experiments, including new diffraction experiments, can and should be performed to verify or falsify these hypotheses. X-ray crystallography will find its future application in drug discovery by the development of specific tools that would allow realistic interpretation of the outcome coordinates and/or support testing of these hypotheses. PMID:24372145

  8. 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.

  9. Cryptic iridescence in a fossil weevil generated by single diamond photonic crystals.

    PubMed

    McNamara, Maria E; Saranathan, Vinod; Locatelli, Emma R; Noh, Heeso; Briggs, Derek E G; Orr, Patrick J; Cao, Hui

    2014-11-06

    Nature's most spectacular colours originate in integumentary tissue architectures that scatter light via nanoscale modulations of the refractive index. The most intricate biophotonic nanostructures are three-dimensional crystals with opal, single diamond or single gyroid lattices. Despite intense interest in their optical and structural properties, the evolution of such nanostructures is poorly understood, due in part to a lack of data from the fossil record. Here, we report preservation of single diamond (Fd-3m) three-dimensional photonic crystals in scales of a 735,000 year old specimen of the brown Nearctic weevil Hypera diversipunctata from Gold Run, Canada, and in extant conspecifics. The preserved red to green structural colours exhibit near-field brilliancy yet are inconspicuous from afar; they most likely had cryptic functions in substrate matching. The discovery of pristine fossil examples indicates that the fossil record is likely to yield further data on the evolution of three-dimensional photonic nanostructures and their biological functions. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  10. Great Originals of Modern Physics

    ERIC Educational Resources Information Center

    Decker, Fred W.

    1972-01-01

    European travel can provide an intimate view of the implements and locales of great discoveries in physics for the knowledgeable traveler. The four museums at Cambridge, London, Remscheid-Lennep, and Munich display a full range of discovery apparatus in modern physics as outlined here. (Author/TS)

  11. Reflections on my journey in biomedical research: the art, science, and politics of advocacy.

    PubMed

    Slavkin, H C

    2013-01-01

    Scientific Discovery often reflects the art, science, and advocacy for biomedical research. Here the author reflects on selected highlights of discovery that contributed to several aspects of our understanding of craniofacial biology and craniofacial diseases and disorders.

  12. Introduction and historical perspective.

    PubMed

    Gunning, Peter

    2008-01-01

    Tropomyosin is a coiled coil dimer which forms a polymer along the major groove of the majority of actin filaments. It is therefore one of the two primary components of the actin filament. Our understanding of the biological function of tropomyosin has been driven almost entirely by its role in striated muscle. This reflects both its original discovery as part of the thin filament in skeletal muscle and its pivotal role in regulating muscle contraction. In contrast, its role in the function of the cytoskeleton of all cells has been poorly understood due, at least in part, to the technical challenge of deciphering the function of a large number of isoforms. This book has brought together many of the leading researchers who have defined the function of tropomyosin in both normal and pathological conditions. Each author brings their own perspective in a series of stand alone reviews of the areas of tropomyosin research they have played a major role in defining.

  13. Ghrelin and cancer progression.

    PubMed

    Lin, Tsung-Chieh; Hsiao, Michael

    2017-08-01

    Ghrelin is a small peptide with 28 amino acids, and has been characterized as the ligand of the growth hormone secretagogue receptor (GHSR). In addition to its original function in stimulating pituitary growth hormone release, ghrelin is multifunctional and plays a role in the regulation of energy balance, gastric acid release, appetite, insulin secretion, gastric motility and the turnover of gastric and intestinal mucosa. The discovery of ghrelin and GHSR expression beyond normal tissues suggests its role other than physiological function. Emerging evidences have revealed ghrelin's function in regulating several processes related to cancer progression, especially in metastasis and proliferation. We further show the relative GHRL and GHSR expression in pan-cancers from The Cancer Genome Atlas (TCGA), suggesting the potential pathological role of the axis in cancers. This review focuses on ghrelin's biological function in cancer progression, and reveals its clinical significance especially the impact on cancer patient outcome. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  14. Fire in the mind: changing understandings of fire in Western civilization.

    PubMed

    Pyne, Stephen J

    2016-06-05

    For most of human history, fire has been a pervasive presence in human life, and so also in human thought. This essay examines the ways in which fire has functioned intellectually in Western civilization as mythology, as religion, as natural philosophy and as modern science. The great phase change occurred with the development of industrial combustion; fire faded from quotidian life, which also removed it from the world of informing ideas. Beginning with the discovery of oxygen, fire as an organizing concept fragmented into various subdisciplines of natural science and forestry. The Anthropocene, however, may revive the intellectual role of fire as an informing idea or at least a narrative conceit.This article is part of the themed issue 'The interaction of fire and mankind'. © 2016 The Author(s).

  15. 16 CFR 1025.31 - General provisions governing discovery.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ...: (1) In general. Parties may obtain discovery regarding any matter, not privileged, which is within the Commission's statutory authority and is relevant to the subject matter involved in the proceedings... any discoverable matter. It is not ground for objection that the information sought will be...

  16. 16 CFR 1025.31 - General provisions governing discovery.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ...: (1) In general. Parties may obtain discovery regarding any matter, not privileged, which is within the Commission's statutory authority and is relevant to the subject matter involved in the proceedings... any discoverable matter. It is not ground for objection that the information sought will be...

  17. 16 CFR 1025.31 - General provisions governing discovery.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ...: (1) In general. Parties may obtain discovery regarding any matter, not privileged, which is within the Commission's statutory authority and is relevant to the subject matter involved in the proceedings... any discoverable matter. It is not ground for objection that the information sought will be...

  18. The Discovery of America

    ERIC Educational Resources Information Center

    Martin, Paul S.

    1973-01-01

    Discusses a model for explaining the spread of human population explosion on North American continent since its discovery 12,000 years ago. The model may help to map the spread of Homo sapiens throughout the New World by using the extinction chronology of the Pleistocene megafauna. (Author/PS)

  19. Progress in the development of animal models of acute kidney injury and its impact on drug discovery.

    PubMed

    Sanz, Ana B; Sanchez-Niño, María Dolores; Martín-Cleary, Catalina; Ortiz, Alberto; Ramos, Adrián M

    2013-07-01

    Acute kidney injury (AKI) is a clinical syndrome characterized by the acute loss of kidney function. AKI is increasingly frequent and is associated with impaired survival and chronic kidney disease progression. Experimental AKI models have contributed to a better understanding of pathophysiological mechanisms but they have not yet resulted in routine clinical application of novel therapeutic approaches. The authors present the advances in experimental AKI models over the last decade. Furthermore, the authors review their current and expected impact on novel drug discovery. New AKI models have been developed in rodents and non-rodents. Non-rodents allow the evaluation of specific aspects of AKI in both bigger animals and simpler organisms such as drosophila and zebrafish. New rodent models have recently reproduced described clinical entities, such as aristolochic and warfarin nephropathies, and have also provided better models for old entities such as thrombotic microangiopathy-induced AKI. Several therapies identified in animal models are now undergoing clinical trials in human AKI, including p53 RNAi and bone-marrow derived mesenchymal stem cells. It is conceivable that further refinement of animal models in combination with ongoing trials and novel trials based on already identified potential targets will eventually yield effective therapies for clinical AKI.

  20. Turning publicly available gene expression data into discoveries using gene set context analysis.

    PubMed

    Ji, Zhicheng; Vokes, Steven A; Dang, Chi V; Ji, Hongkai

    2016-01-08

    Gene Set Context Analysis (GSCA) is an open source software package to help researchers use massive amounts of publicly available gene expression data (PED) to make discoveries. Users can interactively visualize and explore gene and gene set activities in 25,000+ consistently normalized human and mouse gene expression samples representing diverse biological contexts (e.g. different cells, tissues and disease types, etc.). By providing one or multiple genes or gene sets as input and specifying a gene set activity pattern of interest, users can query the expression compendium to systematically identify biological contexts associated with the specified gene set activity pattern. In this way, researchers with new gene sets from their own experiments may discover previously unknown contexts of gene set functions and hence increase the value of their experiments. GSCA has a graphical user interface (GUI). The GUI makes the analysis convenient and customizable. Analysis results can be conveniently exported as publication quality figures and tables. GSCA is available at https://github.com/zji90/GSCA. This software significantly lowers the bar for biomedical investigators to use PED in their daily research for generating and screening hypotheses, which was previously difficult because of the complexity, heterogeneity and size of the data. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  1. G-quadruplex prediction in E. coli genome reveals a conserved putative G-quadruplex-Hairpin-Duplex switch.

    PubMed

    Kaplan, Oktay I; Berber, Burak; Hekim, Nezih; Doluca, Osman

    2016-11-02

    Many studies show that short non-coding sequences are widely conserved among regulatory elements. More and more conserved sequences are being discovered since the development of next generation sequencing technology. A common approach to identify conserved sequences with regulatory roles relies on topological changes such as hairpin formation at the DNA or RNA level. G-quadruplexes, non-canonical nucleic acid topologies with little established biological roles, are increasingly considered for conserved regulatory element discovery. Since the tertiary structure of G-quadruplexes is strongly dependent on the loop sequence which is disregarded by the generally accepted algorithm, we hypothesized that G-quadruplexes with similar topology and, indirectly, similar interaction patterns, can be determined using phylogenetic clustering based on differences in the loop sequences. Phylogenetic analysis of 52 G-quadruplex forming sequences in the Escherichia coli genome revealed two conserved G-quadruplex motifs with a potential regulatory role. Further analysis revealed that both motifs tend to form hairpins and G quadruplexes, as supported by circular dichroism studies. The phylogenetic analysis as described in this work can greatly improve the discovery of functional G-quadruplex structures and may explain unknown regulatory patterns. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

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

    PubMed

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

    2016-01-01

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

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

    PubMed

    Patel, Jigneshkumar

    2013-03-01

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

  4. Cognitive Neuroscience Discoveries and Educational Practices

    ERIC Educational Resources Information Center

    Sylwester, Robert

    2006-01-01

    In this article, the author describes seven movement-related areas of cognitive neuroscience research that will play key roles in shifting the current behavioral orientation of teaching and learning to an orientation that also incorporates cognitive neuroscience discoveries. These areas of brain research include: (1) mirroring system; (2) plastic…

  5. A Location Aware Middleware Framework for Collaborative Visual Information Discovery and Retrieval

    DTIC Science & Technology

    2017-09-14

    Information Discovery and Retrieval Andrew J.M. Compton Follow this and additional works at: https://scholar.afit.edu/etd Part of the Digital...and Dissertations by an authorized administrator of AFIT Scholar. For more information , please contact richard.mansfield@afit.edu. Recommended Citation...

  6. The Parallelism between Scientists' and Students' Resistance to New Scientific Ideas.

    ERIC Educational Resources Information Center

    Campanario, Juan Miguel

    2002-01-01

    Compares resistance by scientists to new ideas in scientific discovery with students' resistance to conceptual change in scientific learning. Studies the resistance by students to abandoning their misconceptions concerning scientific topics and the resistance by scientists to scientific discovery. (Contains 64 references.) (Author/YDS)

  7. 16 CFR 3.31 - General discovery provisions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., including the Bureau of Economics. The Administrative Law Judge may authorize for good cause additional... Judge determines there is good cause to provide such materials. The frequency or extent of use of the... Administrative Law Judge may nonetheless order discovery if the requesting party shows good cause, considering...

  8. 16 CFR 3.31 - General discovery provisions.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ..., including the Bureau of Economics. The Administrative Law Judge may authorize for good cause additional... Judge determines there is good cause to provide such materials. The frequency or extent of use of the... Administrative Law Judge may nonetheless order discovery if the requesting party shows good cause, considering...

  9. 16 CFR 3.31 - General discovery provisions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., including the Bureau of Economics. The Administrative Law Judge may authorize for good cause additional... Judge determines there is good cause to provide such materials. The frequency or extent of use of the... Administrative Law Judge may nonetheless order discovery if the requesting party shows good cause, considering...

  10. 16 CFR § 1025.31 - General provisions governing discovery.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ...: (1) In general. Parties may obtain discovery regarding any matter, not privileged, which is within the Commission's statutory authority and is relevant to the subject matter involved in the proceedings... any discoverable matter. It is not ground for objection that the information sought will be...

  11. Rethinking the Discovery Function of Proof within the Context of Proofs and Refutations

    ERIC Educational Resources Information Center

    Komatsu, Kotaro; Tsujiyama, Yosuke; Sakamaki, Aruta

    2014-01-01

    Proof and proving are important components of school mathematics and have multiple functions in mathematical practice. Among these functions of proof, this paper focuses on the discovery function that refers to invention of a new statement or conjecture by reflecting on or utilizing a constructed proof. Based on two cases in which eighth and ninth…

  12. 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.

  13. The Classes of Authoring Programs.

    ERIC Educational Resources Information Center

    Kozel, Kathy

    1997-01-01

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

  14. Accelerating glioblastoma drug discovery: Convergence of patient-derived models, genome editing and phenotypic screening.

    PubMed

    O'Duibhir, Eoghan; Carragher, Neil O; Pollard, Steven M

    2017-04-01

    Patients diagnosed with glioblastoma (GBM) continue to face a bleak prognosis. It is critical that new effective therapeutic strategies are developed. GBM stem cells have molecular hallmarks of neural stem and progenitor cells and it is possible to propagate both non-transformed normal neural stem cells and GBM stem cells, in defined, feeder-free, adherent culture. These primary stem cell lines provide an experimental model that is ideally suited to cell-based drug discovery or genetic screens in order to identify tumour-specific vulnerabilities. For many solid tumours, including GBM, the genetic disruptions that drive tumour initiation and growth have now been catalogued. CRISPR/Cas-based genome editing technologies have recently emerged, transforming our ability to functionally annotate the human genome. Genome editing opens prospects for engineering precise genetic changes in normal and GBM-derived neural stem cells, which will provide more defined and reliable genetic models, with critical matched pairs of isogenic cell lines. Generation of more complex alleles such as knock in tags or fluorescent reporters is also now possible. These new cellular models can be deployed in cell-based phenotypic drug discovery (PDD). Here we discuss the convergence of these advanced technologies (iPS cells, neural stem cell culture, genome editing and high content phenotypic screening) and how they herald a new era in human cellular genetics that should have a major impact in accelerating glioblastoma drug discovery. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  15. What is feasible with imaging human brain function and connectivity using functional magnetic resonance imaging.

    PubMed

    Ugurbil, Kamil

    2016-10-05

    When we consider all of the methods we employ to detect brain function, from electrophysiology to optical techniques to functional magnetic resonance imaging (fMRI), we do not really have a 'golden technique' that meets all of the needs for studying the brain. We have methods, each of which has significant limitations but provide often complimentary information. Clearly, there are many questions that need to be answered about fMRI, which unlike other methods, allows us to study the human brain. However, there are also extraordinary accomplishments or demonstration of the feasibility of reaching new and previously unexpected scales of function in the human brain. This article reviews some of the work we have pursued, often with extensive collaborations with other co-workers, towards understanding the underlying mechanisms of the methodology, defining its limitations, and developing solutions to advance it. No doubt, our knowledge of human brain function has vastly expanded since the introduction of fMRI. However, methods and instrumentation in this dynamic field have evolved to a state that discoveries about the human brain based on fMRI principles, together with information garnered at a much finer spatial and temporal scale through other methods, are poised to significantly accelerate in the next decade.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'. © 2016 The Author(s).

  16. Knowledge Discovery in Textual Documentation: Qualitative and Quantitative Analyses.

    ERIC Educational Resources Information Center

    Loh, Stanley; De Oliveira, Jose Palazzo M.; Gastal, Fabio Leite

    2001-01-01

    Presents an application of knowledge discovery in texts (KDT) concerning medical records of a psychiatric hospital. The approach helps physicians to extract knowledge about patients and diseases that may be used for epidemiological studies, for training professionals, and to support physicians to diagnose and evaluate diseases. (Author/AEF)

  17. Scientific Discoveries the Year I Was Born

    ERIC Educational Resources Information Center

    Cherif, Abour

    2012-01-01

    The author has successfully used a learning activity titled "The Year I Was Born" to motivate students to conduct historical research and present key scientific discoveries from their birth year. The activity promotes writing, helps students enhance their scientific literacy, and also improves their attitude toward the learning of science. As one…

  18. Discovery

    ERIC Educational Resources Information Center

    de Mestre, Neville

    2010-01-01

    All common fractions can be written in decimal form. In this Discovery article, the author suggests that teachers ask their students to calculate the decimals by actually doing the divisions themselves, and later on they can use a calculator to check their answers. This article presents a lesson based on the research of Bolt (1982).

  19. Staff Workshop: Exploring Science with Young Children

    ERIC Educational Resources Information Center

    Seefeldt, Carol; Rillero, Peter

    2005-01-01

    This article begins with a section entitled, "Involving Parents in Science Discovery" written by Carol Seefeldt. This section discusses staff workshop for exploring discovery science. Here, the author provides the staff workshop instructions. This is followed by a section entitled, "Exploring Science with Young Children" written by Peter Rillero.…

  20. 78 FR 12933 - Proceedings Before the Commodity Futures Trading Commission

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-26

    ... proceedings. These new amendments also provide that Judgment Officers may conduct sua sponte discovery in... discovery; (4) sound risk management practices; and (5) other public interest considerations. The amendments... representative capacity, it was done with full power and authority to do so; (C) To the best of his knowledge...

  1. 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…

  2. The Noble Gases in A-Level Chemistry.

    ERIC Educational Resources Information Center

    Marchant, G. W.

    1983-01-01

    Suggests two methods of developing the study of the noble gases: first, the discovery of the elements and recent discovery of xenon show the human face of chemistry (historical development); second, the properties of noble gas compounds (particularly xenon) can be used to test the framework of conventional chemistry. (Author/JM)

  3. Voltage-Gated Calcium Channels

    NASA Astrophysics Data System (ADS)

    Zamponi, Gerald Werner

    Voltage Gated Calcium Channels is the first comprehensive book in the calcium channel field, encompassing over thirty years of progress towards our understanding of calcium channel structure, function, regulation, physiology, pharmacology, and genetics. This book balances contributions from many of the leading authorities in the calcium channel field with fresh perspectives from risings stars in the area, taking into account the most recent literature and concepts. This is the only all-encompassing calcium channel book currently available, and is an essential resource for academic researchers at all levels in the areas neuroscience, biophysics, and cardiovascular sciences, as well as to researchers in the drug discovery area.

  4. Context and Relationships, Past and Present: The Role of Authority in Information Discovery

    ERIC Educational Resources Information Center

    Adamich, Tom

    2010-01-01

    This article provides an overview of and rationale for the use of authority in school libraries--from both an historical and current/future perspective. First, the importance of consistent, meaningful authority term context and form is discussed. Then, the exciting, yet challenging, role of authority in today's information world is…

  5. Modern Math: Discovery or Justification

    ERIC Educational Resources Information Center

    D'Amour, Gene

    1973-01-01

    Author introduces distinctions that occur between the inductive and deductive approaches to mathematical analysis thereby helping teachers, interested in innovative teaching methods, to understand more clearly the problems they are up against. (Author/RK)

  6. 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

  7. MutationAligner: a resource of recurrent mutation hotspots in protein domains in cancer.

    PubMed

    Gauthier, Nicholas Paul; Reznik, Ed; Gao, Jianjiong; Sumer, Selcuk Onur; Schultz, Nikolaus; Sander, Chris; Miller, Martin L

    2016-01-04

    The MutationAligner web resource, available at http://www.mutationaligner.org, enables discovery and exploration of somatic mutation hotspots identified in protein domains in currently (mid-2015) more than 5000 cancer patient samples across 22 different tumor types. Using multiple sequence alignments of protein domains in the human genome, we extend the principle of recurrence analysis by aggregating mutations in homologous positions across sets of paralogous genes. Protein domain analysis enhances the statistical power to detect cancer-relevant mutations and links mutations to the specific biological functions encoded in domains. We illustrate how the MutationAligner database and interactive web tool can be used to explore, visualize and analyze mutation hotspots in protein domains across genes and tumor types. We believe that MutationAligner will be an important resource for the cancer research community by providing detailed clues for the functional importance of particular mutations, as well as for the design of functional genomics experiments and for decision support in precision medicine. MutationAligner is slated to be periodically updated to incorporate additional analyses and new data from cancer genomics projects. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  8. Cerebral cartography and connectomics.

    PubMed

    Sporns, Olaf

    2015-05-19

    Cerebral cartography and connectomics pursue similar goals in attempting to create maps that can inform our understanding of the structural and functional organization of the cortex. Connectome maps explicitly aim at representing the brain as a complex network, a collection of nodes and their interconnecting edges. This article reflects on some of the challenges that currently arise in the intersection of cerebral cartography and connectomics. Principal challenges concern the temporal dynamics of functional brain connectivity, the definition of areal parcellations and their hierarchical organization into large-scale networks, the extension of whole-brain connectivity to cellular-scale networks, and the mapping of structure/function relations in empirical recordings and computational models. Successfully addressing these challenges will require extensions of methods and tools from network science to the mapping and analysis of human brain connectivity data. The emerging view that the brain is more than a collection of areas, but is fundamentally operating as a complex networked system, will continue to drive the creation of ever more detailed and multi-modal network maps as tools for on-going exploration and discovery in human connectomics. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  9. Organic Superconductor, Made without Metals.

    ERIC Educational Resources Information Center

    Science News, 1980

    1980-01-01

    The discovery of a superconducting organic compound is reported. The compound, (TMTSF)-2, has no metal in its composition, and the author believes that it is the precursor of a family of superconducting organics. (Author/SA)

  10. Research Review: I. Lunar Geology

    ERIC Educational Resources Information Center

    Jacobsen, Sally

    1972-01-01

    An interview with a scientist associated with the lunar rock analysis program in which discoveries concerning the moon and their contribution to the understanding of the origins of the earth-moon system are discussed. (Author/AL)

  11. The SULSA Assay Development Fund: accelerating translation of new biology from academia to pharma.

    PubMed

    McElroy, Stuart P; Jones, Philip S; Barrault, Denise V

    2017-02-01

    With industry increasingly sourcing preclinical drug discovery projects from academia it is important that new academic discoveries are enabled through translation with HTS-ready assays. However, many scientifically interesting, novel molecular targets lack associated high-quality, robust assays suitable for hit finding and development. To bridge this gap, the Scottish Universities Life Sciences Alliance (SULSA) established a fund to develop assays to meet quality criteria such as those of the European Lead Factory. A diverse project portfolio was quickly assembled, and a review of the learnings and successful outcomes showed this fund as a new highly cost-effective model for leveraging significant follow-on resources, training early-career scientists and establishing a culture of translational drug discovery in the academic community. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  12. Disease-in-a-dish: the contribution of patient-specific induced pluripotent stem cell technology to regenerative rehabilitation.

    PubMed

    Mack, David L; Guan, Xuan; Wagoner, Ashley; Walker, Stephen J; Childers, Martin K

    2014-11-01

    Advances in regenerative medicine technologies will lead to dramatic changes in how patients in rehabilitation medicine clinics are treated in the upcoming decades. The multidisciplinary field of regenerative medicine is developing new tools for disease modeling and drug discovery based on induced pluripotent stem cells. This approach capitalizes on the idea of personalized medicine by using the patient's own cells to discover new drugs, increasing the likelihood of a favorable outcome. The search for compounds that can correct disease defects in the culture dish is a conceptual departure from how drug screens were done in the past. This system proposes a closed loop from sample collection from the diseased patient, to in vitro disease model, to drug discovery and Food and Drug Administration approval, to delivering that drug back to the same patient. Here, recent progress in patient-specific induced pluripotent stem cell derivation, directed differentiation toward diseased cell types, and how those cells can be used for high-throughput drug screens are reviewed. Given that restoration of normal function is a driving force in rehabilitation medicine, the authors believe that this drug discovery platform focusing on phenotypic rescue will become a key contributor to therapeutic compounds in regenerative rehabilitation.

  13. Pituitary Medicine From Discovery to Patient-Focused Outcomes

    PubMed Central

    2016-01-01

    Context: This perspective traces a pipeline of discovery in pituitary medicine over the past 75 years. Objective: To place in context past advances and predict future changes in understanding pituitary pathophysiology and clinical care. Design: Author's perspective on reports of pituitary advances in the published literature. Setting: Clinical and translational Endocrinology. Outcomes: Discovery of the hypothalamic-pituitary axis and mechanisms for pituitary control, have culminated in exquisite understanding of anterior pituitary cell function and dysfunction. Challenges facing the discipline include fundamental understanding of pituitary adenoma pathogenesis leading to more effective treatments of inexorably growing and debilitating hormone secreting pituitary tumors as well as medical management of non-secreting pituitary adenomas. Newly emerging pituitary syndromes include those associated with immune-targeted cancer therapies and head trauma. Conclusions: Novel diagnostic techniques including imaging genomic, proteomic, and biochemical analyses will yield further knowledge to enable diagnosis of heretofore cryptic syndromes, as well as sub classifications of pituitary syndromes for personalized treatment approaches. Cost effective personalized approaches to precision therapy must demonstrate value, and will be empowered by multidisciplinary approaches to integrating complex subcellular information to identify therapeutic targets for enabling maximal outcomes. These goals will be challenging to attain given the rarity of pituitary disorders and the difficulty in conducting appropriately powered prospective trials. PMID:26908107

  14. Drug discovery for male subfertility using high-throughput screening: a new approach to an unsolved problem.

    PubMed

    Martins da Silva, Sarah J; Brown, Sean G; Sutton, Keith; King, Louise V; Ruso, Halil; Gray, David W; Wyatt, Paul G; Kelly, Mark C; Barratt, Christopher L R; Hope, Anthony G

    2017-05-01

    Can pharma drug discovery approaches be utilized to transform investigation into novel therapeutics for male infertility? High-throughput screening (HTS) is a viable approach to much-needed drug discovery for male factor infertility. There is both huge demand and a genuine clinical need for new treatment options for infertile men. However, the time, effort and resources required for drug discovery are currently exorbitant, due to the unique challenges of the cellular, physical and functional properties of human spermatozoa and a lack of appropriate assay platform. Spermatozoa were obtained from healthy volunteer research donors and subfertile patients undergoing IVF/ICSI at a hospital-assisted reproductive techniques clinic between January 2012 and November 2016. A HTS assay was developed and validated using intracellular calcium ([Ca2+]i) as a surrogate for motility in human spermatozoa. Calcium fluorescence was detected using a Flexstation microplate reader (384-well platform) and compared with responses evoked by progesterone, a compound known to modify a number of biologically relevant behaviours in human spermatozoa. Hit compounds identified following single point drug screen (10 μM) of an ion channel-focussed library assembled by the University of Dundee Drug Discovery Unit were rescreened to ensure potency using standard 10 point half-logarithm concentration curves, and tested for purity and integrity using liquid chromatography and mass spectrometry. Hit compounds were grouped by structure activity relationships and five representative compounds then further investigated for direct effects on spermatozoa, using computer-assisted sperm assessment, sperm penetration assay and whole-cell patch clamping. Of the 3242 ion channel library ligands screened, 384 compounds (11.8%) elicited a statistically significant increase in calcium fluorescence, with greater than 3× median absolute deviation above the baseline. Seventy-four compounds eliciting ≥50% increase in fluorescence in the primary screen were rescreened and evaluated further, resulting in 48 hit compounds that produced a concentration-dependent increase in [Ca2+]i. Sperm penetration studies confirmed in vitro exposure to two hit compounds (A and B) resulted in significant improvement in functional motility in spermatozoa from healthy volunteer donors (A: 1 cm penetration index 2.54, 2 cm penetration index 2.49; P < 0.005 and B: 1 cm penetration index 2.1, 2 cm penetration index 2.6; P < 0.005), but crucially, also in patient samples from those undergoing fertility treatment (A: 1 cm penetration index 2.4; P = 0.009, 2 cm penetration index 3.6; P = 0.02 and B: 1 cm penetration index 2.2; P = 0.0004, 2 cm penetration index 3.6; P = 0.002). This was primarily as a result of direct or indirect CatSper channel action, supported by evidence from electrophysiology studies of individual sperm. Increase and fluxes in [Ca2+]i are fundamental to the regulation of sperm motility and function, including acrosome reaction. The use of calcium signalling as a surrogate for sperm motility is acknowledged as a potential limitation in this study. We conclude that HTS can robustly, efficiently, identify novel compounds that increase [Ca2+]i in human spermatozoa and functionally modify motility, and propose its use as a cornerstone to build and transform much-needed drug discovery for male infertility. The majority of the data were obtained using funding from TENOVUS Scotland and Chief Scientist Office NRS Fellowship. Additional funding was provided by NHS Tayside, MRC project grants (MR/K013343/1, MR/012492/1) and University of Abertay. The authors declare that there is no conflict of interest. N/A. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

  15. Discovery of functional interactions among actin regulators by analysis of image fluctuations in an unperturbed motile cell system.

    PubMed

    Isogai, Tadamoto; Danuser, Gaudenz

    2018-05-26

    Cell migration is driven by propulsive forces derived from polymerizing actin that pushes and extends the plasma membrane. The underlying actin network is constantly undergoing adaptation to new mechano-chemical environments and intracellular conditions. As such, mechanisms that regulate actin dynamics inherently contain multiple feedback loops and redundant pathways. Given the highly adaptable nature of such a system, studies that use only perturbation experiments (e.g. knockdowns, overexpression, pharmacological activation/inhibition, etc.) are challenged by the nonlinearity and redundancy of the pathway. In these pathway configurations, perturbation experiments at best describe the function(s) of a molecular component in an adapting (e.g. acutely drug-treated) or fully adapted (e.g. permanent gene silenced) cell system, where the targeted component now resides in a non-native equilibrium. Here, we propose how quantitative live-cell imaging and analysis of constitutive fluctuations of molecular activities can overcome these limitations. We highlight emerging actin filament barbed-end biology as a prime example of a complex, nonlinear molecular process that requires a fluctuation analytic approach, especially in an unperturbed cellular system, to decipher functional interactions of barbed-end regulators, actin polymerization and membrane protrusion.This article is part of the theme issue 'Self-organization in cell biology'. © 2018 The Author(s).

  16. Cost efficient operations for Discovery class missions

    NASA Technical Reports Server (NTRS)

    Cameron, G. E.; Landshof, J. A.; Whitworth, G. W.

    1994-01-01

    The Near Earth Asteroid Rendezvous (NEAR) program at The Johns Hopkins University Applied Physics Laboratory is scheduled to launch the first spacecraft in NASA's Discovery program. The Discovery program is to promote low cost spacecraft design, development, and mission operations for planetary space missions. The authors describe the NEAR mission and discuss the design and development of the NEAR Mission Operations System and the NEAR Ground System with an emphasis on those aspects of the design that are conducive to low-cost operations.

  17. The Tenth Circuit View of Title VII Discovery--EEOC v. University of New Mexico, 504 F. 2d 1296 (10th Cir. 1974); Rich v. Martin Marietta Corp., 522 F. 2d 353 (10th Cir. 1975)

    ERIC Educational Resources Information Center

    Hoeltgen, Kristine A.

    1976-01-01

    In both these cases the Tenth Circuit continued the trend begun in earlier Title VII cases of giving a liberal interpretation to the scope of discovery. In these decisions the court began to speak more particularly of the factors to be considered in acting on motions to compel discovery. (Author/LBH)

  18. Dynamic selection mechanism for quality of service aware web services

    NASA Astrophysics Data System (ADS)

    D'Mello, Demian Antony; Ananthanarayana, V. S.

    2010-02-01

    A web service is an interface of the software component that can be accessed by standard Internet protocols. The web service technology enables an application to application communication and interoperability. The increasing number of web service providers throughout the globe have produced numerous web services providing the same or similar functionality. This necessitates the use of tools and techniques to search the suitable services available over the Web. UDDI (universal description, discovery and integration) is the first initiative to find the suitable web services based on the requester's functional demands. However, the requester's requirements may also include non-functional aspects like quality of service (QoS). In this paper, the authors define a QoS model for QoS aware and business driven web service publishing and selection. The authors propose a QoS requirement format for the requesters, to specify their complex demands on QoS for the web service selection. The authors define a tree structure called quality constraint tree (QCT) to represent the requester's variety of requirements on QoS properties having varied preferences. The paper proposes a QoS broker based architecture for web service selection, which facilitates the requesters to specify their QoS requirements to select qualitatively optimal web service. A web service selection algorithm is presented, which ranks the functionally similar web services based on the degree of satisfaction of the requester's QoS requirements and preferences. The paper defines web service provider qualities to distinguish qualitatively competitive web services. The paper also presents the modelling and selection mechanism for the requester's alternative constraints defined on the QoS. The authors implement the QoS broker based system to prove the correctness of the proposed web service selection mechanism.

  19. Implementing a Discovery Layer: A Rookie's Season

    ERIC Educational Resources Information Center

    Brubaker, Noah; Leach-Murray, Susan; Parker, Sherri

    2012-01-01

    The year 2011 was the PALNI (Private Academic Library Network of Indiana) consortium's "rookie season" for the implementation of Primo, the 2010 Discovery Layer 500 race winner. In this article, the authors report on their transition to the cloud within Ex Libris Ltd.'s Primo TotalCare environment: their preparation, the steps involved…

  20. Publications - GMC 390 | Alaska Division of Geological & Geophysical

    Science.gov Websites

    Alaska's Mineral Industry Reports AKGeology.info Rare Earth Elements WebGeochem Engineering Geology Alaska DGGS GMC 390 Publication Details Title: Drill logs (1987) from the Cominco Upper Discovery DDH-1 and Lower Discovery DDH-1 through DDH-5 boreholes, Mt. Estelle Prospect, Tyonek Quadrangle, Alaska Authors

  1. Infertility and Crisis: Self-Discovery and Healing through Poetry Writing.

    ERIC Educational Resources Information Center

    Barney, Anne

    1992-01-01

    Offers a personal narrative on how the author's own poetry helped her cope with the crisis of infertility, serving as a tool for self-discovery and healing. Suggests that specific advantages of poetry writing within the context of psychotherapy include problem solving; expression of feelings; insight; couple communication; and individual and…

  2. Channel-transporter complexes: an emerging theme in cell signaling.

    PubMed

    Abbott, Geoffrey W

    2016-11-01

    In a recent edition of Biochemical Journal, Mistry et al. described the discovery of a novel protein complex, formed from the epithelial sodium channel (ENaC) and the sodium chloride cotransporter (NCC) [Mistry et al. (2016) Biochem. J. 473, 3237–3252]. The importance of these two proteins in the regulation of salt balance and blood pressure has long been known, as has their overlapping expression in the distal convoluted tubule of the kidney. The new study by Mistry et al. now demonstrates their physical interaction in the kidney and when heterologously co-expressed. Furthermore, the authors demonstrate some degree of functional co-dependence between ENaC and NCC, with pharmacological inhibition of the latter diminishing activity of the former when the two are co-assembled. This novel and potentially important interaction adds to a growing number of recently identified channel-transporter ('chansporter') complexes, which together constitute an emerging theme in cell signaling. © 2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  3. 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.

  4. Fragment-based drug discovery and its application to challenging drug targets.

    PubMed

    Price, Amanda J; Howard, Steven; Cons, Benjamin D

    2017-11-08

    Fragment-based drug discovery (FBDD) is a technique for identifying low molecular weight chemical starting points for drug discovery. Since its inception 20 years ago, FBDD has grown in popularity to the point where it is now an established technique in industry and academia. The approach involves the biophysical screening of proteins against collections of low molecular weight compounds (fragments). Although fragments bind to proteins with relatively low affinity, they form efficient, high quality binding interactions with the protein architecture as they have to overcome a significant entropy barrier to bind. Of the biophysical methods available for fragment screening, X-ray protein crystallography is one of the most sensitive and least prone to false positives. It also provides detailed structural information of the protein-fragment complex at the atomic level. Fragment-based screening using X-ray crystallography is therefore an efficient method for identifying binding hotspots on proteins, which can then be exploited by chemists and biologists for the discovery of new drugs. The use of FBDD is illustrated here with a recently published case study of a drug discovery programme targeting the challenging protein-protein interaction Kelch-like ECH-associated protein 1:nuclear factor erythroid 2-related factor 2. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  5. A bioinspired catalytic aerobic oxidative C-H functionalization of primary aliphatic amines: synthesis of 1,2-disubstituted benzimidazoles.

    PubMed

    Nguyen, Khac Minh Huy; Largeron, Martine

    2015-09-01

    Aerobic oxidative CH functionalization of primary aliphatic amines has been accomplished with a biomimetic cooperative catalytic system to furnish 1,2-disubstituted benzimidazoles that play an important role as drug discovery targets. This one-pot atom-economical multistep process, which proceeds under mild conditions, with ambient air and equimolar amounts of each coupling partner, constitutes a convenient environmentally friendly strategy to functionalize non-activated aliphatic amines that remain challenging substrates for non-enzymatic catalytic aerobic systems. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of Creative Commons Attribution NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

  6. Synthesis of partially and fully fused polyaromatics by annulative chlorophenylene dimerization.

    PubMed

    Koga, Yoshito; Kaneda, Takeshi; Saito, Yutaro; Murakami, Kei; Itami, Kenichiro

    2018-01-26

    Since the discovery by Ullmann and Bielecki in 1901, reductive dimerization (or homocoupling) of aryl halides has been extensively exploited for the generation of a range of biaryl-based functional molecules. In contrast to the single-point connection in these products, edge-sharing fused aromatic systems have not generally been accessible from simple aryl halides via annulation cascades. Here we report a single-step synthesis of fused aromatics with a triphenylene core by the palladium-catalyzed annulative dimerization of structurally and functionally diverse chlorophenylenes through double carbon-hydrogen bond activation. The partially fused polyaromatics can be transformed into fully fused, small graphene nanoribbons, which are otherwise difficult to synthesize. This simple, yet powerful, method allows access to functional π-systems of interest in optoelectronics research. Copyright © 2018, The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  7. Development and application of PI3K assays for novel drug discovery.

    PubMed

    Yanamandra, Mahesh; Mitra, Sayan; Giri, Archana

    2015-02-01

    Phosphoinositide 3-kinases (PI3Ks) constitute one of the most important signaling pathways, playing a vital role in cellular differentiation and proliferation with a key function in cellular receptor triggered signal transduction downstream of tyrosine kinase receptors and/or G-protein coupled receptors. PI3K promotes cell survival proliferation, protein synthesis and glucose metabolism by generating secondary messengers phospholipid phosphatidyl 3,4,5-triphosphate and signaling via AKT/mTOR regulation. Deregulation of PI3K pathways have been observed in cancer, diabetes, neurological and inflammatory diseases and is an attractive target for pharmaceutical industries. In this review, the authors explain different PI3K assay methodologies. Furthermore, the authors summarize the techno-scientific principles and their utility in profiling novel chemical entities against PI3Ks. Specifically, the authors compare different PI3K assay formats explaining their mode of detection as well as their advantages and limitations for drug discovery efforts. Developing lipid (PI3K) kinase assays involves significant effort and a rational understanding is needed due to the intrinsic lipidic nature of phospholipid phosphatidyl 4,5-biphosphate, which is used as an in vitro substrate for assays with PI3K isoforms. The assay of choice should be versatile, homogenous and definitely adaptable for high-throughput screening campaigns. Additionally, these assays are expected to dissect the mechanism of action of novel compounds (inhibitor characterization) against PI3K. Existing methods provide the versatility to medicinal chemists such that they can choose one or more assay platform to progress their compounds while profiling and/or inhibitor characterization.

  8. pocketZebra: a web-server for automated selection and classification of subfamily-specific binding sites by bioinformatic analysis of diverse protein families.

    PubMed

    Suplatov, Dmitry; Kirilin, Eugeny; Arbatsky, Mikhail; Takhaveev, Vakil; Svedas, Vytas

    2014-07-01

    The new web-server pocketZebra implements the power of bioinformatics and geometry-based structural approaches to identify and rank subfamily-specific binding sites in proteins by functional significance, and select particular positions in the structure that determine selective accommodation of ligands. A new scoring function has been developed to annotate binding sites by the presence of the subfamily-specific positions in diverse protein families. pocketZebra web-server has multiple input modes to meet the needs of users with different experience in bioinformatics. The server provides on-site visualization of the results as well as off-line version of the output in annotated text format and as PyMol sessions ready for structural analysis. pocketZebra can be used to study structure-function relationship and regulation in large protein superfamilies, classify functionally important binding sites and annotate proteins with unknown function. The server can be used to engineer ligand-binding sites and allosteric regulation of enzymes, or implemented in a drug discovery process to search for potential molecular targets and novel selective inhibitors/effectors. The server, documentation and examples are freely available at http://biokinet.belozersky.msu.ru/pocketzebra and there are no login requirements. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  9. Present and future challenges of induced pluripotent stem cells.

    PubMed

    Ohnuki, Mari; Takahashi, Kazutoshi

    2015-10-19

    Growing old is our destiny. However, the mature differentiated cells making up our body can be rejuvenated to an embryo-like fate called pluripotency which is an ability to differentiate into all cell types by enforced expression of defined transcription factors. The discovery of this induced pluripotent stem cell (iPSC) technology has opened up unprecedented opportunities in regenerative medicine, disease modelling and drug discovery. In this review, we introduce the applications and future perspectives of human iPSCs and we also show how iPSC technology has evolved along the way. © 2015 The Author(s).

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

    PubMed Central

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

    2017-01-01

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

  11. An explanation of resisted discoveries based on construal-level theory.

    PubMed

    Fang, Hui

    2015-02-01

    New discoveries and theories are crucial for the development of science, but they are often initially resisted by the scientific community. This paper analyses resistance to scientific discoveries that supplement previous research results or conclusions with new phenomena, such as long chains in macromolecules, Alfvén waves, parity nonconservation in weak interactions and quasicrystals. Construal-level theory is used to explain that the probability of new discoveries may be underestimated because of psychological distance. Thus, the insufficiently examined scope of an accepted theory may lead to overstating the suitable scope and underestimating the probability of its undiscovered counter-examples. Therefore, psychological activity can result in people instinctively resisting new discoveries. Direct evidence can help people judge the validity of a hypothesis with rational thinking. The effects of authorities and textbooks on the resistance to discoveries are also discussed. From the results of our analysis, suggestions are provided to reduce resistance to real discoveries, which will benefit the development of science.

  12. Highlights from SelectBio 2015: Academic Drug Discovery Conference, Cambridge, UK, 19-20 May 2015.

    PubMed

    Spencer, John; Coaker, Hannah

    2015-01-01

    The SelectBio 2015: Academic Drug Discovery Conference was held in Cambridge, UK, on 19-20 May 2015. Building on the success of academic drug discovery events in the USA, this conference aimed to showcase the exciting new research emerging from academic drug discovery and to help bridge the gap between basic research and commercial application. At the event the authors heard from a number of speakers on a broad array of topics, from partnering models for academia and industry to novel drug discovery approaches across various therapeutic areas, with a few talks, such as those by Susanne Muller-Knapp (Structure Genomics Consortium, Oxford University, Oxford, UK) and Julian Blagg (Institute of Cancer Research, UK), covering both remits, by highlighting a number of such partnerships and then delving into some case studies. The conference concluded with a heated debate on whether phenotypic discovery should be favored over targeted discovery in academia and pharma, in a panel discussion chaired by Roland Wolkowicz (San Diego State University, USA).

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

    PubMed Central

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

    2013-01-01

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

  14. Microwave and continuous flow technologies in drug discovery.

    PubMed

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

    2012-12-01

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

  15. Web service discovery among large service pools utilising semantic similarity and clustering

    NASA Astrophysics Data System (ADS)

    Chen, Fuzan; Li, Minqiang; Wu, Harris; Xie, Lingli

    2017-03-01

    With the rapid development of electronic business, Web services have attracted much attention in recent years. Enterprises can combine individual Web services to provide new value-added services. An emerging challenge is the timely discovery of close matches to service requests among large service pools. In this study, we first define a new semantic similarity measure combining functional similarity and process similarity. We then present a service discovery mechanism that utilises the new semantic similarity measure for service matching. All the published Web services are pre-grouped into functional clusters prior to the matching process. For a user's service request, the discovery mechanism first identifies matching services clusters and then identifies the best matching Web services within these matching clusters. Experimental results show that the proposed semantic discovery mechanism performs better than a conventional lexical similarity-based mechanism.

  16. A Passport to Discovery

    ERIC Educational Resources Information Center

    Taylor, Ellen

    2004-01-01

    Have you ever had an experience too good to be true; one that you could not wait to share with your friends? In this article, the author describes such an experience that she had last summer when she was a part of the "Passport to Discovery" tour offered by CRIZMAC Art and Cultural Education Materials, Inc., and led by founder Stevie Mack and…

  17. The State of the Art in Library Discovery 2010

    ERIC Educational Resources Information Center

    Breeding, Marshall

    2010-01-01

    Resource discovery tops the charts as the foremost issue within the realm of library automation. As a new year commences, the author sees a more pressing need to accelerate the pace with which libraries deliver content and services in ways that users will find compelling, relevant, and convenient. The evolution of the web advances relentlessly,…

  18. Discovering Open Source Discovery: Using VuFind to Create MnPALS Plus

    ERIC Educational Resources Information Center

    Digby, Todd; Elfstrand, Stephen

    2011-01-01

    The goal of having a robust discovery system is a priority of the libraries the authors serve (both work at the Minnesota State Colleges and Universities). Given the current fiscal situation facing public higher education in their state, the current commercial systems were not affordable for most of their libraries. They decided to implement and…

  19. Construction of phosphorylation interaction networks by text mining of full-length articles using the eFIP system.

    PubMed

    Tudor, Catalina O; Ross, Karen E; Li, Gang; Vijay-Shanker, K; Wu, Cathy H; Arighi, Cecilia N

    2015-01-01

    Protein phosphorylation is a reversible post-translational modification where a protein kinase adds a phosphate group to a protein, potentially regulating its function, localization and/or activity. Phosphorylation can affect protein-protein interactions (PPIs), abolishing interaction with previous binding partners or enabling new interactions. Extracting phosphorylation information coupled with PPI information from the scientific literature will facilitate the creation of phosphorylation interaction networks of kinases, substrates and interacting partners, toward knowledge discovery of functional outcomes of protein phosphorylation. Increasingly, PPI databases are interested in capturing the phosphorylation state of interacting partners. We have previously developed the eFIP (Extracting Functional Impact of Phosphorylation) text mining system, which identifies phosphorylated proteins and phosphorylation-dependent PPIs. In this work, we present several enhancements for the eFIP system: (i) text mining for full-length articles from the PubMed Central open-access collection; (ii) the integration of the RLIMS-P 2.0 system for the extraction of phosphorylation events with kinase, substrate and site information; (iii) the extension of the PPI module with new trigger words/phrases describing interactions and (iv) the addition of the iSimp tool for sentence simplification to aid in the matching of syntactic patterns. We enhance the website functionality to: (i) support searches based on protein roles (kinases, substrates, interacting partners) or using keywords; (ii) link protein entities to their corresponding UniProt identifiers if mapped and (iii) support visual exploration of phosphorylation interaction networks using Cytoscape. The evaluation of eFIP on full-length articles achieved 92.4% precision, 76.5% recall and 83.7% F-measure on 100 article sections. To demonstrate eFIP for knowledge extraction and discovery, we constructed phosphorylation-dependent interaction networks involving 14-3-3 proteins identified from cancer-related versus diabetes-related articles. Comparison of the phosphorylation interaction network of kinases, phosphoproteins and interactants obtained from eFIP searches, along with enrichment analysis of the protein set, revealed several shared interactions, highlighting common pathways discussed in the context of both diseases. © The Author(s) 2015. Published by Oxford University Press.

  20. Vaccine candidate discovery for the next generation of malaria vaccines.

    PubMed

    Tuju, James; Kamuyu, Gathoni; Murungi, Linda M; Osier, Faith H A

    2017-10-01

    Although epidemiological observations, IgG passive transfer studies and experimental infections in humans all support the feasibility of developing highly effective malaria vaccines, the precise antigens that induce protective immunity remain uncertain. Here, we review the methodologies applied to vaccine candidate discovery for Plasmodium falciparum malaria from the pre- to post-genomic era. Probing of genomic and cDNA libraries with antibodies of defined specificities or functional activity predominated the former, whereas reverse vaccinology encompassing high throughput in silico analyses of genomic, transcriptomic or proteomic parasite data sets is the mainstay of the latter. Antibody-guided vaccine design spanned both eras but currently benefits from technological advances facilitating high-throughput screening and downstream applications. We make the case that although we have exponentially increased our ability to identify numerous potential vaccine candidates in a relatively short space of time, a significant bottleneck remains in their validation and prioritization for evaluation in clinical trials. Longitudinal cohort studies provide supportive evidence but results are often conflicting between studies. Demonstration of antigen-specific antibody function is valuable but the relative importance of one mechanism over another with regards to protection remains undetermined. Animal models offer useful insights but may not accurately reflect human disease. Challenge studies in humans are preferable but prohibitively expensive. In the absence of reliable correlates of protection, suitable animal models or a better understanding of the mechanisms underlying protective immunity in humans, vaccine candidate discovery per se may not be sufficient to provide the paradigm shift necessary to develop the next generation of highly effective subunit malaria vaccines. © 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.

  1. Toxins and drug discovery.

    PubMed

    Harvey, Alan L

    2014-12-15

    Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine. Drug discovery and development is an inherently risky business, and the main causes of failure during development programmes are outlined in order to highlight steps that might be taken to increase the chances of success with toxin-based drug discovery. These include having a clear focus on unmet therapeutic needs, concentrating on targets that are well-validated in terms of their relevance to the disease in question, making use of phenotypic screening rather than molecular-based assays, and working with development partners with the resources required for the long and expensive development process. Copyright © 2014 The Author. Published by Elsevier Ltd.. All rights reserved.

  2. Novel approaches to anticonvulsant drug discovery.

    PubMed

    Miziak, Barbara; Chrościńska-Krawczyk, Magdalena; Błaszczyk, Barbara; Radzik, Iwona; Czuczwar, Stanisław J

    2013-11-01

    The history of epilepsy dates back to 2000 BC. Yet, it was not until 1912 that the activity of the first antiepileptic, phenobarbital was discovered by accident. After this discovery, the next antiepileptic drugs to be discovered (phenytoin and primidone) were based on the phenobarbital's structure. Then, in 1960, carbamazepine was developed empirically, while in 1962, valproate demonstrated anticonvulsant activity against experimental seizures. The next antiepileptic drugs synthesized were either modifications of the existing drugs (such as oxcarbazepine and pregabalin) or completely novel chemical structures (lacosamide, perampanel and retigabine). The present paper briefly refers to the history of epilepsy and development of antiepileptic drugs. Further, the paper provides a discussion on the antiepileptogenic effects of antiepileptic drugs in terms of the constant percentage of epileptic patients with refractory seizures. The authors also review the likely factors involved in the false refractoriness (such as through the use of caffeine-containing beverages and smoking). Finally, the authors consider future directions in the search of novel antiepileptic drugs. In spite of the considerable number of newer antiepileptic drugs, the number of drug-resistant epileptic patients remains unchanged. This may be rather an indication of the suitability of the currently available discovery procedures for effective antiepileptic drugs in the whole population of epileptic patients. The authors, however, believe that it is likely that models of mimic chronic epilepsy will help bridge the gaps and aid in the discovery of novel antiepileptic drugs - ones that can effectively modify the course of the disease.

  3. The complexity of silk under the spotlight of synthetic biology.

    PubMed

    Vollrath, Fritz

    2016-08-15

    For centuries silkworm filaments have been the focus of R&D innovation centred on textile manufacture with high added value. Most recently, silk research has focused on more fundamental issues concerning bio-polymer structure-property-function relationships. This essay outlines the complexity and fundamentals of silk spinning, and presents arguments for establishing this substance as an interesting and important subject at the interface of systems biology (discovery) and synthetic biology (translation). It is argued that silk is a generic class of materials where each type of silk presents a different embodiment of emergent properties that combine genetically determined (anticipatory) and environmentally responsive components. In spiders' webs the various silks have evolved to form the interactive components of an intricate fabric that provides an extended phenotype to the spider's body morphology. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  4. Multiple Modes of Communication between Neurons and Oligodendrocyte Precursor Cells.

    PubMed

    Maldonado, Paloma P; Angulo, María Cecilia

    2015-06-01

    The surprising discovery of bona fide synapses between neurons and oligodendrocytes precursor cells (OPCs) 15 years ago placed these progenitors as real partners of neurons in the CNS. The role of these synapses has not been established yet, but a main hypothesis is that neuron-OPC synaptic activity is a signaling pathway controlling OPC proliferation/differentiation, influencing the myelination process. However, new evidences describing non-synaptic mechanisms of communication between neurons and OPCs have revealed that neuron-OPC interactions are more complex than expected. The activation of extrasynaptic receptors by ambient neurotransmitter or local spillover and the ability of OPCs to sense neuronal activity through a potassium channel suggest that distinct modes of communication mediate different functions of OPCs in the CNS. This review discusses different mechanisms used by OPCs to interact with neurons and their potential roles during postnatal development and in brain disorders. © The Author(s) 2014.

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

    PubMed

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

    2015-12-01

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

  6. Discovery Bottles: A Unique Inexpensive Tool for the K-2 Science Classroom

    ERIC Educational Resources Information Center

    Watson, Sandy

    2008-01-01

    Discover discovery bottles! These wide-mouth plastic containers of any size filled with objects of different kinds can be terrific tools for science explorations and a great way to cultivate science minds in a K-2 science classroom. In addition, the author has found them to be a useful, inexpensive, and engaging way to help students develop skills…

  7. Early Intervention System for Preschool Children with Autism in the Community: The DISCOVERY Approach in Yokohama, Japan.

    ERIC Educational Resources Information Center

    Honda, Hideo; Shimizu, Yasuo

    2002-01-01

    This article reports on DISCOVERY, a conceptual model for a clinical system of early detection and early intervention in cases of autism that has been implemented in Yokohama, Japan. Longitudinal data from 49 children who participated in a program during 1987-1990 indicate 32 were still being followed in 1999. (Contains references.) (Author/CR)

  8. The Role of the Scientific Discovery Narrative in Middle School Science Education: An Experimental Study

    ERIC Educational Resources Information Center

    Arya, Diana J.; Maul, Andrew

    2012-01-01

    In an experimental study (N = 209), the authors compared the effects of exposure to typical middle-school written science content when presented in the context of the scientific discovery narrative and when presented in a more traditional nonnarrative format on 7th and 8th grade students in the United States. The development of texts was…

  9. On Line Instruction: An Opportunity to Re-Examine and Re-Invent Pedagogy

    ERIC Educational Resources Information Center

    Rosenthal, Irene

    2010-01-01

    Author recounts ten discoveries she made about on-line instruction that were beyond her field of vision when she was still viewing it though the lens of traditional classroom instruction. The discoveries include what she learned by reviewing the research in effective course design and a discourse analysis she conducted of the number and types of…

  10. Just-in-Time Teaching in Sociology or How I Convinced My Students to Actually Read the Assignment

    ERIC Educational Resources Information Center

    Howard, Jay R.

    2004-01-01

    In the process of collecting assessment data in the author's introductory sociology course, he made a startling and disappointing discovery. For the most part, students simply were not bothering to read the basics version of the introductory survey textbook that he assigned. This discovery presented him with two related challenges. First, he had…

  11. The Double-Edged Sword of Pedagogy: Instruction Limits Spontaneous Exploration and Discovery

    ERIC Educational Resources Information Center

    Bonawitz, Elizabeth; Shafto, Patrick; Gweon, Hyowon; Goodman, Noah D.; Spelke, Elizabeth; Schulz, Laura

    2011-01-01

    Motivated by computational analyses, we look at how teaching affects exploration and discovery. In Experiment 1, we investigated children's exploratory play after an adult pedagogically demonstrated a function of a toy, after an interrupted pedagogical demonstration, after a naive adult demonstrated the function, and at baseline. Preschoolers in…

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

    PubMed

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

    2017-11-13

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

  13. 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

  14. Dehydration responsive element binding transcription factors and their applications for the engineering of stress tolerance.

    PubMed

    Agarwal, Pradeep K; Gupta, Kapil; Lopato, Sergiy; Agarwal, Parinita

    2017-04-01

    Dehydration responsive element binding (DREB) factors or CRT element binding factors (CBFs) are members of the AP2/ERF family, which comprises a large number of stress-responsive regulatory genes. This review traverses almost two decades of research, from the discovery of DREB/CBF factors to their optimization for application in plant biotechnology. In this review, we describe (i) the discovery, classification, structure, and evolution of DREB genes and proteins; (ii) induction of DREB genes by abiotic stresses and involvement of their products in stress responses; (iii) protein structure and DNA binding selectivity of different groups of DREB proteins; (iv) post-transcriptional and post-translational mechanisms of DREB transcription factor (TF) regulation; and (v) physical and/or functional interaction of DREB TFs with other proteins during plant stress responses. We also discuss existing issues in applications of DREB TFs for engineering of enhanced stress tolerance and improved performance under stress of transgenic crop plants. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  15. 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.

  16. Mitosis, double strand break repair, and telomeres: a view from the end: how telomeres and the DNA damage response cooperate during mitosis to maintain genome stability.

    PubMed

    Cesare, Anthony J

    2014-11-01

    Double strand break (DSB) repair is suppressed during mitosis because RNF8 and downstream DNA damage response (DDR) factors, including 53BP1, do not localize to mitotic chromatin. Discovery of the mitotic kinase-dependent mechanism that inhibits DSB repair during cell division was recently reported. It was shown that restoring mitotic DSB repair was detrimental, resulting in repair dependent genome instability and covalent telomere fusions. The telomere DDR that occurs naturally during cellular aging and in cancer is known to be refractory to G2/M checkpoint activation. Such DDR-positive telomeres, and those that occur as part of the telomere-dependent prolonged mitotic arrest checkpoint, normally pass through mitosis without covalent ligation, but result in cell growth arrest in G1 phase. The discovery that suppressing DSB repair during mitosis may function primarily to protect DDR-positive telomeres from fusing during cell division reinforces the unique cooperation between telomeres and the DDR to mediate tumor suppression. © 2014 The Author. Bioessays published by WILEY Periodicals, Inc.

  17. Unconscious phantasy as a structural principle and organizer of mental life: The evolution of a concept from Freud to Klein and some of her successors.

    PubMed

    Weiss, Heinz

    2017-06-01

    Starting with Freud's discovery of unconscious phantasy as a means of accessing his patients' internal world, the author discusses the evolution of the concept in the work of Melanie Klein and some of her successors. Whereas Freud sees phantasy as a wish fulfilling imagination, dominated by primary process functioning and kept apart from reality testing, Klein understands phantasies as a structural function and organizer of mental life. From their very beginnings they involve object relations and gradually evolve from primitive body-near experiences to images and symbolic representations. With her concept of projective identification in particular, Klein anticipates the communicative function of unconscious phantasies. They are at the basis of processes of symbolization, but may also be put into the service of complex defensive operations. The author traces the further evolution of the concept from the contributions of S. Isaacs, the theories of thinking proposed by W.R. Bion and R. Money-Kyrle, Hanna Segal's ideas on symbolization and reparation all the way to the latest approaches by R. Britton, J. Steiner and others, including the understanding of transference and counter-transference as a 'total situation'. Points of contact with Freud are to be found particularly in connection with his concept of 'primal phantasies'. In the author's view, the idea of the transmission and communicative potential of unconscious phantasies enabled these authors to overcome the solipsistic origins of drive theory in favour of a notion in which unconscious phantasies both set down the coordinates of the inner world and form and reflect the matrix of inter-subjective relations. Copyright © 2017 Institute of Psychoanalysis.

  18. 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.

  19. Optogenetic Approaches to Drug Discovery in Neuroscience and Beyond.

    PubMed

    Zhang, Hongkang; Cohen, Adam E

    2017-07-01

    Recent advances in optogenetics have opened new routes to drug discovery, particularly in neuroscience. Physiological cellular assays probe functional phenotypes that connect genomic data to patient health. Optogenetic tools, in particular tools for all-optical electrophysiology, now provide a means to probe cellular disease models with unprecedented throughput and information content. These techniques promise to identify functional phenotypes associated with disease states and to identify compounds that improve cellular function regardless of whether the compound acts directly on a target or through a bypass mechanism. This review discusses opportunities and unresolved challenges in applying optogenetic techniques throughout the discovery pipeline - from target identification and validation, to target-based and phenotypic screens, to clinical trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Protecting the Privacy of Individuals in Terrorist Tracking Applications

    DTIC Science & Technology

    2005-04-01

    THE PRIVACY OF INDIVIDUALS IN TERRORIST TRACKING APPLICATIONS 6. AUTHOR(S) Teresa Lunt, Paul Aoki, Dirk Balfanz , Glenn Durfee, Philippe Golle...in Data Mining and Knowledge Discovery. 3) Brent Waters, Dirk Balfanz , Glenn Durfee, and Diana Smetters. Building an encrypted and searchable audit

  1. New materials: Fountainhead for new technologies and new science

    NASA Technical Reports Server (NTRS)

    Rustum, Roy

    1993-01-01

    The role of materials as the benchmark technologies which give epochs of human history their names continues into the present. The discovery of new materials has nearly always been the source of new materials science, and frequently of new technologies. This paper analyzes the actual processes by which new materials are synthesized, i.e. whether driven by serendipitous observations, new knowledge is pulled by the market, or integrated into a technological thrust. This analysis focuses on modern ceramic materials discoveries, since World War 2 and uses 45 years experience in materials synthesis in the author's own laboratory as case studies. A dozen different families of materials or processes are involved: hydrothermal reactions; sol-gel processing; clays and zeolites; electroceramics; zero expansion ceramics; diamond films; and radioactive waste host phases. Nanocomposite concepts introduced by the author a decade ago offer an entire, large, new class of materials which will dominate synthesis for the next period. The future of materials research for the next 25 years cannot be extrapolated from the past 25 years. We are near the asymptote for materials utilization in most metals. Likewise we are approaching saturation in improvement of many useful properties. Justifying much further 'basic' R/D for incremental improvement in civilian-oriented industries will not be easy. In materials synthesis, the near-term future is sure to emphasize not new phases, but tailored micro- and nanocomposites for chemical, electrical, optical, and magnetic uses. Unexpected new discoveries such as the Lanxide process may offer rarer chances for step function advances. The new structure of knowledge management will rely less on local research than on integration of worldwide inputs. Better scientific and technological opportunities will lie in designing knowledge intensive materials to meet the new environmental and conservation goals, and the human needs of the very large numbers at the bottom of the socio-economic structures of the world.

  2. Hypotheses generation as supervised link discovery with automated class labeling on large-scale biomedical concept networks

    PubMed Central

    2012-01-01

    Computational approaches to generate hypotheses from biomedical literature have been studied intensively in recent years. Nevertheless, it still remains a challenge to automatically discover novel, cross-silo biomedical hypotheses from large-scale literature repositories. In order to address this challenge, we first model a biomedical literature repository as a comprehensive network of biomedical concepts and formulate hypotheses generation as a process of link discovery on the concept network. We extract the relevant information from the biomedical literature corpus and generate a concept network and concept-author map on a cluster using Map-Reduce frame-work. We extract a set of heterogeneous features such as random walk based features, neighborhood features and common author features. The potential number of links to consider for the possibility of link discovery is large in our concept network and to address the scalability problem, the features from a concept network are extracted using a cluster with Map-Reduce framework. We further model link discovery as a classification problem carried out on a training data set automatically extracted from two network snapshots taken in two consecutive time duration. A set of heterogeneous features, which cover both topological and semantic features derived from the concept network, have been studied with respect to their impacts on the accuracy of the proposed supervised link discovery process. A case study of hypotheses generation based on the proposed method has been presented in the paper. PMID:22759614

  3. 45 CFR 99.21 - Authority of presiding officer.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... HEARINGS FOR THE CHILD CARE AND DEVELOPMENT FUND Hearing Procedures § 99.21 Authority of presiding officer... therein; (7) Examine witnesses; (8) Receive, rule on, exclude or limit evidence or discovery; (9) Fix the... to compel by subpoena the production of witnesses, papers, or other evidence. ...

  4. 45 CFR 99.21 - Authority of presiding officer.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... HEARINGS FOR THE CHILD CARE AND DEVELOPMENT FUND Hearing Procedures § 99.21 Authority of presiding officer... therein; (7) Examine witnesses; (8) Receive, rule on, exclude or limit evidence or discovery; (9) Fix the... to compel by subpoena the production of witnesses, papers, or other evidence. ...

  5. 45 CFR 99.21 - Authority of presiding officer.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... HEARINGS FOR THE CHILD CARE AND DEVELOPMENT FUND Hearing Procedures § 99.21 Authority of presiding officer... therein; (7) Examine witnesses; (8) Receive, rule on, exclude or limit evidence or discovery; (9) Fix the... to compel by subpoena the production of witnesses, papers, or other evidence. ...

  6. 45 CFR 99.21 - Authority of presiding officer.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... HEARINGS FOR THE CHILD CARE AND DEVELOPMENT FUND Hearing Procedures § 99.21 Authority of presiding officer... therein; (7) Examine witnesses; (8) Receive, rule on, exclude or limit evidence or discovery; (9) Fix the... to compel by subpoena the production of witnesses, papers, or other evidence. ...

  7. Particle swarm optimization with recombination and dynamic linkage discovery.

    PubMed

    Chen, Ying-Ping; Peng, Wen-Chih; Jian, Ming-Chung

    2007-12-01

    In this paper, we try to improve the performance of the particle swarm optimizer by incorporating the linkage concept, which is an essential mechanism in genetic algorithms, and design a new linkage identification technique called dynamic linkage discovery to address the linkage problem in real-parameter optimization problems. Dynamic linkage discovery is a costless and effective linkage recognition technique that adapts the linkage configuration by employing only the selection operator without extra judging criteria irrelevant to the objective function. Moreover, a recombination operator that utilizes the discovered linkage configuration to promote the cooperation of particle swarm optimizer and dynamic linkage discovery is accordingly developed. By integrating the particle swarm optimizer, dynamic linkage discovery, and recombination operator, we propose a new hybridization of optimization methodologies called particle swarm optimization with recombination and dynamic linkage discovery (PSO-RDL). In order to study the capability of PSO-RDL, numerical experiments were conducted on a set of benchmark functions as well as on an important real-world application. The benchmark functions used in this paper were proposed in the 2005 Institute of Electrical and Electronics Engineers Congress on Evolutionary Computation. The experimental results on the benchmark functions indicate that PSO-RDL can provide a level of performance comparable to that given by other advanced optimization techniques. In addition to the benchmark, PSO-RDL was also used to solve the economic dispatch (ED) problem for power systems, which is a real-world problem and highly constrained. The results indicate that PSO-RDL can successfully solve the ED problem for the three-unit power system and obtain the currently known best solution for the 40-unit system.

  8. 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.

  9. New insights into the interplay between the translation machinery and nonsense-mediated mRNA decay factors.

    PubMed

    Raimondeau, Etienne; Bufton, Joshua C; Schaffitzel, Christiane

    2018-06-19

    Faulty mRNAs with a premature stop codon (PTC) are recognized and degraded by nonsense-mediated mRNA decay (NMD). Recognition of a nonsense mRNA depends on translation and on the presence of NMD-enhancing or the absence of NMD-inhibiting factors in the 3'-untranslated region. Our review summarizes our current understanding of the molecular function of the conserved NMD factors UPF3B and UPF1, and of the anti-NMD factor Poly(A)-binding protein, and their interactions with ribosomes translating PTC-containing mRNAs. Our recent discovery that UPF3B interferes with human translation termination and enhances ribosome dissociation in vitro , whereas UPF1 is inactive in these assays, suggests a re-interpretation of previous experiments and modification of prevalent NMD models. Moreover, we discuss recent work suggesting new functions of the key NMD factor UPF1 in ribosome recycling, inhibition of translation re-initiation and nascent chain ubiquitylation. These new findings suggest that the interplay of UPF proteins with the translation machinery is more intricate than previously appreciated, and that this interplay quality-controls the efficiency of termination, ribosome recycling and translation re-initiation. © 2018 The Author(s).

  10. Recent advances in automated protein design and its future challenges.

    PubMed

    Setiawan, Dani; Brender, Jeffrey; Zhang, Yang

    2018-04-25

    Protein function is determined by protein structure which is in turn determined by the corresponding protein sequence. If the rules that cause a protein to adopt a particular structure are understood, it should be possible to refine or even redefine the function of a protein by working backwards from the desired structure to the sequence. Automated protein design attempts to calculate the effects of mutations computationally with the goal of more radical or complex transformations than are accessible by experimental techniques. Areas covered: The authors give a brief overview of the recent methodological advances in computer-aided protein design, showing how methodological choices affect final design and how automated protein design can be used to address problems considered beyond traditional protein engineering, including the creation of novel protein scaffolds for drug development. Also, the authors address specifically the future challenges in the development of automated protein design. Expert opinion: Automated protein design holds potential as a protein engineering technique, particularly in cases where screening by combinatorial mutagenesis is problematic. Considering solubility and immunogenicity issues, automated protein design is initially more likely to make an impact as a research tool for exploring basic biology in drug discovery than in the design of protein biologics.

  11. A fortran program for Monte Carlo simulation of oil-field discovery sequences

    USGS Publications Warehouse

    Bohling, Geoffrey C.; Davis, J.C.

    1993-01-01

    We have developed a program for performing Monte Carlo simulation of oil-field discovery histories. A synthetic parent population of fields is generated as a finite sample from a distribution of specified form. The discovery sequence then is simulated by sampling without replacement from this parent population in accordance with a probabilistic discovery process model. The program computes a chi-squared deviation between synthetic and actual discovery sequences as a function of the parameters of the discovery process model, the number of fields in the parent population, and the distributional parameters of the parent population. The program employs the three-parameter log gamma model for the distribution of field sizes and employs a two-parameter discovery process model, allowing the simulation of a wide range of scenarios. ?? 1993.

  12. Pituitary adenylate cyclase-activating polypeptide: a novel peptide with protean implications.

    PubMed

    Pisegna, Joseph R; Oh, David S

    2007-02-01

    The purpose of this review is to highlight the importance of pituitary adenylate cyclase-activating polypeptide in physiological processes and to describe how this peptide is becoming increasingly recognized as having a major role in the body. Since its discovery in 1989, investigators have sought to determine the site of biological activity and the function of pituitary adenylate cyclase-activating polypeptide in maintaining homeostasis. Since its discovery, pituitary adenylate cyclase-activating polypeptide appears to play an important role in the regulation of processes within the central nervous system and gastrointestinal tract, as well in reproductive biology. Pituitary adenylate cyclase-activating polypeptide has been shown to regulate tumor cell growth and to regulate immune function through its effects on T lympocytes. These discoveries suggest the importance of pituitary adenylate cyclase-activating polypeptide in neuronal development, neuronal function, gastrointestinal tract function and reproduction. Future studies will examine more closely the role of pituitary adenylate cyclase-activating polypeptide in regulation of malignantly transformed cells, as well as in regulation of immune function.

  13. John G. Bartlett: Contributions to the discovery of Clostridium difficile antibiotic-associated diarrhea.

    PubMed

    Gorbach, Sherwood L

    2014-09-15

    In 1975 John Bartlett began trials investigating the problem of antibiotic-associated diarrhea and pseudomembranous colitis. His work led the discovery of Clostridium difficile and he identified it as the leading cause of hospital-associated infections. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  14. ACFIS: a web server for fragment-based drug discovery.

    PubMed

    Hao, Ge-Fei; Jiang, Wen; Ye, Yuan-Nong; Wu, Feng-Xu; Zhu, Xiao-Lei; Guo, Feng-Biao; Yang, Guang-Fu

    2016-07-08

    In order to foster innovation and improve the effectiveness of drug discovery, there is a considerable interest in exploring unknown 'chemical space' to identify new bioactive compounds with novel and diverse scaffolds. Hence, fragment-based drug discovery (FBDD) was developed rapidly due to its advanced expansive search for 'chemical space', which can lead to a higher hit rate and ligand efficiency (LE). However, computational screening of fragments is always hampered by the promiscuous binding model. In this study, we developed a new web server Auto Core Fragment in silico Screening (ACFIS). It includes three computational modules, PARA_GEN, CORE_GEN and CAND_GEN. ACFIS can generate core fragment structure from the active molecule using fragment deconstruction analysis and perform in silico screening by growing fragments to the junction of core fragment structure. An integrated energy calculation rapidly identifies which fragments fit the binding site of a protein. We constructed a simple interface to enable users to view top-ranking molecules in 2D and the binding mode in 3D for further experimental exploration. This makes the ACFIS a highly valuable tool for drug discovery. The ACFIS web server is free and open to all users at http://chemyang.ccnu.edu.cn/ccb/server/ACFIS/. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  15. Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates.

    PubMed

    Sirvent, Juan Alberto; Lücking, Ulrich

    2017-04-06

    Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan-CDK inhibitor), BAY 1143572 (P-TEFb inhibitor), and AZD 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug discovery is clearly on the rise, there remains an incomplete understanding of the medicinal-chemistry-relevant properties of sulfoximines. Herein we report the synthesis and in vitro characterization of a variety of sulfoximine analogues of marketed drugs and advanced clinical candidates to gain a better understanding of this neglected functional group and its potential in drug discovery. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. RNA regulatory networks in animals and plants: a long noncoding RNA perspective.

    PubMed

    Bai, Youhuang; Dai, Xiaozhuan; Harrison, Andrew P; Chen, Ming

    2015-03-01

    A recent highlight of genomics research has been the discovery of many families of transcripts which have function but do not code for proteins. An important group is long noncoding RNAs (lncRNAs), which are typically longer than 200 nt, and whose members originate from thousands of loci across genomes. We review progress in understanding the biogenesis and regulatory mechanisms of lncRNAs. We describe diverse computational and high throughput technologies for identifying and studying lncRNAs. We discuss the current knowledge of functional elements embedded in lncRNAs as well as insights into the lncRNA-based regulatory network in animals. We also describe genome-wide studies of large amount of lncRNAs in plants, as well as knowledge of selected plant lncRNAs with a focus on biotic/abiotic stress-responsive lncRNAs. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  17. Psychology Needs Realism, Not Instrumentalism

    ERIC Educational Resources Information Center

    Haig, Brian D.

    2005-01-01

    In this article, the author presents his comments on "Realism, Instrumentalism, and Scientific Symbiosis: Psychological Theory as a Search for Truth and the Discovery of Solutions" by John T. Cacioppo, Gun R. Semin and Gary G. Berntson. In the original article, the authors recommended the combined use of the philosophies of scientific realism and…

  18. 45 CFR 160.508 - Authority of the ALJ.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Authority of the ALJ. 160.508 Section 160.508 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES ADMINISTRATIVE DATA STANDARDS AND RELATED... scope and timing of documentary discovery as permitted by this subpart; (8) Regulate the course of the...

  19. 28 CFR 76.18 - Authority of the Judge.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Authority of the Judge. 76.18 Section 76.18 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) RULES OF PROCEDURE FOR ASSESSMENT OF... and other procedural matters; (7) Regulate the scope and timing of discovery; (8) Regulate the course...

  20. 28 CFR 76.18 - Authority of the Judge.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Authority of the Judge. 76.18 Section 76.18 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) RULES OF PROCEDURE FOR ASSESSMENT OF... and other procedural matters; (7) Regulate the scope and timing of discovery; (8) Regulate the course...

  1. 28 CFR 76.18 - Authority of the Judge.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Authority of the Judge. 76.18 Section 76.18 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) RULES OF PROCEDURE FOR ASSESSMENT OF... and other procedural matters; (7) Regulate the scope and timing of discovery; (8) Regulate the course...

  2. 28 CFR 76.18 - Authority of the Judge.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Authority of the Judge. 76.18 Section 76.18 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) RULES OF PROCEDURE FOR ASSESSMENT OF... and other procedural matters; (7) Regulate the scope and timing of discovery; (8) Regulate the course...

  3. 28 CFR 76.18 - Authority of the Judge.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Authority of the Judge. 76.18 Section 76.18 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) RULES OF PROCEDURE FOR ASSESSMENT OF... and other procedural matters; (7) Regulate the scope and timing of discovery; (8) Regulate the course...

  4. Teaching Dance: One Man's Journey

    ERIC Educational Resources Information Center

    Ross, Jim

    2006-01-01

    This article illustrates the author's discovery that the key to any successful dance unit is finding ways for students to make connections and want to dance. While reflecting on the purpose of dance in the curriculum, the author identified important skills and concepts he wanted his students to master, such as rhythm, balance, and…

  5. Privacy-Preserving Relationship Path Discovery in Social Networks

    NASA Astrophysics Data System (ADS)

    Mezzour, Ghita; Perrig, Adrian; Gligor, Virgil; Papadimitratos, Panos

    As social networks sites continue to proliferate and are being used for an increasing variety of purposes, the privacy risks raised by the full access of social networking sites over user data become uncomfortable. A decentralized social network would help alleviate this problem, but offering the functionalities of social networking sites is a distributed manner is a challenging problem. In this paper, we provide techniques to instantiate one of the core functionalities of social networks: discovery of paths between individuals. Our algorithm preserves the privacy of relationship information, and can operate offline during the path discovery phase. We simulate our algorithm on real social network topologies.

  6. An update on oxysterol biochemistry: New discoveries in lipidomics.

    PubMed

    Griffiths, William J; Wang, Yuqin

    2018-02-05

    Oxysterols are oxidised derivatives of cholesterol or its precursors post lanosterol. They are intermediates in the biosynthesis of bile acids, steroid hormones and 1,25-dihydroxyvitamin D 3. Although often considered as metabolic intermediates there is a growing body of evidence that many oxysterols are bioactive and their absence or excess may be part of the cause of a disease phenotype. Using global lipidomics approaches oxysterols are underrepresented encouraging the development of targeted approaches. In this article, we discuss recent discoveries important in oxysterol biochemistry and some of the targeted lipidomic approaches used to make these discoveries. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  7. compendiumdb: an R package for retrieval and storage of functional genomics data.

    PubMed

    Nandal, Umesh K; van Kampen, Antoine H C; Moerland, Perry D

    2016-09-15

    Currently, the Gene Expression Omnibus (GEO) contains public data of over 1 million samples from more than 40 000 microarray-based functional genomics experiments. This provides a rich source of information for novel biological discoveries. However, unlocking this potential often requires retrieving and storing a large number of expression profiles from a wide range of different studies and platforms. The compendiumdb R package provides an environment for downloading functional genomics data from GEO, parsing the information into a local or remote database and interacting with the database using dedicated R functions, thus enabling seamless integration with other tools available in R/Bioconductor. The compendiumdb package is written in R, MySQL and Perl. Source code and binaries are available from CRAN (http://cran.r-project.org/web/packages/compendiumdb/) for all major platforms (Linux, MS Windows and OS X) under the GPLv3 license. p.d.moerland@amc.uva.nl Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. 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

  9. 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.

  10. Comparison: Discovery on WSMOLX and miAamics/jABC

    NASA Astrophysics Data System (ADS)

    Kubczak, Christian; Vitvar, Tomas; Winkler, Christian; Zaharia, Raluca; Zaremba, Maciej

    This chapter compares the solutions to the SWS-Challenge discovery problems provided by DERI Galway and the joint solution from the Technical University of Dortmund and University of Postdam. The two approaches are described in depth in Chapters 10 and 13. The discovery scenario raises problems associated with making service discovery an automated process. It requires fine-grained specifications of search requests and service functionality including support for fetching dynamic information during the discovery process (e.g., shipment price). Both teams utilize semantics to describe services, service requests and data models in order to enable search at the required fine-grained level of detail.

  11. Evidence for deep regulatory similarities in early developmental programs across highly diverged insects.

    PubMed

    Kazemian, Majid; Suryamohan, Kushal; Chen, Jia-Yu; Zhang, Yinan; Samee, Md Abul Hassan; Halfon, Marc S; Sinha, Saurabh

    2014-09-01

    Many genes familiar from Drosophila development, such as the so-called gap, pair-rule, and segment polarity genes, play important roles in the development of other insects and in many cases appear to be deployed in a similar fashion, despite the fact that Drosophila-like "long germband" development is highly derived and confined to a subset of insect families. Whether or not these similarities extend to the regulatory level is unknown. Identification of regulatory regions beyond the well-studied Drosophila has been challenging as even within the Diptera (flies, including mosquitoes) regulatory sequences have diverged past the point of recognition by standard alignment methods. Here, we demonstrate that methods we previously developed for computational cis-regulatory module (CRM) discovery in Drosophila can be used effectively in highly diverged (250-350 Myr) insect species including Anopheles gambiae, Tribolium castaneum, Apis mellifera, and Nasonia vitripennis. In Drosophila, we have successfully used small sets of known CRMs as "training data" to guide the search for other CRMs with related function. We show here that although species-specific CRM training data do not exist, training sets from Drosophila can facilitate CRM discovery in diverged insects. We validate in vivo over a dozen new CRMs, roughly doubling the number of known CRMs in the four non-Drosophila species. Given the growing wealth of Drosophila CRM annotation, these results suggest that extensive regulatory sequence annotation will be possible in newly sequenced insects without recourse to costly and labor-intensive genome-scale experiments. We develop a new method, Regulus, which computes a probabilistic score of similarity based on binding site composition (despite the absence of nucleotide-level sequence alignment), and demonstrate similarity between functionally related CRMs from orthologous loci. Our work represents an important step toward being able to trace the evolutionary history of gene regulatory networks and defining the mechanisms underlying insect evolution. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  12. CRTS SNhunt: The First Five Years of Supernova Discoveries

    NASA Astrophysics Data System (ADS)

    Howerton, Stanley C.

    2017-01-01

    CRTS SNhunt: The First Five Years of Supernova Discoveries is a compilation of all supernova and supernova-like discoveries from the first five operational years of the supernova search SNhunt which is one project in the larger Catalina Real-Time Transient Survey (CRTS). SNhunt is perhaps one of the last traditional large-scale searches in which a person compares an image with a reference frame. This kind of search is time consuming as there is not a computer to narrow down the possibilities. The only help is a subtraction frame which shows differences between the two images. Images came from the Catalina Sky Survey, Mount Lemmon Survey, and Siding Spring Survey. Most of the discoveries were by the author. For many, a confirmation or a follow-up image is included. Where possible, a light curve was also created.

  13. 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.

  14. Application of chemical biology in target identification and drug discovery.

    PubMed

    Zhu, Yue; Xiao, Ting; Lei, Saifei; Zhou, Fulai; Wang, Ming-Wei

    2015-09-01

    Drug discovery and development is vital to the well-being of mankind and sustainability of the pharmaceutical industry. Using chemical biology approaches to discover drug leads has become a widely accepted path partially because of the completion of the Human Genome Project. Chemical biology mainly solves biological problems through searching previously unknown targets for pharmacologically active small molecules or finding ligands for well-defined drug targets. It is a powerful tool to study how these small molecules interact with their respective targets, as well as their roles in signal transduction, molecular recognition and cell functions. There have been an increasing number of new therapeutic targets being identified and subsequently validated as a result of advances in functional genomics, which in turn led to the discovery of numerous active small molecules via a variety of high-throughput screening initiatives. In this review, we highlight some applications of chemical biology in the context of drug discovery.

  15. Discovery of novel drug targets and their functions using phenotypic screening of natural products.

    PubMed

    Chang, Junghwa; Kwon, Ho Jeong

    2016-03-01

    Natural products are valuable resources that provide a variety of bioactive compounds and natural pharmacophores in modern drug discovery. Discovery of biologically active natural products and unraveling their target proteins to understand their mode of action have always been critical hurdles for their development into clinical drugs. For effective discovery and development of bioactive natural products into novel therapeutic drugs, comprehensive screening and identification of target proteins are indispensable. In this review, a systematic approach to understanding the mode of action of natural products isolated using phenotypic screening involving chemical proteomics-based target identification is introduced. This review highlights three natural products recently discovered via phenotypic screening, namely glucopiericidin A, ecumicin, and terpestacin, as representative case studies to revisit the pivotal role of natural products as powerful tools in discovering the novel functions and druggability of targets in biological systems and pathological diseases of interest.

  16. Efficient discovery of bioactive scaffolds by activity-directed synthesis

    NASA Astrophysics Data System (ADS)

    Karageorgis, George; Warriner, Stuart; Nelson, Adam

    2014-10-01

    The structures and biological activities of natural products have often provided inspiration in drug discovery. The functional benefits of natural products to the host organism steers the evolution of their biosynthetic pathways. Here, we describe a discovery approach—which we term activity-directed synthesis—in which reactions with alternative outcomes are steered towards functional products. Arrays of catalysed reactions of α-diazo amides, whose outcome was critically dependent on the specific conditions used, were performed. The products were assayed at increasingly low concentration, with the results informing the design of a subsequent reaction array. Finally, promising reactions were scaled up and, after purification, submicromolar ligands based on two scaffolds with no previous annotated activity against the androgen receptor were discovered. The approach enables the discovery, in tandem, of both bioactive small molecules and associated synthetic routes, analogous to the evolution of biosynthetic pathways to yield natural products.

  17. Genomic Enzymology: Web Tools for Leveraging Protein Family Sequence-Function Space and Genome Context to Discover Novel Functions.

    PubMed

    Gerlt, John A

    2017-08-22

    The exponentially increasing number of protein and nucleic acid sequences provides opportunities to discover novel enzymes, metabolic pathways, and metabolites/natural products, thereby adding to our knowledge of biochemistry and biology. The challenge has evolved from generating sequence information to mining the databases to integrating and leveraging the available information, i.e., the availability of "genomic enzymology" web tools. Web tools that allow identification of biosynthetic gene clusters are widely used by the natural products/synthetic biology community, thereby facilitating the discovery of novel natural products and the enzymes responsible for their biosynthesis. However, many novel enzymes with interesting mechanisms participate in uncharacterized small-molecule metabolic pathways; their discovery and functional characterization also can be accomplished by leveraging information in protein and nucleic acid databases. This Perspective focuses on two genomic enzymology web tools that assist the discovery novel metabolic pathways: (1) Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST) for generating sequence similarity networks to visualize and analyze sequence-function space in protein families and (2) Enzyme Function Initiative-Genome Neighborhood Tool (EFI-GNT) for generating genome neighborhood networks to visualize and analyze the genome context in microbial and fungal genomes. Both tools have been adapted to other applications to facilitate target selection for enzyme discovery and functional characterization. As the natural products community has demonstrated, the enzymology community needs to embrace the essential role of web tools that allow the protein and genome sequence databases to be leveraged for novel insights into enzymological problems.

  18. Genomic Enzymology: Web Tools for Leveraging Protein Family Sequence–Function Space and Genome Context to Discover Novel Functions

    PubMed Central

    2017-01-01

    The exponentially increasing number of protein and nucleic acid sequences provides opportunities to discover novel enzymes, metabolic pathways, and metabolites/natural products, thereby adding to our knowledge of biochemistry and biology. The challenge has evolved from generating sequence information to mining the databases to integrating and leveraging the available information, i.e., the availability of “genomic enzymology” web tools. Web tools that allow identification of biosynthetic gene clusters are widely used by the natural products/synthetic biology community, thereby facilitating the discovery of novel natural products and the enzymes responsible for their biosynthesis. However, many novel enzymes with interesting mechanisms participate in uncharacterized small-molecule metabolic pathways; their discovery and functional characterization also can be accomplished by leveraging information in protein and nucleic acid databases. This Perspective focuses on two genomic enzymology web tools that assist the discovery novel metabolic pathways: (1) Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST) for generating sequence similarity networks to visualize and analyze sequence–function space in protein families and (2) Enzyme Function Initiative-Genome Neighborhood Tool (EFI-GNT) for generating genome neighborhood networks to visualize and analyze the genome context in microbial and fungal genomes. Both tools have been adapted to other applications to facilitate target selection for enzyme discovery and functional characterization. As the natural products community has demonstrated, the enzymology community needs to embrace the essential role of web tools that allow the protein and genome sequence databases to be leveraged for novel insights into enzymological problems. PMID:28826221

  19. CRISPR/Cas9: From Genome Engineering to Cancer Drug Discovery

    PubMed Central

    Luo, Ji

    2016-01-01

    Advances in translational research are often driven by new technologies. The advent of microarrays, next-generation sequencing, proteomics and RNA interference (RNAi) have led to breakthroughs in our understanding of the mechanisms of cancer and the discovery of new cancer drug targets. The discovery of the bacterial clustered regularly interspaced palindromic repeat (CRISPR) system and its subsequent adaptation as a tool for mammalian genome engineering has opened up new avenues for functional genomics studies. This review will focus on the utility of CRISPR in the context of cancer drug target discovery. PMID:28603775

  20. PoSSuM v.2.0: data update and a new function for investigating ligand analogs and target proteins of small-molecule drugs.

    PubMed

    Ito, Jun-ichi; Ikeda, Kazuyoshi; Yamada, Kazunori; Mizuguchi, Kenji; Tomii, Kentaro

    2015-01-01

    PoSSuM (http://possum.cbrc.jp/PoSSuM/) is a database for detecting similar small-molecule binding sites on proteins. Since its initial release in 2011, PoSSuM has grown to provide information related to 49 million pairs of similar binding sites discovered among 5.5 million known and putative binding sites. This enlargement of the database is expected to enhance opportunities for biological and pharmaceutical applications, such as predictions of new functions and drug discovery. In this release, we have provided a new service named PoSSuM drug search (PoSSuMds) at http://possum.cbrc.jp/PoSSuM/drug_search/, in which we selected 194 approved drug compounds retrieved from ChEMBL, and detected their known binding pockets and pockets that are similar to them. Users can access and download all of the search results via a new web interface, which is useful for finding ligand analogs as well as potential target proteins. Furthermore, PoSSuMds enables users to explore the binding pocket universe within PoSSuM. Additionally, we have improved the web interface with new functions, including sortable tables and a viewer for visualizing and downloading superimposed pockets. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

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

    PubMed

    Kell, Douglas B

    2013-12-01

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

  2. 42 CFR 137.419 - What authority does the IBIA have under §§ 137.415 through 137.436?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false What authority does the IBIA have under §§ 137...-GOVERNANCE Appeals Pre-Award Disputes § 137.419 What authority does the IBIA have under §§ 137.415 through... to engage in full discovery relevant to any issue raised in the matter; (c) to issue a recommended...

  3. [Discussion on quantum entanglement theory and acupuncture].

    PubMed

    Wang, Jun; Wu, Bin; Chen, Sheng

    2017-11-12

    The quantum entanglement is a new discovery of modern physics and has drawn a widely attention in the world. After learning the quantum entanglement, the authors have found that many characteristics of quantum are reflected in TCM, acupuncture theory and clinical practice. For example, the quantum entanglement phenomenon is mutually verified with the holism, yinyang doctrine, the theory of primary, secondary, root and knot in TCM, etc. It can be applied to interpret the clinical situations which is difficult to be explained in clinical practice, such as the instant effect of acupuncture, multi-point stimulation in one disorder and the points with specific effects. On the basis of the discovery above, the quantum entanglement theory achieved the mutual treatment among the relatives in acupuncture clinical practice and the therapeutic effects were significant. The results suggest that the coupling relationship in quantum entanglement presents between the diseases and the acupoints in the direct relative. The authors believe that the discovery in this study contributes to the exploration on the approaches to the acupuncture treatment in clinical practice and enrich the ideas on the disease prevention.

  4. [Hypothesis and application of bimolecular marking methods in Chinese materia medica].

    PubMed

    Huang, Lu-qi; Qian, Dan; Deng, Chao

    2015-01-01

    Based on the current shortage of genuine/false authentication and quality evaluation in the molecular identification, and the weak functional gene research in the establishment of two-dimensional molecular markering methods for Chinese materia medica, the authors proposed a new method, the bimolecular marking methods (BIMM) for Chinese materia medica, combining DNA marker and metabolomics marker, that could simultaneously research the species and quality differences at the molecular level at the present stage. The authors introduced the concept, principle, methods, and technical process of BIMM, and summarized the technical advantages in this paper. Meanwhile, the application of BIMM in the identification of multiple sources of Chinese materia medica, years-identification, different locations, elite germplasm research, discovery of new drugs resources, protection of new varieties was also discussed. As a supplement of two-dimensional molecular markering method for Chinese materia medica, BIMM would not only expand connotation of identification of Chinese materia medica but also provide another effective way for quality evaluating.

  5. 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

  6. Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures

    PubMed Central

    Stark, Alexander; Lin, Michael F.; Kheradpour, Pouya; Pedersen, Jakob S.; Parts, Leopold; Carlson, Joseph W.; Crosby, Madeline A.; Rasmussen, Matthew D.; Roy, Sushmita; Deoras, Ameya N.; Ruby, J. Graham; Brennecke, Julius; Hodges, Emily; Hinrichs, Angie S.; Caspi, Anat; Paten, Benedict; Park, Seung-Won; Han, Mira V.; Maeder, Morgan L.; Polansky, Benjamin J.; Robson, Bryanne E.; Aerts, Stein; van Helden, Jacques; Hassan, Bassem; Gilbert, Donald G.; Eastman, Deborah A.; Rice, Michael; Weir, Michael; Hahn, Matthew W.; Park, Yongkyu; Dewey, Colin N.; Pachter, Lior; Kent, W. James; Haussler, David; Lai, Eric C.; Bartel, David P.; Hannon, Gregory J.; Kaufman, Thomas C.; Eisen, Michael B.; Clark, Andrew G.; Smith, Douglas; Celniker, Susan E.; Gelbart, William M.; Kellis, Manolis

    2008-01-01

    Sequencing of multiple related species followed by comparative genomics analysis constitutes a powerful approach for the systematic understanding of any genome. Here, we use the genomes of 12 Drosophila species for the de novo discovery of functional elements in the fly. Each type of functional element shows characteristic patterns of change, or ‘evolutionary signatures’, dictated by its precise selective constraints. Such signatures enable recognition of new protein-coding genes and exons, spurious and incorrect gene annotations, and numerous unusual gene structures, including abundant stop-codon readthrough. Similarly, we predict non-protein-coding RNA genes and structures, and new microRNA (miRNA) genes. We provide evidence of miRNA processing and functionality from both hairpin arms and both DNA strands. We identify several classes of pre- and post-transcriptional regulatory motifs, and predict individual motif instances with high confidence. We also study how discovery power scales with the divergence and number of species compared, and we provide general guidelines for comparative studies. PMID:17994088

  7. Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer.

    PubMed

    Young, Jonathan H; Peyton, Michael; Seok Kim, Hyun; McMillan, Elizabeth; Minna, John D; White, Michael A; Marcotte, Edward M

    2016-05-01

    Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets. Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding. In particular, many NSCLC cell lines were especially sensitive to the loss of components of the LSm2-8 protein complex or the CCT/TRiC chaperonin. Different vulnerabilities were also found for different cell line subgroups. Furthermore, the predicted vulnerability of a single adenocarcinoma cell line to loss of the Wnt pathway was experimentally validated with screening of small-molecule Wnt inhibitors against an extensive cell line panel. The clustering algorithm is implemented in Python and is freely available at https://bitbucket.org/youngjh/nsclc_paper marcotte@icmb.utexas.edu or jon.young@utexas.edu Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

  8. Quantifying complexity in translational research: an integrated approach.

    PubMed

    Munoz, David A; Nembhard, Harriet Black; Kraschnewski, Jennifer L

    2014-01-01

    The purpose of this paper is to quantify complexity in translational research. The impact of major operational steps and technical requirements is calculated with respect to their ability to accelerate moving new discoveries into clinical practice. A three-phase integrated quality function deployment (QFD) and analytic hierarchy process (AHP) method was used to quantify complexity in translational research. A case study in obesity was used to usability. Generally, the evidence generated was valuable for understanding various components in translational research. Particularly, the authors found that collaboration networks, multidisciplinary team capacity and community engagement are crucial for translating new discoveries into practice. As the method is mainly based on subjective opinion, some argue that the results may be biased. However, a consistency ratio is calculated and used as a guide to subjectivity. Alternatively, a larger sample may be incorporated to reduce bias. The integrated QFD-AHP framework provides evidence that could be helpful to generate agreement, develop guidelines, allocate resources wisely, identify benchmarks and enhance collaboration among similar projects. Current conceptual models in translational research provide little or no clue to assess complexity. The proposed method aimed to fill this gap. Additionally, the literature review includes various features that have not been explored in translational research.

  9. The development of high-content screening (HCS) technology and its importance to drug discovery.

    PubMed

    Fraietta, Ivan; Gasparri, Fabio

    2016-01-01

    High-content screening (HCS) was introduced about twenty years ago as a promising analytical approach to facilitate some critical aspects of drug discovery. Its application has spread progressively within the pharmaceutical industry and academia to the point that it today represents a fundamental tool in supporting drug discovery and development. Here, the authors review some of significant progress in the HCS field in terms of biological models and assay readouts. They highlight the importance of high-content screening in drug discovery, as testified by its numerous applications in a variety of therapeutic areas: oncology, infective diseases, cardiovascular and neurodegenerative diseases. They also dissect the role of HCS technology in different phases of the drug discovery pipeline: target identification, primary compound screening, secondary assays, mechanism of action studies and in vitro toxicology. Recent advances in cellular assay technologies, such as the introduction of three-dimensional (3D) cultures, induced pluripotent stem cells (iPSCs) and genome editing technologies (e.g., CRISPR/Cas9), have tremendously expanded the potential of high-content assays to contribute to the drug discovery process. Increasingly predictive cellular models and readouts, together with the development of more sophisticated and affordable HCS readers, will further consolidate the role of HCS technology in drug discovery.

  10. Bio-TDS: bioscience query tool discovery system.

    PubMed

    Gnimpieba, Etienne Z; VanDiermen, Menno S; Gustafson, Shayla M; Conn, Bill; Lushbough, Carol M

    2017-01-04

    Bioinformatics and computational biology play a critical role in bioscience and biomedical research. As researchers design their experimental projects, one major challenge is to find the most relevant bioinformatics toolkits that will lead to new knowledge discovery from their data. The Bio-TDS (Bioscience Query Tool Discovery Systems, http://biotds.org/) has been developed to assist researchers in retrieving the most applicable analytic tools by allowing them to formulate their questions as free text. The Bio-TDS is a flexible retrieval system that affords users from multiple bioscience domains (e.g. genomic, proteomic, bio-imaging) the ability to query over 12 000 analytic tool descriptions integrated from well-established, community repositories. One of the primary components of the Bio-TDS is the ontology and natural language processing workflow for annotation, curation, query processing, and evaluation. The Bio-TDS's scientific impact was evaluated using sample questions posed by researchers retrieved from Biostars, a site focusing on BIOLOGICAL DATA ANALYSIS: The Bio-TDS was compared to five similar bioscience analytic tool retrieval systems with the Bio-TDS outperforming the others in terms of relevance and completeness. The Bio-TDS offers researchers the capacity to associate their bioscience question with the most relevant computational toolsets required for the data analysis in their knowledge discovery process. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  11. The future (and past) of quantum theory after the Higgs boson: a quantum-informational viewpoint.

    PubMed

    Plotnitsky, Arkady

    2016-05-28

    Taking as its point of departure the discovery of the Higgs boson, this article considers quantum theory, including quantum field theory, which predicted the Higgs boson, through the combined perspective of quantum information theory and the idea of technology, while also adopting anon-realistinterpretation, in 'the spirit of Copenhagen', of quantum theory and quantum phenomena themselves. The article argues that the 'events' in question in fundamental physics, such as the discovery of the Higgs boson (a particularly complex and dramatic, but not essentially different, case), are made possible by the joint workings of three technologies: experimental technology, mathematical technology and, more recently, digital computer technology. The article will consider the role of and the relationships among these technologies, focusing on experimental and mathematical technologies, in quantum mechanics (QM), quantum field theory (QFT) and finite-dimensional quantum theory, with which quantum information theory has been primarily concerned thus far. It will do so, in part, by reassessing the history of quantum theory, beginning with Heisenberg's discovery of QM, in quantum-informational and technological terms. This history, the article argues, is defined by the discoveries of increasingly complex configurations of observed phenomena and the emergence of the increasingly complex mathematical formalism accounting for these phenomena, culminating in the standard model of elementary-particle physics, defining the current state of QFT. © 2016 The Author(s).

  12. REVIEWS OF TOPICAL PROBLEMS: Prediction and discovery of new structures in spiral galaxies

    NASA Astrophysics Data System (ADS)

    Fridman, Aleksei M.

    2007-02-01

    A review is given of the last 20 years of published research into the nature, origin mechanisms, and observed features of spiral-vortex structures found in galaxies. The so-called rotating shallow water experiments are briefly discussed, carried out with a facility designed by the present author and built at the Russian Scientific Center 'Kurchatov Institute' to model the origin of galactic spiral structures. The discovery of new vortex-anticyclone structures in these experiments stimulated searching for them astronomically using the RAS Special Astrophysical Observatory's 6-meter BTA optical telescope, formerly the world's and now Europe's largest. Seven years after the pioneering experiments, Afanasyev and the present author discovered the predicted giant anticyclones in the galaxy Mrk 1040 by using BTA. Somewhat later, the theoretical prediction of giant cyclones in spiral galaxies was made, also to be verified by BTA afterwards. To use the observed line-of-sight velocity field for reconstructing the 3D velocity vector distribution in a galactic disk, a method for solving a problem from the class of ill-posed astrophysical problems was developed by the present author and colleagues. In addition to the vortex structure, other new features were discovered — in particular, slow bars (another theoretical prediction), for whose discovery an observational test capable of distinguishing them from their earlier-studied normal (fast) counterparts was designed.

  13. Fruitful research: drug target discovery for neurodegenerative diseases in Drosophila.

    PubMed

    Konsolaki, Mary

    2013-12-01

    Although vertebrate model systems have obvious advantages in the study of human disease, invertebrate organisms have contributed enormously to this field as well. The conservation of genome structure and physiology among organisms poses unexpected peculiarities, and the redundancy in certain gene families or the presence of polymorphisms that can slightly alter gene expression can, in certain instances, bring invertebrate systems, such as Drosophila, closer to humans than mice and vice versa. This necessitates the analysis of disease pathways in multiple model organisms. The author highlights findings from Drosophila models of neurodegenerative diseases that have occurred in the past few years. She also highlights and discusses various molecular, genetic and genomic tools used in flies, as well as methods for generating disease models. Finally, the author describes Drosophila models of Alzheimer's, Parkinson's tri-nucleotide repeat diseases, and Fragile X syndrome and summarizes insights in disease mechanisms that have been discovered directly in fly models. Full genome genetic screens in Drosophila can lead to the rapid identification of drug target candidates that can be subsequently validated in a vertebrate system. In addition, the Drosophila models of neurodegeneration may often show disease phenotypes that are absent in equivalent mouse models. The author believes that the extensive contribution of Drosophila to both new disease drug target discovery, in addition to target validation, makes them indispensible to drug discovery and development.

  14. A collaboration investigating endocannabinoid signalling in brain and bone.

    PubMed

    Zimmer, Andreas

    2016-05-01

    Investigations into the cellular and molecular mechanisms underlying the psychoactive effects of cannabis preparations have led to the discovery of the endocannabinoid system. Interest in the central nervous system effects was initially the main focus of the research, but it soon became evident that the endocannabinoid system affects virtually every organ. The research field has therefore experienced a tremendous growth over the last decade and is now truly interdisciplinary. This short review provides a personal account of an interdisciplinary collaboration between Itai Bab from the Hebrew University of Jerusalem and the author. It describes the discovery of the endocannabinoid system in bone and the analysis of its functions. I am summarising the role of CB1 signalling as a modulator of sympathetic inhibition of bone formation. Thus, activation of CB1 receptors on sympathetic nerve terminals in bone, presumably from endocannabinoids released from apposing osteoblasts, reduces the inhibition of bone formation of sympathetic norepinephrine. CB2 receptors on osteoblasts and osteoclasts also modulate the proliferation and functions of these cells. Thus, activation of CB2 stimulates bone formation and represses bone resorption, whereas the genetic disruption of CB2 results in an osteoporosis-like phenotype. This signalling mechanism is clinically relevant, as shown by the association of polymorphisms in the CB2 receptor gene, CNR2, with bone density and osteoporosis. Finally, the review provides a summary of the recently discovered role of endocannabinoid signalling in one elongation. This review will also discuss the benefits of interdisciplinary and international collaborations.

  15. The story of an exceptional serine protease, tissue-type plasminogen activator (tPA).

    PubMed

    Hébert, M; Lesept, F; Vivien, D; Macrez, R

    2016-03-01

    The only acute treatment of ischemic stroke approved by the health authorities is tissue recombinant plasminogen activator (tPA)-induced thrombolysis. Under physiological conditions, tPA, belonging to the serine protease family, is secreted by endothelial and brain cells (neurons, astrocytes, microglia, oligodendrocytes). Although revascularisation induced by tPA is beneficial during a stroke, research over the past 20 years shows that tPA can also be deleterious for the brain parenchyma. Thus, in this review of the literature, after a brief history on the discovery of tPA, we reviewed current knowledge of mechanisms by which tPA can influence brain function in physiological and pathological conditions. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  16. Leveraging the contribution of thermodynamics in drug discovery with the help of fluorescence-based thermal shift assays.

    PubMed

    Hau, Jean Christophe; Fontana, Patrizia; Zimmermann, Catherine; De Pover, Alain; Erdmann, Dirk; Chène, Patrick

    2011-06-01

    The development of new drugs with better pharmacological and safety properties mandates the optimization of several parameters. Today, potency is often used as the sole biochemical parameter to identify and select new molecules. Surprisingly, thermodynamics, which is at the core of any interaction, is rarely used in drug discovery, even though it has been suggested that the selection of scaffolds according to thermodynamic criteria may be a valuable strategy. This poor integration of thermodynamics in drug discovery might be due to difficulties in implementing calorimetry experiments despite recent technological progress in this area. In this report, the authors show that fluorescence-based thermal shift assays could be used as prescreening methods to identify compounds with different thermodynamic profiles. This approach allows a reduction in the number of compounds to be tested in calorimetry experiments, thus favoring greater integration of thermodynamics in drug discovery.

  17. A renaissance of neural networks in drug discovery.

    PubMed

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

    2016-08-01

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

  18. Direct AUC optimization of regulatory motifs.

    PubMed

    Zhu, Lin; Zhang, Hong-Bo; Huang, De-Shuang

    2017-07-15

    The discovery of transcription factor binding site (TFBS) motifs is essential for untangling the complex mechanism of genetic variation under different developmental and environmental conditions. Among the huge amount of computational approaches for de novo identification of TFBS motifs, discriminative motif learning (DML) methods have been proven to be promising for harnessing the discovery power of accumulated huge amount of high-throughput binding data. However, they have to sacrifice accuracy for speed and could fail to fully utilize the information of the input sequences. We propose a novel algorithm called CDAUC for optimizing DML-learned motifs based on the area under the receiver-operating characteristic curve (AUC) criterion, which has been widely used in the literature to evaluate the significance of extracted motifs. We show that when the considered AUC loss function is optimized in a coordinate-wise manner, the cost function of each resultant sub-problem is a piece-wise constant function, whose optimal value can be found exactly and efficiently. Further, a key step of each iteration of CDAUC can be efficiently solved as a computational geometry problem. Experimental results on real world high-throughput datasets illustrate that CDAUC outperforms competing methods for refining DML motifs, while being one order of magnitude faster. Meanwhile, preliminary results also show that CDAUC may also be useful for improving the interpretability of convolutional kernels generated by the emerging deep learning approaches for predicting TF sequences specificities. CDAUC is available at: https://drive.google.com/drive/folders/0BxOW5MtIZbJjNFpCeHlBVWJHeW8 . dshuang@tongji.edu.cn. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

  19. Discovery of rice essential genes by characterizing a CRISPR-edited mutation of closely related rice MAP kinase genes.

    PubMed

    Minkenberg, Bastian; Xie, Kabin; Yang, Yinong

    2017-02-01

    The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 nuclease (Cas9) system depends on a guide RNA (gRNA) to specify its target. By efficiently co-expressing multiple gRNAs that target different genomic sites, the polycistronic tRNA-gRNA gene (PTG) strategy enables multiplex gene editing in the family of closely related mitogen-activated protein kinase (MPK) genes in Oryza sativa (rice). In this study, we identified MPK1 and MPK6 (Arabidopsis AtMPK6 and AtMPK4 orthologs, respectively) as essential genes for rice development by finding the preservation of MPK functional alleles and normal phenotypes in CRISPR-edited mutants. The true knock-out mutants of MPK1 were severely dwarfed and sterile, and homozygous mpk1 seeds from heterozygous parents were defective in embryo development. By contrast, heterozygous mpk6 mutant plants completely failed to produce homozygous mpk6 seeds. In addition, the functional importance of specific MPK features could be evaluated by characterizing CRISPR-induced allelic variation in the conserved kinase domain of MPK6. By simultaneously targeting between two and eight genomic sites in the closely related MPK genes, we demonstrated 45-86% frequency of biallelic mutations and the successful creation of single, double and quadruple gene mutants. Indels and fragment deletion were both stably inherited to the next generations, and transgene-free mutants of rice MPK genes were readily obtained via genetic segregation, thereby eliminating any positional effects of transgene insertions. Taken together, our study reveals the essentiality of MPK1 and MPK6 in rice development, and enables the functional discovery of previously inaccessible genes or domains with phenotypes masked by lethality or redundancy. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

  20. Data Warehouse Discovery Framework: The Case Study

    NASA Astrophysics Data System (ADS)

    Apanowicz, Cas

    The cost of building an Enterprise Data Warehouse Environment runs usually in millions of dollars and takes years to complete. Even bigger than cost is the risk that all the design and development of the Data Warehouse and Business Intelligence Environment may not bring the result expected by the user. This was the main incentive behind author's effort of laying down the foundation for new methodology called Data Warehouse Discovery [1]. The foundation met with acceptance by some scientific groups on one hand and industry interest on the other. At that point, the author faced a major challenge. In order to get industry full acceptance as viable tool for the development and maintenance of a robust DW/BI environment, an actual implementation of the methodology in production was necessary. The DW/BI Strategy and Design Project that author was just conducting for the Canadian Federal Government was a perfect opportunity to propose and implement the methodology. This paper is presenting the conduct and results of that business case.

  1. Mass spectrometry for fragment screening.

    PubMed

    Chan, Daniel Shiu-Hin; Whitehouse, Andrew J; Coyne, Anthony G; Abell, Chris

    2017-11-08

    Fragment-based approaches in chemical biology and drug discovery have been widely adopted worldwide in both academia and industry. Fragment hits tend to interact weakly with their targets, necessitating the use of sensitive biophysical techniques to detect their binding. Common fragment screening techniques include differential scanning fluorimetry (DSF) and ligand-observed NMR. Validation and characterization of hits is usually performed using a combination of protein-observed NMR, isothermal titration calorimetry (ITC) and X-ray crystallography. In this context, MS is a relatively underutilized technique in fragment screening for drug discovery. MS-based techniques have the advantage of high sensitivity, low sample consumption and being label-free. This review highlights recent examples of the emerging use of MS-based techniques in fragment screening. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  2. The Literary Changes: From the Book Room to the Discovery of American Literatures and NCTE

    ERIC Educational Resources Information Center

    Rodriguez, R. Joseph

    2011-01-01

    Using his own experiences as a reader, the author advocates for increased attention to diverse literatures. Since joining National Council of Teachers of English (NCTE) in 1997, the author has worked with members who include preservice, beginning, and experienced educators and scholars; they have formed committees and founded groups for…

  3. Yoga for Exceptional Parents

    ERIC Educational Resources Information Center

    Kuhn, Jackie

    2008-01-01

    In this article, the author shares how Yoga can help make life easier for parents. The author started practicing with a Hatha Yoga teacher once a week at the local church community center. The breath (Pranayama) leads to self-discovery, Yoga poses (asanas) lead to quieting of the mind and self-connection. That was seven years ago, and since then,…

  4. Reading Wide Awake: Politics, Pedagogies, and Possibilities

    ERIC Educational Resources Information Center

    Shannon, Patrick

    2011-01-01

    In his new book, popular author Patrick Shannon examines reading as agency--why reading critically is essential to civic engagement and a healthy democracy. We follow the author on a journey of self discovery as he practices "wide-awake reading" with a variety of everyday texts, from radio programs to legal documents to more traditional books and…

  5. Cognitive Changes, Critical Sessions, and Sudden Gains in Cognitive-Behavioral Therapy for Depression

    ERIC Educational Resources Information Center

    Tang, Tony Z.; DeRubeis, Robert J.; Beberman, Rachel; Pham, Thu

    2005-01-01

    Using an independent cognitive-behavioral therapy (CBT) data set, the authors replicated T. Z. Tang and R. J. DeRubeis' (1999) discovery of sudden gains--sudden and large decreases in depression severity in a single between-session interval. By incorporating therapy session transcripts, the authors of this study improved the reliability of the…

  6. Inspirations in medical genetics.

    PubMed

    Asadollahi, Reza

    2016-02-01

    There are abundant instances in the history of genetics and medical genetics to illustrate how curiosity, charisma of mentors, nature, art, the saving of lives and many other matters have inspired great discoveries. These achievements from deciphering genetic concepts to characterizing genetic disorders have been crucial for management of the patients. There remains, however, a long pathway ahead. © The Author(s) 2014.

  7. What Difference Does It Make? Assessing Outcomes from Participation in a Residential Environmental Education Program

    ERIC Educational Resources Information Center

    Stern, Marc J.; Powell, Robert B.; Ardoin, Nicole M.

    2008-01-01

    The authors explored the influences of 3- and 5-day residential environmental education programs at the Great Smoky Mountains Institute at Tremont (TN) on participants' connections with nature, environmental stewardship, interest in learning and discovery, and awareness of the Great Smoky Mountains National Park and biodiversity. The authors found…

  8. Drug discovery strategies to outer membrane targets in Gram-negative pathogens.

    PubMed

    Brown, Dean G

    2016-12-15

    This review will cover selected recent examples of drug discovery strategies which target the outer membrane (OM) of Gram-negative bacteria either by disruption of outer membrane function or by inhibition of essential gene products necessary for outer membrane assembly. Significant advances in pathway elucidation, structural biology and molecular inhibitor designs have created new opportunities for drug discovery within this target-class space. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. 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.

  10. Data Discovery of Big and Diverse Climate Change Datasets - Options, Practices and Challenges

    NASA Astrophysics Data System (ADS)

    Palanisamy, G.; Boden, T.; McCord, R. A.; Frame, M. T.

    2013-12-01

    Developing data search tools is a very common, but often confusing, task for most of the data intensive scientific projects. These search interfaces need to be continually improved to handle the ever increasing diversity and volume of data collections. There are many aspects which determine the type of search tool a project needs to provide to their user community. These include: number of datasets, amount and consistency of discovery metadata, ancillary information such as availability of quality information and provenance, and availability of similar datasets from other distributed sources. Environmental Data Science and Systems (EDSS) group within the Environmental Science Division at the Oak Ridge National Laboratory has a long history of successfully managing diverse and big observational datasets for various scientific programs via various data centers such as DOE's Atmospheric Radiation Measurement Program (ARM), DOE's Carbon Dioxide Information and Analysis Center (CDIAC), USGS's Core Science Analytics and Synthesis (CSAS) metadata Clearinghouse and NASA's Distributed Active Archive Center (ORNL DAAC). This talk will showcase some of the recent developments for improving the data discovery within these centers The DOE ARM program recently developed a data discovery tool which allows users to search and discover over 4000 observational datasets. These datasets are key to the research efforts related to global climate change. The ARM discovery tool features many new functions such as filtered and faceted search logic, multi-pass data selection, filtering data based on data quality, graphical views of data quality and availability, direct access to data quality reports, and data plots. The ARM Archive also provides discovery metadata to other broader metadata clearinghouses such as ESGF, IASOA, and GOS. In addition to the new interface, ARM is also currently working on providing DOI metadata records to publishers such as Thomson Reuters and Elsevier. The ARM program also provides a standards based online metadata editor (OME) for PIs to submit their data to the ARM Data Archive. USGS CSAS metadata Clearinghouse aggregates metadata records from several USGS projects and other partner organizations. The Clearinghouse allows users to search and discover over 100,000 biological and ecological datasets from a single web portal. The Clearinghouse also enabled some new data discovery functions such as enhanced geo-spatial searches based on land and ocean classifications, metadata completeness rankings, data linkage via digital object identifiers (DOIs), and semantically enhanced keyword searches. The Clearinghouse also currently working on enabling a dashboard which allows the data providers to look at various statistics such as number their records accessed via the Clearinghouse, most popular keywords, metadata quality report and DOI creation service. The Clearinghouse also publishes metadata records to broader portals such as NSF DataONE and Data.gov. The author will also present how these capabilities are currently reused by the recent and upcoming data centers such as DOE's NGEE-Arctic project. References: [1] Devarakonda, R., Palanisamy, G., Wilson, B. E., & Green, J. M. (2010). Mercury: reusable metadata management, data discovery and access system. Earth Science Informatics, 3(1-2), 87-94. [2]Devarakonda, R., Shrestha, B., Palanisamy, G., Hook, L., Killeffer, T., Krassovski, M., ... & Frame, M. (2014, October). OME: Tool for generating and managing metadata to handle BigData. In BigData Conference (pp. 8-10).

  11. Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates

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

    Katz, Francine S.; Pecic, Stevan; Tran, Timothy H.

    Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups—Mannich phenols and general bases—that are capable of reactivating OPC-inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data,more » significantly broaden the available approaches for reactivation of AChE.« less

  12. Deeper than rhizomes, becoming decalcomaniacal: a reflexive response to Murakami and Siegel's "Becoming Bermuda grass"

    NASA Astrophysics Data System (ADS)

    Mitchell, Debra Bailey

    2017-09-01

    In responding to Murakami and Siegel's "Becoming Bermuda grass," one is led to reflect on one's own practice in what becomes an example of reflexivity. Following the authors' lead of incorporating Deleuze and Guattari's rhizomatic theory and the art form of decalcomania to reflect on practice, discoveries are made regarding the practice of a middle school science teacher. These reflective discoveries can be used to inform teaching practice in a manner that supports the development of identities of participation.

  13. Closed-Loop Multitarget Optimization for Discovery of New Emulsion Polymerization Recipes

    PubMed Central

    2015-01-01

    Self-optimization of chemical reactions enables faster optimization of reaction conditions or discovery of molecules with required target properties. The technology of self-optimization has been expanded to discovery of new process recipes for manufacture of complex functional products. A new machine-learning algorithm, specifically designed for multiobjective target optimization with an explicit aim to minimize the number of “expensive” experiments, guides the discovery process. This “black-box” approach assumes no a priori knowledge of chemical system and hence particularly suited to rapid development of processes to manufacture specialist low-volume, high-value products. The approach was demonstrated in discovery of process recipes for a semibatch emulsion copolymerization, targeting a specific particle size and full conversion. PMID:26435638

  14. CLIP-seq analysis of multi-mapped reads discovers novel functional RNA regulatory sites in the human transcriptome.

    PubMed

    Zhang, Zijun; Xing, Yi

    2017-09-19

    Crosslinking or RNA immunoprecipitation followed by sequencing (CLIP-seq or RIP-seq) allows transcriptome-wide discovery of RNA regulatory sites. As CLIP-seq/RIP-seq reads are short, existing computational tools focus on uniquely mapped reads, while reads mapped to multiple loci are discarded. We present CLAM (CLIP-seq Analysis of Multi-mapped reads). CLAM uses an expectation-maximization algorithm to assign multi-mapped reads and calls peaks combining uniquely and multi-mapped reads. To demonstrate the utility of CLAM, we applied it to a wide range of public CLIP-seq/RIP-seq datasets involving numerous splicing factors, microRNAs and m6A RNA methylation. CLAM recovered a large number of novel RNA regulatory sites inaccessible by uniquely mapped reads. The functional significance of these sites was demonstrated by consensus motif patterns and association with alternative splicing (splicing factors), transcript abundance (AGO2) and mRNA half-life (m6A). CLAM provides a useful tool to discover novel protein-RNA interactions and RNA modification sites from CLIP-seq and RIP-seq data, and reveals the significant contribution of repetitive elements to the RNA regulatory landscape of the human transcriptome. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  15. Sulfoquinovose in the biosphere: occurrence, metabolism and functions.

    PubMed

    Goddard-Borger, Ethan D; Williams, Spencer J

    2017-02-20

    The sulfonated carbohydrate sulfoquinovose (SQ) is produced in quantities estimated at some 10 billion tonnes annually and is thus a major participant in the global sulfur biocycle. SQ is produced by most photosynthetic organisms and incorporated into the sulfolipid sulfoquinovosyl diacylglycerol (SQDG), as well as within some archaea for incorporation into glycoprotein N-glycans. SQDG is found mainly within the thylakoid membranes of the chloroplast, where it appears to be important for membrane structure and function and for optimal activity of photosynthetic protein complexes. SQDG metabolism within the sulfur cycle involves complex biosynthetic and catabolic processes. SQDG biosynthesis is largely conserved within plants, algae and bacteria. On the other hand, two major sulfoglycolytic pathways have been discovered for SQDG degradation, the sulfo-Embden-Meyerhof-Parnas (sulfo-EMP) and sulfo-Entner-Doudoroff (sulfo-ED) pathways, which mirror the major steps in the glycolytic EMP and ED pathways. Sulfoglycolysis produces C3-sulfonates, which undergo biomineralization to inorganic sulfur species, completing the sulfur cycle. This review discusses the discovery and structural elucidation of SQDG and archaeal N-glycans, the occurrence, distribution, and speciation of SQDG, and metabolic pathways leading to the biosynthesis of SQDG and its catabolism through sulfoglycolytic and biomineralization pathways to inorganic sulfur. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  16. Loss of function of a rice TPR-domain RNA-binding protein confers broad-spectrum disease resistance.

    PubMed

    Zhou, Xiaogang; Liao, Haicheng; Chern, Mawsheng; Yin, Junjie; Chen, Yufei; Wang, Jianping; Zhu, Xiaobo; Chen, Zhixiong; Yuan, Can; Zhao, Wen; Wang, Jing; Li, Weitao; He, Min; Ma, Bingtian; Wang, Jichun; Qin, Peng; Chen, Weilan; Wang, Yuping; Liu, Jiali; Qian, Yangwen; Wang, Wenming; Wu, Xianjun; Li, Ping; Zhu, Lihuang; Li, Shigui; Ronald, Pamela C; Chen, Xuewei

    2018-03-20

    Crops carrying broad-spectrum resistance loci provide an effective strategy for controlling infectious disease because these loci typically confer resistance to diverse races of a pathogen or even multiple species of pathogens. Despite their importance, only a few crop broad-spectrum resistance loci have been reported. Here, we report the identification and characterization of the rice bsr-k1 (broad-spectrum resistance Kitaake-1) mutant, which confers broad-spectrum resistance against Magnaporthe oryzae and Xanthomonas oryzae pv oryzae with no major penalty on key agronomic traits. Map-based cloning reveals that Bsr-k1 encodes a tetratricopeptide repeats (TPRs)-containing protein, which binds to mRNAs of multiple OsPAL ( OsPAL1-7 ) genes and promotes their turnover. Loss of function of the Bsr-k1 gene leads to accumulation of OsPAL1-7 mRNAs in the bsr-k1 mutant. Furthermore, overexpression of OsPAL1 in wild-type rice TP309 confers resistance to M. oryzae , supporting the role of OsPAL1 Our discovery of the bsr-k1 allele constitutes a significant conceptual advancement and provides a valuable tool for breeding broad-spectrum resistant rice. Copyright © 2018 the Author(s). Published by PNAS.

  17. Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study.

    PubMed

    Pasqualini, Renata; Millikan, Randall E; Christianson, Dawn R; Cardó-Vila, Marina; Driessen, Wouter H P; Giordano, Ricardo J; Hajitou, Amin; Hoang, Anh G; Wen, Sijin; Barnhart, Kirstin F; Baze, Wallace B; Marcott, Valerie D; Hawke, David H; Do, Kim-Anh; Navone, Nora M; Efstathiou, Eleni; Troncoso, Patricia; Lobb, Roy R; Logothetis, Christopher J; Arap, Wadih

    2015-07-15

    Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors ("vascular zip codes") within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature. The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα-based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer. BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m(2) ). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine. These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that functional tumor vascular ligand-receptor targeting systems may be identified through direct combinatorial selection of peptide libraries in cancer patients. © 2015 American Cancer Society.

  18. A Missense Variant in PLEC Increases Risk of Atrial Fibrillation.

    PubMed

    Thorolfsdottir, Rosa B; Sveinbjornsson, Gardar; Sulem, Patrick; Helgadottir, Anna; Gretarsdottir, Solveig; Benonisdottir, Stefania; Magnusdottir, Audur; Davidsson, Olafur B; Rajamani, Sridharan; Roden, Dan M; Darbar, Dawood; Pedersen, Terje R; Sabatine, Marc S; Jonsdottir, Ingileif; Arnar, David O; Thorsteinsdottir, Unnur; Gudbjartsson, Daniel F; Holm, Hilma; Stefansson, Kari

    2017-10-24

    Genome-wide association studies (GWAS) have yielded variants at >30 loci that associate with atrial fibrillation (AF), including rare coding mutations in the sarcomere genes MYH6 and MYL4. The aim of this study was to search for novel AF associations and in doing so gain insights into the mechanisms whereby variants affect AF risk, using electrocardiogram (ECG) measurements. The authors performed a GWAS of 14,255 AF cases and 374,939 controls, using whole-genome sequence data from the Icelandic population, and tested novel signals in 2,002 non-Icelandic cases and 12,324 controls. They then tested the AF variants for effect on cardiac electrical function by using measurements in 289,297 ECGs from 62,974 individuals. The authors discovered 2 novel AF variants, the intergenic variant rs72700114, between the genes LINC01142 and METTL11B (risk allele frequency = 8.1%; odds ratio [OR]: 1.26; p = 3.1 × 10 -18 ), and the missense variant p.Gly4098Ser in PLEC (frequency = 1.2%; OR: 1.55; p = 8.0 × 10 -10 ), encoding plectin, a cytoskeletal cross-linking protein that contributes to integrity of cardiac tissue. The authors also confirmed 29 reported variants. p.Gly4098Ser in PLEC significantly affects various ECG measurements in the absence of AF. Other AF variants have diverse effects on the conduction system, ranging from none to extensive. The discovery of a missense variant in PLEC affecting AF combined with recent discoveries of variants in the sarcomere genes MYH6 and MYL4 points to an important role of myocardial structure in the pathogenesis of the disease. The diverse associations between AF variants and ECG measurements suggest fundamentally different categories of mechanisms contributing to the development of AF. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  19. Evolution of coreceptor utilization to escape CCR5 antagonist therapy.

    PubMed

    Zhang, Jie; Gao, Xiang; Martin, John; Rosa, Bruce; Chen, Zheng; Mitreva, Makedonka; Henrich, Timothy; Kuritzkes, Daniel; Ratner, Lee

    2016-07-01

    The HIV-1 envelope interacts with coreceptors CCR5 and CXCR4 in a dynamic, multi-step process, its molecular details not clearly delineated. Use of CCR5 antagonists results in tropism shift and therapeutic failure. Here we describe a novel approach using full-length patient-derived gp160 quasispecies libraries cloned into HIV-1 molecular clones, their separation based on phenotypic tropism in vitro, and deep sequencing of the resultant variants for structure-function analyses. Analysis of functionally validated envelope sequences from patients who failed CCR5 antagonist therapy revealed determinants strongly associated with coreceptor specificity, especially at the gp120-gp41 and gp41-gp41 interaction surfaces that invite future research on the roles of subunit interaction and envelope trimer stability in coreceptor usage. This study identifies important structure-function relationships in HIV-1 envelope, and demonstrates proof of concept for a new integrated analysis method that facilitates laboratory discovery of resistant mutants to aid in development of other therapeutic agents. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  20. The Popeye domain containing protein family--A novel class of cAMP effectors with important functions in multiple tissues.

    PubMed

    Schindler, Roland F R; Brand, Thomas

    2016-01-01

    Popeye domain containing (Popdc) proteins are a unique family, which combine several different properties and functions in a surprisingly complex fashion. They are expressed in multiple tissues and cell types, present in several subcellular compartments, interact with different classes of proteins, and are associated with a variety of physiological and pathophysiological processes. Moreover, Popdc proteins bind the second messenger cAMP with high affinity and it is thought that they act as a novel class of cAMP effector proteins. Here, we will review the most important findings about the Popdc family, which accumulated since its discovery about 15 years ago. We will be focussing on Popdc protein interaction and function in striated muscle tissue. However, as a full picture only emerges if all aspects are taken into account, we will also describe what is currently known about the role of Popdc proteins in epithelial cells and in various types of cancer, and discuss these findings with regard to their relevance for cardiac and skeletal muscle. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

    PubMed Central

    Tsaioun, Katya; Bottlaender, Michel; Mabondzo, Aloise

    2009-01-01

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

  2. [Frontiers in Live Bone Imaging Researches. Novel drug discovery by means of intravital bone imaging technology].

    PubMed

    Ishii, Masaru

    2015-06-01

    Recent advances in intravital bone imaging technology has enabled us to grasp the real cellular behaviors and functions in vivo , revolutionizing the field of drug discovery for novel therapeutics against intractable bone diseases. In this chapter, I introduce various updated information on pharmacological actions of several antibone resorptive agents, which could only be derived from advanced imaging techniques, and also discuss the future perspectives of this new trend in drug discovery.

  3. FORGE Canada Consortium: outcomes of a 2-year national rare-disease gene-discovery project.

    PubMed

    Beaulieu, Chandree L; Majewski, Jacek; Schwartzentruber, Jeremy; Samuels, Mark E; Fernandez, Bridget A; Bernier, Francois P; Brudno, Michael; Knoppers, Bartha; Marcadier, Janet; Dyment, David; Adam, Shelin; Bulman, Dennis E; Jones, Steve J M; Avard, Denise; Nguyen, Minh Thu; Rousseau, Francois; Marshall, Christian; Wintle, Richard F; Shen, Yaoqing; Scherer, Stephen W; Friedman, Jan M; Michaud, Jacques L; Boycott, Kym M

    2014-06-05

    Inherited monogenic disease has an enormous impact on the well-being of children and their families. Over half of the children living with one of these conditions are without a molecular diagnosis because of the rarity of the disease, the marked clinical heterogeneity, and the reality that there are thousands of rare diseases for which causative mutations have yet to be identified. It is in this context that in 2010 a Canadian consortium was formed to rapidly identify mutations causing a wide spectrum of pediatric-onset rare diseases by using whole-exome sequencing. The FORGE (Finding of Rare Disease Genes) Canada Consortium brought together clinicians and scientists from 21 genetics centers and three science and technology innovation centers from across Canada. From nation-wide requests for proposals, 264 disorders were selected for study from the 371 submitted; disease-causing variants (including in 67 genes not previously associated with human disease; 41 of these have been genetically or functionally validated, and 26 are currently under study) were identified for 146 disorders over a 2-year period. Here, we present our experience with four strategies employed for gene discovery and discuss FORGE's impact in a number of realms, from clinical diagnostics to the broadening of the phenotypic spectrum of many diseases to the biological insight gained into both disease states and normal human development. Lastly, on the basis of this experience, we discuss the way forward for rare-disease genetic discovery both in Canada and internationally. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Balancing novelty with confined chemical space in modern drug discovery.

    PubMed

    Medina-Franco, José L; Martinez-Mayorga, Karina; Meurice, Nathalie

    2014-02-01

    The concept of chemical space has broad applications in drug discovery. In response to the needs of drug discovery campaigns, different approaches are followed to efficiently populate, mine and select relevant chemical spaces that overlap with biologically relevant chemical spaces. This paper reviews major trends in current drug discovery and their impact on the mining and population of chemical space. We also survey different approaches to develop screening libraries with confined chemical spaces balancing physicochemical properties. In this context, the confinement is guided by criteria that can be divided in two broad categories: i) library design focused on a relevant therapeutic target or disease and ii) library design focused on the chemistry or a desired molecular function. The design and development of chemical libraries should be associated with the specific purpose of the library and the project goals. The high complexity of drug discovery and the inherent imperfection of individual experimental and computational technologies prompt the integration of complementary library design and screening approaches to expedite the identification of new and better drugs. Library design approaches including diversity-oriented synthesis, biological-oriented synthesis or combinatorial library design, to name a few, and the design of focused libraries driven by target/disease, chemical structure or molecular function are more efficient if they are guided by multi-parameter optimization. In this context, consideration of pharmaceutically relevant properties is essential for balancing novelty with chemical space in drug discovery.

  5. Plasticity and response to action observation: a longitudinal FMRI study of potential mirror neurons in patients with subacute stroke.

    PubMed

    Brunner, Iris C; Skouen, Jan Sture; Ersland, Lars; Grüner, Renate

    2014-01-01

    Action observation has been suggested as a possible gateway to retraining arm motor function post stroke. However, it is unclear if the neuronal response to action observation is affected by stroke and if it changes during the course of recovery. To examine longitudinal changes in neuronal activity in a group of patients with subacute stroke when observing and executing a bimanual movement task. Eighteen patients were examined twice using 3-T functional magnetic resonance imaging; 1 to 2 weeks and 3 months post stroke symptom onset. Eighteen control participants were examined once. Image time series were analyzed (SPM8) and correlated with clinical motor function scores. During action observation and execution, an overlap of neuronal activation was observed in the superior and inferior parietal lobe, precentral gyrus, insula, and inferior temporal gyrus in both control participants and patients (P < .05; false discovery rate corrected). The neuronal response in the observation task increased from 1 to 2 weeks to 3 months after stroke. Most activated clusters were observed in the inferior temporal gyrus, the thalamus and movement-related areas, such as the premotor, supplementary and motor cortex (BA4, BA6). Increased activation of cerebellum and premotor area correlated with improved arm motor function. Most patients had regained full movement ability. Plastic changes in neurons responding to action observation and action execution occurred in accordance with clinical recovery. The involvement of motor areas when observing actions early and later after stroke may constitute a possible access to the motor system. © The Author(s) 2014.

  6. Dual function of MG53 in membrane repair and insulin signaling

    PubMed Central

    Tan, Tao; Ko, Young-Gyu; Ma, Jianjie

    2016-01-01

    MG53 is a member of the TRIM-family protein that acts as a key component of the cell membrane repair machinery. MG53 is also an E3-ligase that ubiquinates insulin receptor substrate-1 and controls insulin signaling in skeletal muscle cells. Since its discovery in 2009, research efforts have been devoted to translate this basic discovery into clinical applications in human degenerative and metabolic diseases. This review article highlights the dual function of MG53 in cell membrane repair and insulin signaling, the mechanism that underlies the control of MG53 function, and the therapeutic value of targeting MG53 function in regenerative medicine. [BMB Reports 2016; 49(8): 414-423] PMID:27174502

  7. Dream Machines.

    ERIC Educational Resources Information Center

    Merrow, Josh

    1998-01-01

    Junior high students designed their own bicycles from scratch and built them from steel tubing and salvaged parts. The project led to discoveries in math and physics and confidence in working with tools and materials. (Author/JOW)

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

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

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

    1988-10-01

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

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

    USGS Publications Warehouse

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

    1988-01-01

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

  10. The Transuranium Elements: Early History (Nobel Lecture)

    DOE R&D Accomplishments Database

    McMillan, E. M.

    1951-12-12

    In this talk the author tells of the circumstances that led to the discovery of neptunium, the first element beyond uranium, and the partial identification of plutonium, the next one beyond that. The part of the story that lies before 1939 has already been recounted here in the Nobel lectures of Fermi and Hahn. Rather the author starts with the discovery of fission by Hahn and Strassmann. News of this momentous discovery reached Berkeley early in 1939. The staff of the Radiation Laboratory was put into a state of great excitement and several experiments of a nature designed to check and extend the announced results were started, using ionization chambers and pulse amplifiers, cloud chambers, chemical methods, and so forth. The author decided to do an experiment of a very simple kind. When a nucleus of uranium absorbs a neutron and fission takes place, the two resulting fragments fly apart with great violence, sufficient to propel them through air or other matter for some distance. This distance, called the "range", is quantity of some interest, and the author undertook to measure it by observing the depth of penetration of the fission fragments in a stack of thin aluminum foils. The fission fragments came from a thin layer of uranium oxide spread on a sheet of paper, and exposed to neutrons from a beryllium target bombarded by 8 Mev deuterons in the 37-inch cyclotron. The aluminum foils, each with a thickness of about half a milligram per square centimeter, were stacked like the pages of a book in immediate contact with the layer of uranium oxide. After exposure to the neutrons, the sheets of aluminum were separated and examined for radioactivity by means of an ionization chamber. The fission fragments of course are radioactive atoms, and their activity is found where they stop.

  11. The glia doctrine: addressing the role of glial cells in healthy brain ageing.

    PubMed

    Nagelhus, Erlend A; Amiry-Moghaddam, Mahmood; Bergersen, Linda H; Bjaalie, Jan G; Eriksson, Jens; Gundersen, Vidar; Leergaard, Trygve B; Morth, J Preben; Storm-Mathisen, Jon; Torp, Reidun; Walhovd, Kristine B; Tønjum, Tone

    2013-10-01

    Glial cells in their plurality pervade the human brain and impact on brain structure and function. A principal component of the emerging glial doctrine is the hypothesis that astrocytes, the most abundant type of glial cells, trigger major molecular processes leading to brain ageing. Astrocyte biology has been examined using molecular, biochemical and structural methods, as well as 3D brain imaging in live animals and humans. Exosomes are extracelluar membrane vesicles that facilitate communication between glia, and have significant potential for biomarker discovery and drug delivery. Polymorphisms in DNA repair genes may indirectly influence the structure and function of membrane proteins expressed in glial cells and predispose specific cell subgroups to degeneration. Physical exercise may reduce or retard age-related brain deterioration by a mechanism involving neuro-glial processes. It is most likely that additional information about the distribution, structure and function of glial cells will yield novel insight into human brain ageing. Systematic studies of glia and their functions are expected to eventually lead to earlier detection of ageing-related brain dysfunction and to interventions that could delay, reduce or prevent brain dysfunction. Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  12. Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies.

    PubMed

    Kao, Chung-Feng; Chen, Hui-Wen; Chen, Hsi-Chung; Yang, Jenn-Hwai; Huang, Ming-Chyi; Chiu, Yi-Hang; Lin, Shih-Ku; Lee, Ya-Chin; Liu, Chih-Min; Chuang, Li-Chung; Chen, Chien-Hsiun; Wu, Jer-Yuarn; Lu, Ru-Band; Kuo, Po-Hsiu

    2016-12-01

    This study aimed to identify susceptible loci and enriched pathways for bipolar disorder subtype II. We conducted a genome-wide association scan in discovery samples with 189 bipolar disorder subtype II patients and 1773 controls, and replication samples with 283 bipolar disorder subtype II patients and 500 controls in a Taiwanese Han population using Affymetrix Axiom Genome-Wide CHB1 Array. We performed single-marker and gene-based association analyses, as well as calculated polygeneic risk scores for bipolar disorder subtype II. Pathway enrichment analyses were employed to reveal significant biological pathways. Seven markers were found to be associated with bipolar disorder subtype II in meta-analysis combining both discovery and replication samples (P<5.0×10 -6 ), including markers in or close to MYO16, HSP90AB3P, noncoding gene LOC100507632, and markers in chromosomes 4 and 10. A novel locus, ETF1, was associated with bipolar disorder subtype II (P<6.0×10 -3 ) in gene-based association tests. Results of risk evaluation demonstrated that higher genetic risk scores were able to distinguish bipolar disorder subtype II patients from healthy controls in both discovery (P=3.9×10 -4 ~1.0×10 -3 ) and replication samples (2.8×10 -4 ~1.7×10 -3 ). Genetic variance explained by chip markers for bipolar disorder subtype II was substantial in the discovery (55.1%) and replication (60.5%) samples. Moreover, pathways related to neurodevelopmental function, signal transduction, neuronal system, and cell adhesion molecules were significantly associated with bipolar disorder subtype II. We reported novel susceptible loci for pure bipolar subtype II disorder that is less addressed in the literature. Future studies are needed to confirm the roles of these loci for bipolar disorder subtype II. © The Author 2016. Published by Oxford University Press on behalf of CINP.

  13. Functional Metagenomics: Construction and High-Throughput Screening of Fosmid Libraries for Discovery of Novel Carbohydrate-Active Enzymes.

    PubMed

    Ufarté, Lisa; Bozonnet, Sophie; Laville, Elisabeth; Cecchini, Davide A; Pizzut-Serin, Sandra; Jacquiod, Samuel; Demanèche, Sandrine; Simonet, Pascal; Franqueville, Laure; Veronese, Gabrielle Potocki

    2016-01-01

    Activity-based metagenomics is one of the most efficient approaches to boost the discovery of novel biocatalysts from the huge reservoir of uncultivated bacteria. In this chapter, we describe a highly generic procedure of metagenomic library construction and high-throughput screening for carbohydrate-active enzymes. Applicable to any bacterial ecosystem, it enables the swift identification of functional enzymes that are highly efficient, alone or acting in synergy, to break down polysaccharides and oligosaccharides.

  14. Fluorescence anisotropy (polarization): from drug screening to precision medicine

    PubMed Central

    Zhang, Hairong; Wu, Qian; Berezin, Mikhail Y.

    2016-01-01

    Introduction Fluorescence anisotropy (FA) is one of the major established methods accepted by industry and regulatory agencies for understanding the mechanisms of drug action and selecting drug candidates utilizing a high-throughput format. Areas covered This review covers the basics of FA and complementary methods, such as fluorescence lifetime anisotropy and their roles in the drug discovery process. The authors highlight the factors affecting FA readouts, fluorophore selection, and instrumentation. Furthermore, the authors describe the recent development of a successful, commercially valuable FA assay for Long QT syndrome drug toxicity to illustrate the role that FA can play in the early stages of drug discovery. Expert opinion Despite the success in drug discovery, the FA-based technique experiences competitive pressure from other homogeneous assays. That being said, FA is an established yet rapidly developing technique, recognized by academic institutions, the pharmaceutical industry, and regulatory agencies across the globe. The technical problems encountered in working with small molecules in homogeneous assays are largely solved, and new challenges come from more complex biological molecules and nanoparticles. With that, FA will remain one of the major work-horse techniques leading to precision (personalized) medicine. PMID:26289575

  15. Hypnocounseling: Ericksonian Hypnosis for Counselors.

    ERIC Educational Resources Information Center

    Gunnison, Hugh

    1990-01-01

    Describes ways in which Erickson's discoveries and thinking might be used by counselors, specifically describing hypnocounseling. Discusses how Ericksonian language patterns can be adapted by most counselors to their primary orientations and techniques. (Author/ABL)

  16. The Circle of Apollonius: A Discovery Activity.

    ERIC Educational Resources Information Center

    Cain, Ralph W.

    1994-01-01

    Presents an activity using simple constructions and a knowledge of proportions to discover that the sets of points generated by the described procedures are circles. Presents a proof of the result. (Author/MKR)

  17. Economic Geology (Metals)

    ERIC Educational Resources Information Center

    Gair, Jacob E.

    1972-01-01

    Reviews metalliferous ore-deposit research reported in 1971. Research was dominated by isotopic studies, and worldwide metals exploration was marked by announcements of important new discoveries of base metals, iron ore, nickel, titanium, and uranium. (Author/PR)

  18. Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study

    PubMed Central

    Pasqualini, Renata; Millikan, Randall E; Christianson, Dawn R; Cardó-Vila, Marina; Driessen, Wouter H P; Giordano, Ricardo J; Hajitou, Amin; Hoang, Anh G; Wen, Sijin; Barnhart, Kirstin F; Baze, Wallace B; Marcott, Valerie D; Hawke, David H; Do, Kim-Anh; Navone, Nora M; Efstathiou, Eleni; Troncoso, Patricia; Lobb, Roy R; Logothetis, Christopher J; Arap, Wadih

    2015-01-01

    BACKGROUND Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors (“vascular zip codes”) within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature. METHODS The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα–based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer. RESULTS BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m2). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine. CONCLUSIONS These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that functional tumor vascular ligand-receptor targeting systems may be identified through direct combinatorial selection of peptide libraries in cancer patients. Cancer 2015;121:2411–2421. © 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. The authors report on the development of a new ligand-directed peptidomimetic (termed bone metastasis-targeting peptidomimetic-11) for interleukin-11 receptor-based human vascular targeting, including the translation from preclinical studies to a first-in-class, first-in-man clinical trial in patients with metastatic, castrate-resistant prostate cancer. PMID:25832466

  19. About probabilistic integration of ill-posed geophysical tomography and logging data: A knowledge discovery approach versus petrophysical transfer function concepts illustrated using cross-borehole radar-, P- and S-wave traveltime tomography in combination with cone penetration and dielectric logging data

    NASA Astrophysics Data System (ADS)

    Paasche, Hendrik

    2018-01-01

    Site characterization requires detailed and ideally spatially continuous information about the subsurface. Geophysical tomographic experiments allow for spatially continuous imaging of physical parameter variations, e.g., seismic wave propagation velocities. Such physical parameters are often related to typical geotechnical or hydrological target parameters, e.g. as achieved from 1D direct push or borehole logging. Here, the probabilistic inference of 2D tip resistance, sleeve friction, and relative dielectric permittivity distributions in near-surface sediments is constrained by ill-posed cross-borehole seismic P- and S-wave and radar wave traveltime tomography. In doing so, we follow a discovery science strategy employing a fully data-driven approach capable of accounting for tomographic ambiguity and differences in spatial resolution between the geophysical tomograms and the geotechnical logging data used for calibration. We compare the outcome to results achieved employing classical hypothesis-driven approaches, i.e., deterministic transfer functions derived empirically for the inference of 2D sleeve friction from S-wave velocity tomograms and theoretically for the inference of 2D dielectric permittivity from radar wave velocity tomograms. The data-driven approach offers maximal flexibility in combination with very relaxed considerations about the character of the expected links. This makes it a versatile tool applicable to almost any combination of data sets. However, error propagation may be critical and justify thinking about a hypothesis-driven pre-selection of an optimal database going along with the risk of excluding relevant information from the analyses. Results achieved by transfer function rely on information about the nature of the link and optimal calibration settings drawn as retrospective hypothesis by other authors. Applying such transfer functions at other sites turns them into a priori valid hypothesis, which can, particularly for empirically derived transfer functions, result in poor predictions. However, a mindful utilization and critical evaluation of the consequences of turning a retrospectively drawn hypothesis into an a priori valid hypothesis can also result in good results for inference and prediction problems when using classical transfer function concepts.

  20. Measuring the effectiveness and impact of an open innovation platform.

    PubMed

    Carroll, Glenn P; Srivastava, Sanjay; Volini, Adam S; Piñeiro-Núñez, Marta M; Vetman, Tatiana

    2017-05-01

    Today, most pharmaceutical companies complement their traditional R&D models with some variation on the Open Innovation (OI) approach in an effort to better access global scientific talent, ideas and hypotheses. Traditional performance indicators that measure economic returns from R&D through commercialization are often not applicable to the practical assessment of these OI approaches, particularly within the context of early drug discovery. This leaves OI programs focused on early R&D without a standard assessment framework from which to evaluate overall performance. This paper proposes a practical dashboard for such assessment, encompassing quantitative and qualitative elements, to enable decision-making and improvement of future performance. The use of this dashboard is illustrated using real-time data from the Lilly Open Innovation Drug Discovery (OIDD) program. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  1. Role of folic acid in nitric oxide bioavailability and vascular endothelial function.

    PubMed

    Stanhewicz, Anna E; Kenney, W Larry

    2017-01-01

    Folic acid is a member of the B-vitamin family and is essential for amino acid metabolism. Adequate intake of folic acid is vital for metabolism, cellular homeostasis, and DNA synthesis. Since the initial discovery of folic acid in the 1940s, folate deficiency has been implicated in numerous disease states, primarily those associated with neural tube defects in utero and neurological degeneration later in life. However, in the past decade, epidemiological studies have identified an inverse relation between both folic acid intake and blood folate concentration and cardiovascular health. This association inspired a number of clinical studies that suggested that folic acid supplementation could reverse endothelial dysfunction in patients with cardiovascular disease (CVD). Recently, in vitro and in vivo studies have begun to elucidate the mechanism(s) through which folic acid improves vascular endothelial function. These studies, which are the focus of this review, suggest that folic acid and its active metabolite 5-methyl tetrahydrofolate improve nitric oxide (NO) bioavailability by increasing endothelial NO synthase coupling and NO production as well as by directly scavenging superoxide radicals. By improving NO bioavailability, folic acid may protect or improve endothelial function, thereby preventing or reversing the progression of CVD in those with overt disease or elevated CVD risk. © The Author(s) 2016. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. Elongator-dependent modification of cytoplasmic tRNALysUUU is required for mitochondrial function under stress conditions.

    PubMed

    Tigano, Marco; Ruotolo, Roberta; Dallabona, Cristina; Fontanesi, Flavia; Barrientos, Antoni; Donnini, Claudia; Ottonello, Simone

    2015-09-30

    To gain a wider view of the pathways that regulate mitochondrial function, we combined the effect of heat stress on respiratory capacity with the discovery potential of a genome-wide screen in Saccharomyces cerevisiae. We identified 105 new genes whose deletion impairs respiratory growth at 37°C by interfering with processes such as transcriptional regulation, ubiquitination and cytosolic tRNA wobble uridine modification via 5-methoxycarbonylmethyl-2-thiouridine formation. The latter process, specifically required for efficient decoding of AA-ending codons under stress conditions, was covered by multiple genes belonging to the Elongator (e.g. ELP3) and urmylation (e.g., NCS6) pathways. ELP3 or NCS6 deletants had impaired mitochondrial protein synthesis. Their respiratory deficiency was selectively rescued by overexpression of tRNA(Lys) UUU as well by overexpression of genes (BCK1 and HFM1) with a strong bias for the AAA codon read by this tRNA. These data extend the mitochondrial regulome, demonstrate that heat stress can impair respiration by disturbing cytoplasmic translation of proteins critically involved in mitochondrial function and document, for the first time, the involvement in such process of the Elongator and urmylation pathways. Given the conservation of these pathways, the present findings may pave the way to a better understanding of the human mitochondrial regulome in health and disease. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  3. Process Pharmacology: A Pharmacological Data Science Approach to Drug Development and Therapy.

    PubMed

    Lötsch, Jörn; Ultsch, Alfred

    2016-04-01

    A novel functional-genomics based concept of pharmacology that uses artificial intelligence techniques for mining and knowledge discovery in "big data" providing comprehensive information about the drugs' targets and their functional genomics is proposed. In "process pharmacology", drugs are associated with biological processes. This puts the disease, regarded as alterations in the activity in one or several cellular processes, in the focus of drug therapy. In this setting, the molecular drug targets are merely intermediates. The identification of drugs for therapeutic or repurposing is based on similarities in the high-dimensional space of the biological processes that a drug influences. Applying this principle to data associated with lymphoblastic leukemia identified a short list of candidate drugs, including one that was recently proposed as novel rescue medication for lymphocytic leukemia. The pharmacological data science approach provides successful selections of drug candidates within development and repurposing tasks. © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  4. Homogeneous time-resolved G protein-coupled receptor-ligand binding assay based on fluorescence cross-correlation spectroscopy.

    PubMed

    Antoine, Thomas; Ott, David; Ebell, Katharina; Hansen, Kerrin; Henry, Luc; Becker, Frank; Hannus, Stefan

    2016-06-01

    G protein-coupled receptors (GPCRs) mediate many important physiological functions and are considered as one of the most successful therapeutic target classes for a wide spectrum of diseases. Drug discovery projects generally benefit from a broad range of experimental approaches for screening compound libraries and for the characterization of binding modes of drug candidates. Owing to the difficulties in solubilizing and purifying GPCRs, assay formats have been so far mainly limited to cell-based functional assays and radioligand binding assays. In this study, we used fluorescence cross-correlation spectroscopy (FCCS) to analyze the interaction of detergent-solubilized receptors to various types of GPCR ligands: endogenous peptides, small molecules, and a large surrogate antagonist represented by a blocking monoclonal antibody. Our work demonstrates the suitability of the homogeneous and time-resolved FCCS assay format for a robust, high-throughput determination of receptor-ligand binding affinities and kinetic rate constants for various therapeutically relevant GPCRs. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  5. The application of absolute quantitative (1)H NMR spectroscopy in drug discovery and development.

    PubMed

    Singh, Suruchi; Roy, Raja

    2016-07-01

    The identification of a drug candidate and its structural determination is the most important step in the process of the drug discovery and for this, nuclear magnetic resonance (NMR) is one of the most selective analytical techniques. The present review illustrates the various perspectives of absolute quantitative (1)H NMR spectroscopy in drug discovery and development. It deals with the fundamentals of quantitative NMR (qNMR), the physiochemical properties affecting qNMR, and the latest referencing techniques used for quantification. The precise application of qNMR during various stages of drug discovery and development, namely natural product research, drug quantitation in dosage forms, drug metabolism studies, impurity profiling and solubility measurements is elaborated. To achieve this, the authors explore the literature of NMR in drug discovery and development between 1963 and 2015. It also takes into account several other reviews on the subject. qNMR experiments are used for drug discovery and development processes as it is a non-destructive, versatile and robust technique with high intra and interpersonal variability. However, there are several limitations also. qNMR of complex biological samples is incorporated with peak overlap and a low limit of quantification and this can be overcome by using hyphenated chromatographic techniques in addition to NMR.

  6. Applying ADLs to Assess Emerging Industry Specifications for Dynamic Discovery of Ad Hoc Network Services

    DTIC Science & Technology

    2001-01-31

    function of Jini, UPnP, SLP, Bluetooth , and HAVi • Projected specific UML models for Jini, UPnP, and SLP • Developed a Rapide Model of Jini...is used by all JINI entities in directed -- discovery mode. It is part of the SCM_Discovery -- Module. Sends Unicast messages to SCMs on list of... SCMS to be discovered until all SCMS are found. -- Receives updates from SCM DB of discovered SCMs and -- removes SCMs accordingly -- NOTE

  7. 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

  8. Biological Awareness: Statements for Self-Discovery.

    ERIC Educational Resources Information Center

    Edington, D.W.; Cunningham, Lee

    This guide to biological awareness through guided self-discovery is based on 51 single focus statements concerning the human body. For each statement there are explanations of the underlying physiological principles and suggested activities and discussion ideas to encourage understanding of the statement in terms of the human body's functions,…

  9. From Mere Coincidences to Meaningful Discoveries

    ERIC Educational Resources Information Center

    Griffiths, Thomas L.; Tenenbaum, Joshua B.

    2007-01-01

    People's reactions to coincidences are often cited as an illustration of the irrationality of human reasoning about chance. We argue that coincidences may be better understood in terms of rational statistical inference, based on their functional role in processes of causal discovery and theory revision. We present a formal definition of…

  10. CTD² Dashboard: a searchable web interface to connect validated results from the Cancer Target Discovery and Development Network* | Office of Cancer Genomics

    Cancer.gov

    The Cancer Target Discovery and Development (CTD2) Network aims to use functional genomics to accelerate the translation of high-throughput and high-content genomic and small-molecule data towards use in precision oncology.

  11. How the discovery of ribozymes cast RNA in the roles of both chicken and egg in origin-of-life theories.

    PubMed

    Sankaran, Neeraja

    2012-12-01

    Scientific theories about the origin-of-life theories have historically been characterized by the chicken-and-egg problem of which essential aspect of life was the first to appear, replication or self-sustenance. By the 1950s the question was cast in molecular terms and DNA and proteins had come to represent the carriers of the two functions. Meanwhile, RNA, the other nucleic acid, had played a capricious role in origin theories. Because it contained building blocks very similar to DNA, biologists recognized early that RNA could store information in its linear sequences. With the discovery in the 1980s that RNA molecules were capable of biological catalysis, a function hitherto ascribed to proteins alone, RNA took on the role of the single entity that could act as both chicken and egg. Within a few years of the discovery of these catalytic RNAs (ribozymes) scientists had formulated an RNA World hypothesis that posited an early phase in the evolution of life where all key functions were performed by RNA molecules. This paper traces the history the role of RNA in origin-of-life theories with a focus on how the discovery of ribozymes influenced the discourse. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Neoclassic drug discovery: the case for lead generation using phenotypic and functional approaches.

    PubMed

    Lee, Jonathan A; Berg, Ellen L

    2013-12-01

    Innovation and new molecular entity production by the pharmaceutical industry has been below expectations. Surprisingly, more first-in-class small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) between 1999 and 2008 were identified by functional phenotypic lead generation strategies reminiscent of pre-genomics pharmacology than contemporary molecular targeted strategies that encompass the vast majority of lead generation efforts. This observation, in conjunction with the difficulty in validating molecular targets for drug discovery, has diminished the impact of the "genomics revolution" and has led to a growing grassroots movement and now broader trend in pharma to reconsider the use of modern physiology-based or phenotypic drug discovery (PDD) strategies. This "From the Guest Editors" column provides an introduction and overview of the two-part special issues of Journal of Biomolecular Screening on PDD. Terminology and the business case for use of PDD are defined. Key issues such as assay performance, chemical optimization, target identification, and challenges to the organization and implementation of PDD are discussed. Possible solutions for these challenges and a new neoclassic vision for PDD that combines phenotypic and functional approaches with technology innovations resulting from the genomics-driven era of target-based drug discovery (TDD) are also described. Finally, an overview of the manuscripts in this special edition is provided.

  13. Intersecting transcriptomic profiling technologies and long non-coding RNA function in lung adenocarcinoma: discovery, mechanisms, and therapeutic applications

    PubMed Central

    Castillo, Jonathan; Stueve, Theresa R.; Marconett, Crystal N.

    2017-01-01

    Previously thought of as junk transcripts and pseudogene remnants, long non-coding RNAs (lncRNAs) have come into their own over the last decade as an essential component of cellular activity, regulating a plethora of functions within multicellular organisms. lncRNAs are now known to participate in development, cellular homeostasis, immunological processes, and the development of disease. With the advent of next generation sequencing technology, hundreds of thousands of lncRNAs have been identified. However, movement beyond mere discovery to the understanding of molecular processes has been stymied by the complicated genomic structure, tissue-restricted expression, and diverse regulatory roles lncRNAs play. In this review, we will focus on lncRNAs involved in lung cancer, the most common cause of cancer-related death in the United States and worldwide. We will summarize their various methods of discovery, provide consensus rankings of deregulated lncRNAs in lung cancer, and describe in detail the limited functional analysis that has been undertaken so far. PMID:29113413

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

    PubMed

    Thaut, Michael H

    2015-01-01

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

  15. Application of encoded library technology (ELT) to a protein-protein interaction target: discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists.

    PubMed

    Kollmann, Christopher S; Bai, Xiaopeng; Tsai, Ching-Hsuan; Yang, Hongfang; Lind, Kenneth E; Skinner, Steven R; Zhu, Zhengrong; Israel, David I; Cuozzo, John W; Morgan, Barry A; Yuki, Koichi; Xie, Can; Springer, Timothy A; Shimaoka, Motomu; Evindar, Ghotas

    2014-04-01

    The inhibition of protein-protein interactions remains a challenge for traditional small molecule drug discovery. Here we describe the use of DNA-encoded library technology for the discovery of small molecules that are potent inhibitors of the interaction between lymphocyte function-associated antigen 1 and its ligand intercellular adhesion molecule 1. A DNA-encoded library with a potential complexity of 4.1 billion compounds was exposed to the I-domain of the target protein and the bound ligands were affinity selected, yielding an enriched small-molecule hit family. Compounds representing this family were synthesized without their DNA encoding moiety and found to inhibit the lymphocyte function-associated antigen 1/intercellular adhesion molecule-1 interaction with submicromolar potency in both ELISA and cell adhesion assays. Re-synthesized compounds conjugated to DNA or a fluorophore were demonstrated to bind to cells expressing the target protein. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Greater than the sum of its parts: single-nucleus sequencing identifies convergent evolution of independent EGFR mutants in GBM.

    PubMed

    Gini, Beatrice; Mischel, Paul S

    2014-08-01

    Single-cell sequencing approaches are needed to characterize the genomic diversity of complex tumors, shedding light on their evolutionary paths and potentially suggesting more effective therapies. In this issue of Cancer Discovery, Francis and colleagues develop a novel integrative approach to identify distinct tumor subpopulations based on joint detection of clonal and subclonal events from bulk tumor and single-nucleus whole-genome sequencing, allowing them to infer a subclonal architecture. Surprisingly, the authors identify convergent evolution of multiple, mutually exclusive, independent EGFR gain-of-function variants in a single tumor. This study demonstrates the value of integrative single-cell genomics and highlights the biologic primacy of EGFR as an actionable target in glioblastoma. ©2014 American Association for Cancer Research.

  17. Ten years of Nature Reviews Neuroscience: insights from the highly cited

    PubMed Central

    Luo, Liqun; Rodriguez, Eugenio; Jerbi, Karim; Lachaux, Jean-Philippe; Martinerie, Jacques; Corbetta, Maurizio; Shulman, Gordon L.; Piomelli, Daniele; Turrigiano, Gina G.; Nelson, Sacha B.; Joëls, Marian; de Kloet, E. Ronald; Holsboer, Florian; Amodio, David M.; Frith, Chris D.; Block, Michelle L.; Zecca, Luigi; Hong, Jau-Shyong; Dantzer, Robert; Kelley, Keith W.; Craig, A. D. (Bud)

    2012-01-01

    To celebrate the first 10 years of Nature Reviews Neuroscience, we invited the authors of the most cited article of each year to look back on the state of their field of research at the time of publication and the impact their article has had, and to discuss the questions that might be answered in the next 10 years. This selection of highly cited articles provides interesting snapshots of the progress that has been made in diverse areas of neuroscience. They show the enormous influence of neuroimaging techniques and highlight concepts that have generated substantial interest in the past decade, such as neuroimmunology, social neuroscience and the `network approach' to brain function. These advancements will pave the way for further exciting discoveries that lie ahead. PMID:20852655

  18. Integrated Computational Analysis of Genes Associated with Human Hereditary Insensitivity to Pain. A Drug Repurposing Perspective

    PubMed Central

    Lötsch, Jörn; Lippmann, Catharina; Kringel, Dario; Ultsch, Alfred

    2017-01-01

    Genes causally involved in human insensitivity to pain provide a unique molecular source of studying the pathophysiology of pain and the development of novel analgesic drugs. The increasing availability of “big data” enables novel research approaches to chronic pain while also requiring novel techniques for data mining and knowledge discovery. We used machine learning to combine the knowledge about n = 20 genes causally involved in human hereditary insensitivity to pain with the knowledge about the functions of thousands of genes. An integrated computational analysis proposed that among the functions of this set of genes, the processes related to nervous system development and to ceramide and sphingosine signaling pathways are particularly important. This is in line with earlier suggestions to use these pathways as therapeutic target in pain. Following identification of the biological processes characterizing hereditary insensitivity to pain, the biological processes were used for a similarity analysis with the functions of n = 4,834 database-queried drugs. Using emergent self-organizing maps, a cluster of n = 22 drugs was identified sharing important functional features with hereditary insensitivity to pain. Several members of this cluster had been implicated in pain in preclinical experiments. Thus, the present concept of machine-learned knowledge discovery for pain research provides biologically plausible results and seems to be suitable for drug discovery by identifying a narrow choice of repurposing candidates, demonstrating that contemporary machine-learned methods offer innovative approaches to knowledge discovery from available evidence. PMID:28848388

  19. Flower development: the evolutionary history and functions of the AGL6 subfamily MADS-box genes.

    PubMed

    Dreni, Ludovico; Zhang, Dabing

    2016-03-01

    AGL6 is an ancient subfamily of MADS-box genes found in both gymnosperms and angiosperms. Its functions remained elusive despite the fact that the MADS-box genes and the ABC model have been studied for >20 years. Nevertheless, recent discoveries in petunia, rice, and maize support its involvement in the 'E' function of floral development, very similar to the closely related AGL2 (SEPALLATA) subfamily which has been well characterized. The known functions of AGL6 span from ancient conserved roles to new functions acquired in specific plant families. The AGL6 genes are involved in floral meristem regulation, in floral organs, and ovule (integument) and seed development, and have possible roles in both male and female germline and gametophyte development. In grasses, they are also important for the development of the first whorl of the flower, whereas in Arabidopsis they may play additional roles before floral meristem formation. This review covers these recent insights and some other aspects that are not yet fully elucidated, which deserve more studies in the future. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  20. DUBLIN CORE

    EPA Science Inventory

    The Dublin Core is a metadata element set intended to facilitate discovery of electronic resources. It was originally conceived for author-generated descriptions of Web resources, and the Dublin Core has attracted broad ranging international and interdisciplinary support. The cha...

  1. 42 CFR 426.405 - Authority of the ALJ.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...) Consult with scientific and clinical experts on his or her own motion concerning clinical or scientific... documentary discovery as permitted by this part. (15) Regulate the course of a hearing and the conduct of...

  2. 42 CFR 426.405 - Authority of the ALJ.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...) Consult with scientific and clinical experts on his or her own motion concerning clinical or scientific... documentary discovery as permitted by this part. (15) Regulate the course of a hearing and the conduct of...

  3. Hunting Spinning Asteroids with the Faulkes Telescopes

    NASA Astrophysics Data System (ADS)

    Miles, Richard

    2008-08-01

    The Faulkes telescopes are proving a dab hand at allowing schools and amateurs to do real science. The author discusses the latest Faulkes research project, and his record-breaking discovery that was pert of it.

  4. Molecular genetics of early-onset Alzheimer's disease revisited.

    PubMed

    Cacace, Rita; Sleegers, Kristel; Van Broeckhoven, Christine

    2016-06-01

    As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Space and Place and the "American" Legacy: Female Protagonists and the Discovery of Self in Two Novels for Young Adults

    ERIC Educational Resources Information Center

    Glenn, Wendy J.

    2017-01-01

    This qualitative literary analysis explores the intersection of place, space, and identity in two novels for young adults to explore how the provision of a new physical place provides space for independence development among female teen protagonists and the implications of this development given the authors' identities as non-US authors writing…

  6. Five Decades of Research in Speech Motor Control: What Have We Learned, and Where Should We Go from Here?

    ERIC Educational Resources Information Center

    Perkell, Joseph S.

    2013-01-01

    Purpose: The author presents a view of research in speech motor control over the past 5 decades, as observed from within Ken Stevens's Speech Communication Group (SCG) in the Research Laboratory of Electronics at MIT. Method: The author presents a limited overview of some important developments and discoveries. The perspective is based…

  7. Daisies on the Road: Tracing the Political Potential of Our Postmodernist, Feminist Approach to Life Story Research

    ERIC Educational Resources Information Center

    Roets, Griet; Goedgeluck, Marijke

    2007-01-01

    In this article, the authors trace the possible political potential of their post-modernist, feminist approach to life story research with people with the label of "learning difficulties." As a self-advocate with an ally, they define tagging along with each other as discovery science. The authors reflect on how they openly and critically write…

  8. Thinking Is Fun! Thinking Skills Stimulate Enjoyment in the Classroom for Both Teachers and Pupils

    ERIC Educational Resources Information Center

    Boardman, Pam

    2004-01-01

    This article tells the story of the author's discovery of thinking skills, how this has affected her teaching, and how these ideas have now spread to other curriculum areas in her school. In November 2001 the author began to carry out a research project on thinking skills, introducing new activities into lessons to encourage pupils to think and…

  9. Self-Discovery through Character Connections: Opening up to Gayness in "Angels in America"

    ERIC Educational Resources Information Center

    Blazar, David

    2009-01-01

    In this article, the author describes how he uses performance pedagogy to open students' minds to sexuality and gender issues. The author uses Tony Kushner's "Angels in America: A Gay Fantasia on National Themes"--an epic play about the AIDS epidemic and its impact on the gay community in the 1980s. Through the possibilities of drama available in…

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

    PubMed

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

    2014-02-15

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

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

    PubMed

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

    2012-12-01

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

  12. On the cradle of CCM research: discovery, development, and challenges ahead.

    PubMed

    Kaplan, Aaron

    2017-06-01

    Herein, 40 years after its discovery, I briefly and critically survey the development of ideas that propelled research on CO2-concentrating mechanisms (CCMs; a term proposed by Dean Price) of phytoplankton, mainly focusing on cyanobacteria. This is not a comprehensive review on CCM research, but a personal view on the past developments and challenges that lie ahead. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  13. Process model-based atomic service discovery and composition of composite semantic web services using web ontology language for services (OWL-S)

    NASA Astrophysics Data System (ADS)

    Paulraj, D.; Swamynathan, S.; Madhaiyan, M.

    2012-11-01

    Web Service composition has become indispensable as a single web service cannot satisfy complex functional requirements. Composition of services has received much interest to support business-to-business (B2B) or enterprise application integration. An important component of the service composition is the discovery of relevant services. In Semantic Web Services (SWS), service discovery is generally achieved by using service profile of Ontology Web Languages for Services (OWL-S). The profile of the service is a derived and concise description but not a functional part of the service. The information contained in the service profile is sufficient for atomic service discovery, but it is not sufficient for the discovery of composite semantic web services (CSWS). The purpose of this article is two-fold: first to prove that the process model is a better choice than the service profile for service discovery. Second, to facilitate the composition of inter-organisational CSWS by proposing a new composition method which uses process ontology. The proposed service composition approach uses an algorithm which performs a fine grained match at the level of atomic process rather than at the level of the entire service in a composite semantic web service. Many works carried out in this area have proposed solutions only for the composition of atomic services and this article proposes a solution for the composition of composite semantic web services.

  14. Targeting BCL2 With BH3 Mimetics: Basic Science and Clinical Application of Venetoclax in Chronic Lymphocytic Leukemia and Related B Cell Malignancies.

    PubMed

    Roberts, A W; Huang, Dcs

    2017-01-01

    The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed. Venetoclax (formerly ABT-199) is the first to achieve US Food and Drug Administration approval, with an indication for treatment of patients with previously treated chronic lymphocytic leukemia (CLL) bearing deletion of the long arm of chromosome 17. Here, we review key aspects of the science underpinning the clinical application of BCL2 inhibitors and explore both our current knowledge and unresolved questions about its clinical utility, both in CLL and in other B-cell malignancies that highly express BCL2. © 2016 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  15. Strategies for discovery and improvement of enzyme function: state of the art and opportunities.

    PubMed

    Kaul, Praveen; Asano, Yasuhisa

    2012-01-01

    Developments in biocatalysis have been largely fuelled by consumer demands for new products, industrial attempts to improving existing process and minimizing waste, coupled with governmental measures to regulate consumer safety along with scientific advancements. One of the major hurdles to application of biocatalysis to chemical synthesis is unavailability of the desired enzyme to catalyse the reaction to allow for a viable process development. Even when the desired enzyme is available it often forces the process engineers to alter process parameters due to inadequacies of the enzyme, such as instability, inhibition, low yield or selectivity, etc. Developments in the field of enzyme or reaction engineering have allowed access to means to achieve the ends, such as directed evolution, de novo protein design, use of non-conventional media, using new substrates for old enzymes, active-site imprinting, altering temperature, etc. Utilization of enzyme discovery and improvement tools therefore provides a feasible means to overcome this problem. Judicious employment of these tools has resulted in significant advancements that have leveraged the research from laboratory to market thus impacting economic growth; however, there are further opportunities that have not yet been explored. The present review attempts to highlight some of these achievements and potential opportunities. © 2011 The Authors. Microbial Biotechnology © 2011 Society for Applied Microbiology and Blackwell Publishing Ltd.

  16. Scaling up discovery of hidden diversity in fungi: impacts of barcoding approaches.

    PubMed

    Yahr, Rebecca; Schoch, Conrad L; Dentinger, Bryn T M

    2016-09-05

    The fungal kingdom is a hyperdiverse group of multicellular eukaryotes with profound impacts on human society and ecosystem function. The challenge of documenting and describing fungal diversity is exacerbated by their typically cryptic nature, their ability to produce seemingly unrelated morphologies from a single individual and their similarity in appearance to distantly related taxa. This multiplicity of hurdles resulted in the early adoption of DNA-based comparisons to study fungal diversity, including linking curated DNA sequence data to expertly identified voucher specimens. DNA-barcoding approaches in fungi were first applied in specimen-based studies for identification and discovery of taxonomic diversity, but are now widely deployed for community characterization based on sequencing of environmental samples. Collectively, fungal barcoding approaches have yielded important advances across biological scales and research applications, from taxonomic, ecological, industrial and health perspectives. A major outstanding issue is the growing problem of 'sequences without names' that are somewhat uncoupled from the traditional framework of fungal classification based on morphology and preserved specimens. This review summarizes some of the most significant impacts of fungal barcoding, its limitations, and progress towards the challenge of effective utilization of the exponentially growing volume of data gathered from high-throughput sequencing technologies.This article is part of the themed issue 'From DNA barcodes to biomes'. © 2016 The Authors.

  17. Discovery and preclinical development of dasabuvir for the treatment of hepatitis C infection.

    PubMed

    El Kassas, Mohamed; Elbaz, Tamer; Hafez, Enas; Wifi, Mohamed Naguib; Esmat, Gamal

    2017-06-01

    Hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality. Positively, the introduction of new directly-acting antivirals (DAAs) have led to dramatic improvements in response rates to antiviral therapy. Furthermore, newer generations of DAAs have demonstrated better safety profiles as well as efficacy than older generations. Current treatment recommendations are based on different combinations of DAAs. Current combination therapies rely on agents that target the different steps of viral replication by using different molecules from various DAAs families. Areas covered: In this review, the authors summarize data from of one of the recently developed NS5B polymerase inhibitors, dasabuvir, formerly known as ABT-333. Herein, the authors discuss the drug discovery data for dasabuvir including data from preclinical, toxicological resistance studies. The authors also review dasabuvir's clinical efficacy across various clinical challenges, in addition to its limitations in clinical practice. Expert opinion: Dasabuvir represents an important medical advance when used as a combination therapy for HCV. Unfortunately, it does present limitations like low genotypic coverage and further research is still required to address some of the lingering issues.

  18. Genomics and transcriptomics in drug discovery.

    PubMed

    Dopazo, Joaquin

    2014-02-01

    The popularization of genomic high-throughput technologies is causing a revolution in biomedical research and, particularly, is transforming the field of drug discovery. Systems biology offers a framework to understand the extensive human genetic heterogeneity revealed by genomic sequencing in the context of the network of functional, regulatory and physical protein-drug interactions. Thus, approaches to find biomarkers and therapeutic targets will have to take into account the complex system nature of the relationships of the proteins with the disease. Pharmaceutical companies will have to reorient their drug discovery strategies considering the human genetic heterogeneity. Consequently, modeling and computational data analysis will have an increasingly important role in drug discovery. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Open Drug Discovery Toolkit (ODDT): a new open-source player in the drug discovery field.

    PubMed

    Wójcikowski, Maciej; Zielenkiewicz, Piotr; Siedlecki, Pawel

    2015-01-01

    There has been huge progress in the open cheminformatics field in both methods and software development. Unfortunately, there has been little effort to unite those methods and software into one package. We here describe the Open Drug Discovery Toolkit (ODDT), which aims to fulfill the need for comprehensive and open source drug discovery software. The Open Drug Discovery Toolkit was developed as a free and open source tool for both computer aided drug discovery (CADD) developers and researchers. ODDT reimplements many state-of-the-art methods, such as machine learning scoring functions (RF-Score and NNScore) and wraps other external software to ease the process of developing CADD pipelines. ODDT is an out-of-the-box solution designed to be easily customizable and extensible. Therefore, users are strongly encouraged to extend it and develop new methods. We here present three use cases for ODDT in common tasks in computer-aided drug discovery. Open Drug Discovery Toolkit is released on a permissive 3-clause BSD license for both academic and industrial use. ODDT's source code, additional examples and documentation are available on GitHub (https://github.com/oddt/oddt).

  20. Drug discovery for male subfertility using high-throughput screening: a new approach to an unsolved problem

    PubMed Central

    Martins da Silva, Sarah J.; Brown, Sean G.; Sutton, Keith; King, Louise V.; Ruso, Halil; Gray, David W.; Wyatt, Paul G.; Kelly, Mark C.; Barratt, Christopher L.R.; Hope, Anthony G.

    2017-01-01

    Abstract STUDY QUESTION Can pharma drug discovery approaches be utilized to transform investigation into novel therapeutics for male infertility? SUMMARY ANSWER High-throughput screening (HTS) is a viable approach to much-needed drug discovery for male factor infertility. WHAT IS KNOWN ALREADY There is both huge demand and a genuine clinical need for new treatment options for infertile men. However, the time, effort and resources required for drug discovery are currently exorbitant, due to the unique challenges of the cellular, physical and functional properties of human spermatozoa and a lack of appropriate assay platform. STUDY DESIGN, SIZE, DURATION Spermatozoa were obtained from healthy volunteer research donors and subfertile patients undergoing IVF/ICSI at a hospital-assisted reproductive techniques clinic between January 2012 and November 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS A HTS assay was developed and validated using intracellular calcium ([Ca2+]i) as a surrogate for motility in human spermatozoa. Calcium fluorescence was detected using a Flexstation microplate reader (384-well platform) and compared with responses evoked by progesterone, a compound known to modify a number of biologically relevant behaviours in human spermatozoa. Hit compounds identified following single point drug screen (10 μM) of an ion channel-focussed library assembled by the University of Dundee Drug Discovery Unit were rescreened to ensure potency using standard 10 point half-logarithm concentration curves, and tested for purity and integrity using liquid chromatography and mass spectrometry. Hit compounds were grouped by structure activity relationships and five representative compounds then further investigated for direct effects on spermatozoa, using computer-assisted sperm assessment, sperm penetration assay and whole-cell patch clamping. MAIN RESULTS AND THE ROLE OF CHANCE Of the 3242 ion channel library ligands screened, 384 compounds (11.8%) elicited a statistically significant increase in calcium fluorescence, with greater than 3× median absolute deviation above the baseline. Seventy-four compounds eliciting ≥50% increase in fluorescence in the primary screen were rescreened and evaluated further, resulting in 48 hit compounds that produced a concentration-dependent increase in [Ca2+]i. Sperm penetration studies confirmed in vitro exposure to two hit compounds (A and B) resulted in significant improvement in functional motility in spermatozoa from healthy volunteer donors (A: 1 cm penetration index 2.54, 2 cm penetration index 2.49; P < 0.005 and B: 1 cm penetration index 2.1, 2 cm penetration index 2.6; P < 0.005), but crucially, also in patient samples from those undergoing fertility treatment (A: 1 cm penetration index 2.4; P = 0.009, 2 cm penetration index 3.6; P = 0.02 and B: 1 cm penetration index 2.2; P = 0.0004, 2 cm penetration index 3.6; P = 0.002). This was primarily as a result of direct or indirect CatSper channel action, supported by evidence from electrophysiology studies of individual sperm. LIMITATIONS, REASONS FOR CAUTION Increase and fluxes in [Ca2+]i are fundamental to the regulation of sperm motility and function, including acrosome reaction. The use of calcium signalling as a surrogate for sperm motility is acknowledged as a potential limitation in this study. WIDER IMPLICATIONS OF THE FINDINGS We conclude that HTS can robustly, efficiently, identify novel compounds that increase [Ca2+]i in human spermatozoa and functionally modify motility, and propose its use as a cornerstone to build and transform much-needed drug discovery for male infertility. STUDY FUNDING/COMPETING INTEREST(S) The majority of the data were obtained using funding from TENOVUS Scotland and Chief Scientist Office NRS Fellowship. Additional funding was provided by NHS Tayside, MRC project grants (MR/K013343/1, MR/012492/1) and University of Abertay. The authors declare that there is no conflict of interest. TRAIL REGISTRATION NUMBER N/A. PMID:28333338

  1. Early Probe and Drug Discovery in Academia: A Minireview.

    PubMed

    Roy, Anuradha

    2018-02-09

    Drug discovery encompasses processes ranging from target selection and validation to the selection of a development candidate. While comprehensive drug discovery work flows are implemented predominantly in the big pharma domain, early discovery focus in academia serves to identify probe molecules that can serve as tools to study targets or pathways. Despite differences in the ultimate goals of the private and academic sectors, the same basic principles define the best practices in early discovery research. A successful early discovery program is built on strong target definition and validation using a diverse set of biochemical and cell-based assays with functional relevance to the biological system being studied. The chemicals identified as hits undergo extensive scaffold optimization and are characterized for their target specificity and off-target effects in in vitro and in animal models. While the active compounds from screening campaigns pass through highly stringent chemical and Absorption, Distribution, Metabolism, and Excretion (ADME) filters for lead identification, the probe discovery involves limited medicinal chemistry optimization. The goal of probe discovery is identification of a compound with sub-µM activity and reasonable selectivity in the context of the target being studied. The compounds identified from probe discovery can also serve as starting scaffolds for lead optimization studies.

  2. Modeling & Informatics at Vertex Pharmaceuticals Incorporated: our philosophy for sustained impact

    NASA Astrophysics Data System (ADS)

    McGaughey, Georgia; Patrick Walters, W.

    2017-03-01

    Molecular modelers and informaticians have the unique opportunity to integrate cross-functional data using a myriad of tools, methods and visuals to generate information. Using their drug discovery expertise, information is transformed to knowledge that impacts drug discovery. These insights are often times formulated locally and then applied more broadly, which influence the discovery of new medicines. This is particularly true in an organization where the members are exposed to projects throughout an organization, such as in the case of the global Modeling & Informatics group at Vertex Pharmaceuticals. From its inception, Vertex has been a leader in the development and use of computational methods for drug discovery. In this paper, we describe the Modeling & Informatics group at Vertex and the underlying philosophy, which has driven this team to sustain impact on the discovery of first-in-class transformative medicines.

  3. The ``Missing Compounds'' affair in functionality-driven material discovery

    NASA Astrophysics Data System (ADS)

    Zunger, Alex

    2014-03-01

    In the paradigm of ``data-driven discovery,'' underlying one of the leading streams of the Material Genome Initiative (MGI), one attempts to compute high-throughput style as many of the properties of as many of the N (about 10**5- 10**6) compounds listed in databases of previously known compounds. One then inspects the ensuing Big Data, searching for useful trends. The alternative and complimentary paradigm of ``functionality-directed search and optimization'' used here, searches instead for the n much smaller than N configurations and compositions that have the desired value of the target functionality. Examples include the use of genetic and other search methods that optimize the structure or identity of atoms on lattice sites, using atomistic electronic structure (such as first-principles) approaches in search of a given electronic property. This addresses a few of the bottlenecks that have faced the alternative, data-driven/high throughput/Big Data philosophy: (i) When the configuration space is theoretically of infinite size, building a complete data base as in data-driven discovery is impossible, yet searching for the optimum functionality, is still a well-posed problem. (ii) The configuration space that we explore might include artificially grown, kinetically stabilized systems (such as 2D layer stacks; superlattices; colloidal nanostructures; Fullerenes) that are not listed in compound databases (used by data-driven approaches), (iii) a large fraction of chemically plausible compounds have not been experimentally synthesized, so in the data-driven approach these are often skipped. In our approach we search explicitly for such ``Missing Compounds''. It is likely that many interesting material properties will be found in cases (i)-(iii) that elude high throughput searches based on databases encapsulating existing knowledge. I will illustrate (a) Functionality-driven discovery of topological insulators and valley-split quantum-computer semiconductors, as well as (b) Use of ``first principles thermodynamics'' to discern which of the previously ``missing compounds'' should, in fact exist and in which structure. Synthesis efforts by Poeppelmeier group at NU realized 20 never-before-made half-Heusler compounds out of the 20 predicted ones, in our predicted space groups. This type of theory-led experimental search of designed materials with target functionalities may shorten the current process of discovery of interesting functional materials. Supported by DOE ,Office of Science, Energy Frontier Research Center for Inverse Design

  4. Ties that bind: the integration of plastid signalling pathways in plant cell metabolism.

    PubMed

    Brunkard, Jacob O; Burch-Smith, Tessa M

    2018-04-13

    Plastids are critical organelles in plant cells that perform diverse functions and are central to many metabolic pathways. Beyond their major roles in primary metabolism, of which their role in photosynthesis is perhaps best known, plastids contribute to the biosynthesis of phytohormones and other secondary metabolites, store critical biomolecules, and sense a range of environmental stresses. Accordingly, plastid-derived signals coordinate a host of physiological and developmental processes, often by emitting signalling molecules that regulate the expression of nuclear genes. Several excellent recent reviews have provided broad perspectives on plastid signalling pathways. In this review, we will highlight recent advances in our understanding of chloroplast signalling pathways. Our discussion focuses on new discoveries illuminating how chloroplasts determine life and death decisions in cells and on studies elucidating tetrapyrrole biosynthesis signal transduction networks. We will also examine the role of a plastid RNA helicase, ISE2, in chloroplast signalling, and scrutinize intriguing results investigating the potential role of stromules in conducting signals from the chloroplast to other cellular locations. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  5. Sustainable funding for biocuration: The Arabidopsis Information Resource (TAIR) as a case study of a subscription-based funding model.

    PubMed

    Reiser, Leonore; Berardini, Tanya Z; Li, Donghui; Muller, Robert; Strait, Emily M; Li, Qian; Mezheritsky, Yarik; Vetushko, Andrey; Huala, Eva

    2016-01-01

    Databases and data repositories provide essential functions for the research community by integrating, curating, archiving and otherwise packaging data to facilitate discovery and reuse. Despite their importance, funding for maintenance of these resources is increasingly hard to obtain. Fueled by a desire to find long term, sustainable solutions to database funding, staff from the Arabidopsis Information Resource (TAIR), founded the nonprofit organization, Phoenix Bioinformatics, using TAIR as a test case for user-based funding. Subscription-based funding has been proposed as an alternative to grant funding but its application has been very limited within the nonprofit sector. Our testing of this model indicates that it is a viable option, at least for some databases, and that it is possible to strike a balance that maximizes access while still incentivizing subscriptions. One year after transitioning to subscription support, TAIR is self-sustaining and Phoenix is poised to expand and support additional resources that wish to incorporate user-based funding strategies. Database URL: www.arabidopsis.org. © The Author(s) 2016. Published by Oxford University Press.

  6. Ethical, legal, and social issues related to genomics and cancer research: the impending crisis.

    PubMed

    Ellerin, Bruce E; Schneider, Robert J; Stern, Arnold; Toniolo, Paolo G; Formenti, Silvia C

    2005-11-01

    Cancer research is a multibillion-dollar enterprise validated by the clinical trial process and increasingly defined by genomics. The continued success of the endeavor depends on the smooth functioning of the clinical trial system, which in turn depends on human subject participation. Yet human subject participation can exist only in an atmosphere of trust between research participants and research sponsors, and the advent of genomics has raised a multitude of ethical, legal, and social issues that threaten this trust. The authors examine 6 of these issues: (1) informed consent; (2) privacy, confidentiality, and family disclosure dilemmas; (3) property rights in genomic discoveries; (4) individual and institutional conflicts of interest; (5) insurance and employment issues; and (6) litigation under the federal False Claims Act. The authors conclude that failure to resolve these issues may lead to a sufficient impairment of trust in genomics-based clinical trials on the part of potential research participants that the clinical trial system may implode for lack of willing participants, thus threatening the future of cancer research.

  7. Overcoming HERG affinity in the discovery of the CCR5 antagonist maraviroc.

    PubMed

    Price, David A; Armour, Duncan; de Groot, Marcel; Leishman, Derek; Napier, Carolyn; Perros, Manos; Stammen, Blanda L; Wood, Anthony

    2006-09-01

    The discovery of maraviroc 17 is described with particular reference to the generation of high selectivity over affinity for the HERG potassium channel. This was achieved through the use of a high throughput binding assay for the HERG channel that is known to show an excellent correlation with functional effects.

  8. Some Applications of Fourier's Great Discovery for Beginners

    ERIC Educational Resources Information Center

    Kraftmakher, Yaakov

    2012-01-01

    Nearly two centuries ago, Fourier discovered that any periodic function of period T can be presented as a sum of sine waveforms of frequencies equal to an integer times the fundamental frequency [omega] = 2[pi]/T (Fourier's series). It is impossible to overestimate the importance of Fourier's discovery, and all physics or engineering students…

  9. Discovery of novel anti-HIV agents via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry-based approach.

    PubMed

    Gao, Ping; Sun, Lin; Zhou, Junsu; Li, Xiao; Zhan, Peng; Liu, Xinyong

    2016-09-01

    In recent years, a variety of new synthetic methodologies and concepts have been proposed in the search for new pharmaceutical lead structures and optimization. Notably, the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry approach has drawn great attention and has become a powerful tool for the generation of privileged medicinal skeletons in the discovery of anti-HIV agents. This is due to the high degree of reliability, complete specificity (chemoselectivity and regioselectivity), mild conditions, and the biocompatibility of the reactants. Herein, the authors describe the progress thus far on the discovery of novel anti-HIV agents via the CuAAC click chemistry-based approach. CuAAC click chemistry is a proven protocol for synthesizing triazole products which could serve as basic pharmacophores, act as replacements of traditional scaffold or substituent modification, be a linker of dual-target or dual-site inhibitors and more for the discovery of novel anti-HIV agents. What's more, it also provides convenience and feasibility for dynamic combinatorial chemistry and in situ screening. It is envisioned that click chemistry will draw more attention and make more contributions in anti-HIV drug discovery in the future.

  10. The reproducibility issue and preclinical academic drug discovery: educational and institutional initiatives fostering translation success.

    PubMed

    Janero, David R

    2016-09-01

    Drug discovery depends critically upon published results from the academy. The reproducibility of preclinical research findings reported by academia in the peer-reviewed literature has been called into question, seriously jeopardizing the value of academic science for inventing therapeutics. The corrosive effects of the reproducibility issue on drug discovery are considered. Purported correctives imposed upon academia from the outside deal mainly with expunging fraudulent literature and imposing punitive sanctions on the responsible authors. The salutary influence of such post facto actions on the reproducibility of discovery-relevant preclinical research data from academia appears limited. Rather, intentional doctoral-scientist education focused on data replicability and translationally-meaningful science and active participation of university entities charged with research innovation and asset commercialization toward ensuring data quality are advocated as key academic initiatives for addressing the reproducibility issue. A mindset shift on the part of both senior university faculty and the academy to take responsibility for the data reproducibility crisis and commit proactively to positive educational, incentivization, and risk- and reward-sharing practices will be fundamental for improving the value of published preclinical academic research to drug discovery.

  11. 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.

  12. Stabilization of protein-protein interactions in drug discovery.

    PubMed

    Andrei, Sebastian A; Sijbesma, Eline; Hann, Michael; Davis, Jeremy; O'Mahony, Gavin; Perry, Matthew W D; Karawajczyk, Anna; Eickhoff, Jan; Brunsveld, Luc; Doveston, Richard G; Milroy, Lech-Gustav; Ottmann, Christian

    2017-09-01

    PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.

  13. An overview of aldehyde oxidase: an enzyme of emerging importance in novel drug discovery.

    PubMed

    Rashidi, Mohammad-Reza; Soltani, Somaieh

    2017-03-01

    Given the rising trend in medicinal chemistry strategy to reduce cytochrome P450-dependent metabolism, aldehyde oxidase (AOX) has recently gained increased attention in drug discovery programs and the number of drug candidates that are metabolized by AOX is steadily growing. Areas covered: Despite the emerging importance of AOX in drug discovery, there are certain major recognized problems associated with AOX-mediated metabolism of drugs. Intra- and inter-species variations in AOX activity, the lack of reliable and predictive animal models using the common experimental animals, and failure in the predictions of in vivo metabolic activity of AOX using traditional in vitro methods are among these issues that are covered in this article. A comprehensive review of computational human AOX (hAOX) related studies are also provided. Expert opinion: Following the recent progress in the stem cell field, the authors recommend the application of organoids technology as an effective tool to solve the fundamental problems associated with the evaluation of AOX in drug discovery. The recent success in resolving the hAOX crystal structure can too be another valuable data source for the study of AOX-catalyzed metabolism of new drug candidates, using computer-aided drug discovery methods.

  14. Discovery and bio-optimization of human antibody therapeutics using the XenoMouse® transgenic mouse platform.

    PubMed

    Foltz, Ian N; Gunasekaran, Kannan; King, Chadwick T

    2016-03-01

    Since the late 1990s, the use of transgenic animal platforms has transformed the discovery of fully human therapeutic monoclonal antibodies. The first approved therapy derived from a transgenic platform--the epidermal growth factor receptor antagonist panitumumab to treat advanced colorectal cancer--was developed using XenoMouse(®) technology. Since its approval in 2006, the science of discovering and developing therapeutic monoclonal antibodies derived from the XenoMouse(®) platform has advanced considerably. The emerging array of antibody therapeutics developed using transgenic technologies is expected to include antibodies and antibody fragments with novel mechanisms of action and extreme potencies. In addition to these impressive functional properties, these antibodies will be designed to have superior biophysical properties that enable highly efficient large-scale manufacturing methods. Achieving these new heights in antibody drug discovery will ultimately bring better medicines to patients. Here, we review best practices for the discovery and bio-optimization of monoclonal antibodies that fit functional design goals and meet high manufacturing standards. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Pre-marital and Marital Counselling: Implications for the School Guidance Counsellor

    ERIC Educational Resources Information Center

    Schlesinger, Benjamin

    1978-01-01

    One of the foremost tasks of young people contemplating marriage is the discovery of their basic selfhood and their continued growth as people; this is the first goal in pre-marital counseliling. (Author)

  16. Meeting the Psychosocial and Rehabilitative Needs of the Visually Impaired Diabetic.

    ERIC Educational Resources Information Center

    Oehler-Giarratana, Judith

    1978-01-01

    The psychosocial and visual problems of proliferating diabetic retinopathy are discussed in terms of four stages: discovery of the diagnosis, developing awareness of the diagnosis, realization of disability, and stabilization of vision. (Author)

  17. Chemistry of americium

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

    Schulz, W.W.

    1976-01-01

    Essential features of the descriptive chemistry of americium are reviewed. Chapter titles are: discovery, atomic and nuclear properties, collateral reading, production and uses, chemistry in aqueous solution, metal, alloys, and compounds, and, recovery, separation, purification. Author and subject indexes are included. (JCB)

  18. Looking Back on Books and Other Guides.

    ERIC Educational Resources Information Center

    Anderson, Carl D.

    1981-01-01

    Presents 11 responses received from U.S. scientists who have won Nobel Prizes (physics or physics-related work) indicating what books, discoveries, people, or issues of the last 50 years have most decisively influenced them. (Author/JN)

  19. A Concept of Native Title

    ERIC Educational Resources Information Center

    Little Bear, Leroy

    1977-01-01

    Discovery was meant to give to a European power who came to the shores of North America the right to deal exclusively with the Indians whose territory covered or included the particular area discovered by that European power. (Author)

  20. [History of kidney transplantation surgery].

    PubMed

    Timsit, M O; Kleinclauss, F; Thuret, R

    2016-11-01

    To perform a state of the art about the history of kidney transplantation. An exhaustive systematic review of the scientific literature was performed in the Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of the following keywords (MESH): kidney transplantation, history, vascular anastomosis. From the first vascular ligations to the discovery of ciclosporin, the history of organ transplantation was made of surgical bets and medical discoveries, such as blood group, HLA-system, immunity, etc. The audacity of some surgeons led to the onset of renal transplantation as the treatment of choice for end stage renal disease. This article aims to describe the first surgical methods for vascular anastomosis and renal transplantation. Through a comprehensive search within the archives of the French National Library, the authors provide a precise description of the first renal transplantations performed, the technique that have been used and their authors. Copyright © 2016. Published by Elsevier Masson SAS.

  1. Ebolaviruses: New roles for old proteins.

    PubMed

    Cantoni, Diego; Rossman, Jeremy S

    2018-05-01

    In 2014, the world witnessed the largest Ebolavirus outbreak in recorded history. The subsequent humanitarian effort spurred extensive research, significantly enhancing our understanding of ebolavirus replication and pathogenicity. The main functions of each ebolavirus protein have been studied extensively since the discovery of the virus in 1976; however, the recent expansion of ebolavirus research has led to the discovery of new protein functions. These newly discovered roles are revealing new mechanisms of virus replication and pathogenicity, whilst enhancing our understanding of the broad functions of each ebolavirus viral protein (VP). Many of these new functions appear to be unrelated to the protein's primary function during virus replication. Such new functions range from bystander T-lymphocyte death caused by VP40-secreted exosomes to new roles for VP24 in viral particle formation. This review highlights the newly discovered roles of ebolavirus proteins in order to provide a more encompassing view of ebolavirus replication and pathogenicity.

  2. Ebolaviruses: New roles for old proteins

    PubMed Central

    2018-01-01

    In 2014, the world witnessed the largest Ebolavirus outbreak in recorded history. The subsequent humanitarian effort spurred extensive research, significantly enhancing our understanding of ebolavirus replication and pathogenicity. The main functions of each ebolavirus protein have been studied extensively since the discovery of the virus in 1976; however, the recent expansion of ebolavirus research has led to the discovery of new protein functions. These newly discovered roles are revealing new mechanisms of virus replication and pathogenicity, whilst enhancing our understanding of the broad functions of each ebolavirus viral protein (VP). Many of these new functions appear to be unrelated to the protein’s primary function during virus replication. Such new functions range from bystander T-lymphocyte death caused by VP40-secreted exosomes to new roles for VP24 in viral particle formation. This review highlights the newly discovered roles of ebolavirus proteins in order to provide a more encompassing view of ebolavirus replication and pathogenicity. PMID:29723187

  3. Bion's discovery of alpha function: thinking under fire on the battlefield and in the consulting room.

    PubMed

    Brown, Lawrence J

    2012-10-01

    This paper has traced Bion's discovery of alpha function and its subsequent elaboration. His traumatic experiences as a young tank commander in World War I (overlaid on, and intertwined with, childhood conflicts) gave him firsthand exposure to very painful emotions that tested his capacity to manage. Later, in the 1950s, after his analysis with Melanie Klein and marriage to Francesca Bion, he undertook the analysis of psychotic patients and learned how they disassembled their ability to know reality as a defense against unbearable emotional truths in their lives. This led Bion to identify an aspect of dreaming that was necessary in order for reality experience to be given personal meaning so that one may learn from experience. Simultaneous with working out this new theory of dreaming, Bion also revisited his World War I experiences that had remained undigested and all these elements coalesced into a selected fact - his discovery of alpha function. In subsequent writings, Bion explored the constituent factors of alpha function, including the container/contained relationship, the PS↔D balance, reverie, tolerated doubt and other factors which I have termed the 'Constellation for Thinking'. Copyright © 2012 Institute of Psychoanalysis.

  4. How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems.

    PubMed

    Murphy, Dennis L; Fox, Meredith A; Timpano, Kiara R; Moya, Pablo R; Ren-Patterson, Renee; Andrews, Anne M; Holmes, Andrew; Lesch, Klaus-Peter; Wendland, Jens R

    2008-11-01

    Discovered and crystallized over sixty years ago, serotonin's important functions in the brain and body were identified over the ensuing years by neurochemical, physiological and pharmacological investigations. This 2008 M. Rapport Memorial Serotonin Review focuses on some of the most recent discoveries involving serotonin that are based on genetic methodologies. These include examples of the consequences that result from direct serotonergic gene manipulation (gene deletion or overexpression) in mice and other species; an evaluation of some phenotypes related to functional human serotonergic gene variants, particularly in SLC6A4, the serotonin transporter gene; and finally, a consideration of the pharmacogenomics of serotonergic drugs with respect to both their therapeutic actions and side effects. The serotonin transporter (SERT) has been the most comprehensively studied of the serotonin system molecular components, and will be the primary focus of this review. We provide in-depth examples of gene-based discoveries primarily related to SLC6A4 that have clarified serotonin's many important homeostatic functions in humans, non-human primates, mice and other species.

  5. 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.

  6. Electrotherapy in the treatment of patients affected by rabies: experiments conducted at the "Maggiore" hospital of Milan in 1865.

    PubMed

    Marinozzi, Silvia; Gulino, Matteo; Gazzaniga, Valentina

    2016-12-01

    During the nineteenth century, the scientific context of rabies treatment was weak due to the lack of the literature on specific nosology of the rabies disease, and unspecific and ineffective therapy approaches. Electrotherapy already represented an important therapeutic approach for nervous system diseases, although not specifically for rabies. In the present paper, the authors discuss the use of electrotherapy in the treatment of humans affected by rabies in an experimental study conducted at the Maggiore Hospital of Milan, with the aim of establishing the discovery of a possible specific therapy. By analyzing the printed scientific sources available in the Braidense Library of Milan, the authors describe four experiments conducted on patients of different ages. Symptoms and effects both during and after the electrotherapy are also highlighted. The experiments demonstrated that electricity is not an effective therapy in the treatment of rabies, being rather able to cause serious functional and organic alterations in all the patients. Analyzing the Milanese experiments, the authors reported specific Italian history of a scientific and medical approach to rabies at the end of the 18th century, which led to the promotion of health education, reinforced prevention strategies and opened the way to the vaccination era.

  7. Walsh McDermott and changing conceptions of tuberculosis antibiotic therapy: latent lessons for health care reform.

    PubMed

    Pohl, Barbara; Fins, Joseph J

    2014-04-01

    Although health care reform efforts are laudably directed at promoting quality and efficiency, added bureaucracy may have the unintended consequence of constraining physicians' creativity. This has the potential to undermine clinicians' freedom to reframe their thinking in response to unfolding biological knowledge, a defining feature of academic medicine. In this Perspective, the authors illustrate the confluence of creativity, context, and discovery through a historical example: the evolution of tuberculosis (TB) multidrug chemotherapy as espoused by Walsh McDermott and his colleagues during the 1940s and 1950s.Before the discovery of streptomycin in 1943, clinician-researchers aimed to identify a "magic bullet" that would rapidly eradicate tubercle bacilli from the body. In the years following the discovery of streptomycin, it became clear that the biology of TB did not conform to researchers' expectations. The recognition that treatment would neither be simple nor quick prompted further attempts to devise an optimal streptomycin regimen, which would enable the host's immune system to suppress infection and prevent the emergence of streptomycin-resistant strains. By the late 1950s, investigators clarified the limits of streptomycin's effectiveness, which led to combined chemotherapy. In so doing, they gained a better understanding of drug-bacilli-host interactions and shifted attention from the host to the drug-resistant microbe.The authors argue that this tale of discovery offers a latent lesson for academic medicine: As the health care system undergoes systemic restructuring, it is essential to preserve the freedom to reframe thinking and creatively solve translational problems in research and practice.

  8. Exploring relation types for literature-based discovery.

    PubMed

    Preiss, Judita; Stevenson, Mark; Gaizauskas, Robert

    2015-09-01

    Literature-based discovery (LBD) aims to identify "hidden knowledge" in the medical literature by: (1) analyzing documents to identify pairs of explicitly related concepts (terms), then (2) hypothesizing novel relations between pairs of unrelated concepts that are implicitly related via a shared concept to which both are explicitly related. Many LBD approaches use simple techniques to identify semantically weak relations between concepts, for example, document co-occurrence. These generate huge numbers of hypotheses, difficult for humans to assess. More complex techniques rely on linguistic analysis, for example, shallow parsing, to identify semantically stronger relations. Such approaches generate fewer hypotheses, but may miss hidden knowledge. The authors investigate this trade-off in detail, comparing techniques for identifying related concepts to discover which are most suitable for LBD. A generic LBD system that can utilize a range of relation types was developed. Experiments were carried out comparing a number of techniques for identifying relations. Two approaches were used for evaluation: replication of existing discoveries and the "time slicing" approach.(1) RESULTS: Previous LBD discoveries could be replicated using relations based either on document co-occurrence or linguistic analysis. Using relations based on linguistic analysis generated many fewer hypotheses, but a significantly greater proportion of them were candidates for hidden knowledge. The use of linguistic analysis-based relations improves accuracy of LBD without overly damaging coverage. LBD systems often generate huge numbers of hypotheses, which are infeasible to manually review. Improving their accuracy has the potential to make these systems significantly more usable. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association.

  9. What have positron emission tomography and 'Zippy' told us about the neuropharmacology of drug addiction?

    PubMed

    Cumming, Paul; Caprioli, Daniele; Dalley, Jeffrey W

    2011-08-01

    Translational molecular imaging with positron emission tomography (PET) and allied technologies offer unrivalled applications in the discovery of biomarkers and aetiological mechanisms relevant to human disease. Foremost among clinical PET findings during the past two decades of addiction research is the seminal discovery of reduced dopamine D(2/3) receptor expression in the striatum of drug addicts, which could indicate a predisposing factor and/or compensatory reaction to the chronic abuse of stimulant drugs. In parallel, recent years have witnessed significant improvements in the performance of small animal tomographs (microPET) and a refinement of animal models of addiction based on clinically relevant diagnostic criteria. This review surveys the utility of PET in the elucidation of neuropharmacological mechanisms underlying drug addiction. It considers the consequences of chronic drug exposure on regional brain metabolism and neurotransmitter function and identifies those areas where further research is needed, especially concerning the implementation of PET tracers targeting neurotransmitter systems other than dopamine, which increasingly have been implicated in the pathophysiology of drug addiction. In addition, this review considers the causal effects of behavioural traits such as impulsivity and novelty/sensation-seeking on the emergence of compulsive drug-taking. Previous research indicates that spontaneously high-impulsive rats--as exemplified by 'Zippy'--are pre-disposed to escalate intravenous cocaine self-administration, and subsequently to develop compulsive drug taking tendencies that endure despite concurrent adverse consequences of such behaviour, just as in human addiction. The discovery using microPET of pre-existing differences in dopamine D(2/3) receptor expression in the striatum of high-impulsive rats suggests a neural endophenotype that may likewise pre-dispose to stimulant addiction in humans. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  10. [Patents and innovations. Definitions--modes of action].

    PubMed

    Lodde, J P

    1994-06-01

    The author presents the various methods available for the doctor to protect and exploit his inventions or technological discoveries. In the medical field, as in other fields, there are three titles of industrial property: patent, registered model and trademark. The modalities of each of these titles are explained. Based on the his own experience, the author presents advice concerning the use of patents, contracts and the choice of industrial partners.

  11. The Living Experience of Feeling Unsure: A Parsesciencing Inquiry.

    PubMed

    Bunkers, Sandra Schmidt

    2016-10-01

    The purpose of this article is to report the discovery of a Parsesciencing inquiry on the universal humanuniverse living experience of feeling unsure. In discussion with the scholar, 10 historians described their experiences. The discerning extant moment of the living experience of feeling unsure was found to be as follows: Feeling unsure is disquieting trepidation with pursuing endeavors arising with joining with-distancing from affiliations. © The Author(s) 2016.

  12. "Making a Mess in the Mud": The Discovery of Toddlers' Special Needs by Child Scientists in the 1930s in the Netherlands

    ERIC Educational Resources Information Center

    Bakker, Nelleke

    2012-01-01

    In this article, the author discusses plans that were launched at three consecutive conferences on care for toddlers between 1929 and 1938 in the Netherlands. These plans and their realisation are evaluated in terms of what was seen as the missing link in the supply of institutional care for young children. The author identifies the professional…

  13. Interdisciplinary Laboratory Course Facilitating Knowledge Integration, Mutualistic Teaming, and Original Discovery.

    PubMed

    Full, Robert J; Dudley, Robert; Koehl, M A R; Libby, Thomas; Schwab, Cheryl

    2015-11-01

    Experiencing the thrill of an original scientific discovery can be transformative to students unsure about becoming a scientist, yet few courses offer authentic research experiences. Increasingly, cutting-edge discoveries require an interdisciplinary approach not offered in current departmental-based courses. Here, we describe a one-semester, learning laboratory course on organismal biomechanics offered at our large research university that enables interdisciplinary teams of students from biology and engineering to grow intellectually, collaborate effectively, and make original discoveries. To attain this goal, we avoid traditional "cookbook" laboratories by training 20 students to use a dozen research stations. Teams of five students rotate to a new station each week where a professor, graduate student, and/or team member assists in the use of equipment, guides students through stages of critical thinking, encourages interdisciplinary collaboration, and moves them toward authentic discovery. Weekly discussion sections that involve the entire class offer exchange of discipline-specific knowledge, advice on experimental design, methods of collecting and analyzing data, a statistics primer, and best practices for writing and presenting scientific papers. The building of skills in concert with weekly guided inquiry facilitates original discovery via a final research project that can be presented at a national meeting or published in a scientific journal. © The Author 2015. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

  14. A Synthetic Community System for Probing Microbial Interactions Driven by Exometabolites

    PubMed Central

    Chodkowski, John L.

    2017-01-01

    ABSTRACT Though most microorganisms live within a community, we have modest knowledge about microbial interactions and their implications for community properties and ecosystem functions. To advance understanding of microbial interactions, we describe a straightforward synthetic community system that can be used to interrogate exometabolite interactions among microorganisms. The filter plate system (also known as the Transwell system) physically separates microbial populations, but allows for chemical interactions via a shared medium reservoir. Exometabolites, including small molecules, extracellular enzymes, and antibiotics, are assayed from the reservoir using sensitive mass spectrometry. Community member outcomes, such as growth, productivity, and gene regulation, can be determined using flow cytometry, biomass measurements, and transcript analyses, respectively. The synthetic community design allows for determination of the consequences of microbiome diversity for emergent community properties and for functional changes over time or after perturbation. Because it is versatile, scalable, and accessible, this synthetic community system has the potential to practically advance knowledge of microbial interactions that occur within both natural and artificial communities. IMPORTANCE Understanding microbial interactions is a fundamental objective in microbiology and ecology. The synthetic community system described here can set into motion a range of research to investigate how the diversity of a microbiome and interactions among its members impact its function, where function can be measured as exometabolites. The system allows for community exometabolite profiling to be coupled with genome mining, transcript analysis, and measurements of member productivity and population size. It can also facilitate discovery of natural products that are only produced within microbial consortia. Thus, this synthetic community system has utility to address fundamental questions about a diversity of possible microbial interactions that occur in both natural and engineered ecosystems. Author Video: An author video summary of this article is available. PMID:29152587

  15. The impact of genetics on future drug discovery in schizophrenia.

    PubMed

    Matsumoto, Mitsuyuki; Walton, Noah M; Yamada, Hiroshi; Kondo, Yuji; Marek, Gerard J; Tajinda, Katsunori

    2017-07-01

    Failures of investigational new drugs (INDs) for schizophrenia have left huge unmet medical needs for patients. Given the recent lackluster results, it is imperative that new drug discovery approaches (and resultant drug candidates) target pathophysiological alterations that are shared in specific, stratified patient populations that are selected based on pre-identified biological signatures. One path to implementing this paradigm is achievable by leveraging recent advances in genetic information and technologies. Genome-wide exome sequencing and meta-analysis of single nucleotide polymorphism (SNP)-based association studies have already revealed rare deleterious variants and SNPs in patient populations. Areas covered: Herein, the authors review the impact that genetics have on the future of schizophrenia drug discovery. The high polygenicity of schizophrenia strongly indicates that this disease is biologically heterogeneous so the identification of unique subgroups (by patient stratification) is becoming increasingly necessary for future investigational new drugs. Expert opinion: The authors propose a pathophysiology-based stratification of genetically-defined subgroups that share deficits in particular biological pathways. Existing tools, including lower-cost genomic sequencing and advanced gene-editing technology render this strategy ever more feasible. Genetically complex psychiatric disorders such as schizophrenia may also benefit from synergistic research with simpler monogenic disorders that share perturbations in similar biological pathways.

  16. Delineation of metabolic gene clusters in plant genomes by chromatin signatures.

    PubMed

    Yu, Nan; Nützmann, Hans-Wilhelm; MacDonald, James T; Moore, Ben; Field, Ben; Berriri, Souha; Trick, Martin; Rosser, Susan J; Kumar, S Vinod; Freemont, Paul S; Osbourn, Anne

    2016-03-18

    Plants are a tremendous source of diverse chemicals, including many natural product-derived drugs. It has recently become apparent that the genes for the biosynthesis of numerous different types of plant natural products are organized as metabolic gene clusters, thereby unveiling a highly unusual form of plant genome architecture and offering novel avenues for discovery and exploitation of plant specialized metabolism. Here we show that these clustered pathways are characterized by distinct chromatin signatures of histone 3 lysine trimethylation (H3K27me3) and histone 2 variant H2A.Z, associated with cluster repression and activation, respectively, and represent discrete windows of co-regulation in the genome. We further demonstrate that knowledge of these chromatin signatures along with chromatin mutants can be used to mine genomes for cluster discovery. The roles of H3K27me3 and H2A.Z in repression and activation of single genes in plants are well known. However, our discovery of highly localized operon-like co-regulated regions of chromatin modification is unprecedented in plants. Our findings raise intriguing parallels with groups of physically linked multi-gene complexes in animals and with clustered pathways for specialized metabolism in filamentous fungi. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  17. Small Molecule Inhibitors of Protein Arginine Methyltransferases

    PubMed Central

    Hu, Hao; Qian, Kun; Ho, Meng-Chiao; Zheng, Y. George

    2016-01-01

    Introduction Arginine methylation is an abundant posttranslational modification occurring in mammalian cells and catalyzed by protein arginine methyltransferases (PRMTs). Misregulation and aberrant expression of PRMTs are associated with various disease states, notably cancer. PRMTs are prominent therapeutic targets in drug discovery. Areas covered The authors provide an updated review of the research on the development of chemical modulators for PRMTs. Great efforts are seen in screening and designing potent and selective PRMT inhibitors, and a number of micromolar and submicromolar inhibitors have been obtained for key PRMT enzymes such as PRMT1, CARM1, and PRMT5. The authors provide a focus on their chemical structures, mechanism of action, and pharmacological activities. Pros and cons of each type of inhibitors are also discussed. Expert opinion Several key challenging issues exist in PRMT inhibitor discovery. Structural mechanisms of many PRMT inhibitors remain unclear. There lacks consistency in potency data due to divergence of assay methods and conditions. Physiologically relevant cellular assays are warranted. Substantial engagements are needed to investigate pharmacodynamics and pharmacokinetics of the new PRMT inhibitors in pertinent disease models. Discovery and evaluation of potent, isoform-selective, cell-permeable and in vivo-active PRMT modulators will continue to be an active arena of research in years ahead. PMID:26789238

  18. Winning or Losing the Production Game.

    ERIC Educational Resources Information Center

    Smith, Roger A.

    1995-01-01

    With the use of "The Production Game," technology teachers can introduce concepts associated with manufacturing and marketing. The game directs students in the discovery of ideas associated with material resources, technology, and laborers, the leading components of industrial manufacturing. (Author/JOW)

  19. The University as a Community of Learners

    ERIC Educational Resources Information Center

    Daniel, Wallace

    2014-01-01

    Building on classical and recent studies of the learning paradigm of higher education, the author distinguishes between receiving ideas and using them and how universities might educate students to be more open to the world, open to discovery and creativity.

  20. Dreams, Daydreams and Discovery.

    ERIC Educational Resources Information Center

    Brown, R. A.; Luckcock, R. G.

    1978-01-01

    It has been discovered that dreams and daydreams can be productive states in the process of scientific innovation. An attempt is made to provide some typical examples of insights which have come to scientists during dream-like states and in sleep. (Author/MA)

  1. Complex Disease Endotypes and Implications for GWAS and Exposomics***

    EPA Science Inventory

    Presentation Type: Symposia Symposium Title: Human Exposome Discovery and Disease Investigation Abstract Title: Complex Disease Endotypes and Implications for GWAS and Exposomics Authors: Stephen W. Edwards1, David M. Reif, Elaine Cohen Hubaf, ClarLynda Williams-DeVa...

  2. Feature Discovery by Competitive Learning.

    ERIC Educational Resources Information Center

    Rumelhart, David E.; Zipser, David

    1985-01-01

    Reports results of studies with an unsupervised learning paradigm called competitive learning which is examined using computer simulation and formal analysis. When competitive learning is applied to parallel networks of neuron-like elements, many potentially useful learning tasks can be accomplished. (Author)

  3. Discovery of the porcine NGN3 gene and testing its endocrine function in the pig

    USDA-ARS?s Scientific Manuscript database

    Neurogenin 3 (NGN3) is a member of the basic helix-loop-helix transcription factor family. NGN3 is both necessary and sufficient to drive endocrine differentiation in the developing pancreas in mouse and humans. Until now, the sequence for NGN3 eluded discovery despite completion of the pig genome a...

  4. Huygens Identifies Rings Around Saturn : 350 Years Later

    NASA Astrophysics Data System (ADS)

    Deau, Estelle; Fulchignoni, M.

    2006-09-01

    On March 6, 1656, nearly forty years after Galileo discovered a strange object around Saturn and remained enigmatic until this time, a young unknown dutch of the name of Christiaan Huygens published a surprising article entitled "De Saturni luna observatio nova” in which he makes share to the erudite world of the first discovered satellite around Saturn. It finishes this article of only three pages by a logogriph which announces another discovery of which he hopes to be the first author while launching a call to all the astronomers of Europe. This second discovery much more resounding than the first ensured a world fame thereafter to him. We return here on this famous discovery: the identification of the Saturn's rings by the phyical explanation of its changing appearance. 350 years later, the physical assumptions of Huygens are used to understand ring's geometry.

  5. The re-emergence of natural products for drug discovery in the genomics era.

    PubMed

    Harvey, Alan L; Edrada-Ebel, RuAngelie; Quinn, Ronald J

    2015-02-01

    Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein-protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

  6. [Neuroendocrine and psychopharmacologic aspects of the pineal function. Melatonin and psychiatric disorders].

    PubMed

    Morguenstern, E A

    1989-01-01

    The development of psychiatric thought has always been in close association with the pineal gland. The importance of a relationship between pineal, and mental functions was stressed by Descartes when he placed the seat of rational thought as well as the confluence of body and soul in this organ (Cf. Descartes, L'Homme, 1664). His writings exerted such a strong influence that, quite soon indeed, physicians started regarding this gland as being the source of many mental disorders. In an attempt to find and explain a possible link between mental abnormalities, and the discovery of calcified pineals in necroptic studies, many theories were put forward during the 18th, and the 19th century. Afterwards, the importance of the gland went almost unnoticed until 1920, when Becker treated psychotic patients with pineal extracts. An up-to-1950 review by Kitay and Altschule (1954) reported 17 cases where pineal extracts were successfully injected to psychotic patients. In the present review, the author tries and summarizes several reports dealing with the influence of the pineal function on affective disorders, schizophrenia, sleep cycle, Parkinson disease, etc., as a contribution to future research work in this field.

  7. Improving and accelerating the differentiation and functional maturation of human stem cell-derived neurons: role of extracellular calcium and GABA.

    PubMed

    Kemp, Paul J; Rushton, David J; Yarova, Polina L; Schnell, Christian; Geater, Charlene; Hancock, Jane M; Wieland, Annalena; Hughes, Alis; Badder, Luned; Cope, Emma; Riccardi, Daniela; Randall, Andrew D; Brown, Jonathan T; Allen, Nicholas D; Telezhkin, Vsevolod

    2016-11-15

    Neurons differentiated from pluripotent stem cells using established neural culture conditions often exhibit functional deficits. Recently, we have developed enhanced media which both synchronize the neurogenesis of pluripotent stem cell-derived neural progenitors and accelerate their functional maturation; together these media are termed SynaptoJuice. This pair of media are pro-synaptogenic and generate authentic, mature synaptic networks of connected forebrain neurons from a variety of induced pluripotent and embryonic stem cell lines. Such enhanced rate and extent of synchronized maturation of pluripotent stem cell-derived neural progenitor cells generates neurons which are characterized by a relatively hyperpolarized resting membrane potential, higher spontaneous and induced action potential activity, enhanced synaptic activity, more complete development of a mature inhibitory GABA A receptor phenotype and faster production of electrical network activity when compared to standard differentiation media. This entire process - from pre-patterned neural progenitor to active neuron - takes 3 weeks or less, making it an ideal platform for drug discovery and disease modelling in the fields of human neurodegenerative and neuropsychiatric disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease and Schizophrenia. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

  8. Undergraduate Program: New Orleans

    NASA Astrophysics Data System (ADS)

    Betsock, Lori

    2008-03-01

    Undergraduate chemical science students—join us in New Orleans on April 6-7, 2008 for an educational program designed specifically for you. Attend symposia on chemistry in sports and health and learn how it impacts your life everyday; meet with graduate school recruiters. Focus on your professional future in chemistry by learning more about careers in public health and how to communicate and work effectively with cross-functional teams. Hear eminent scientist Richard B. Silverman (John Evans Professor of Chemistry, Northwestern University and author of The Organic Chemistry of Drug Design and Drug Action 2004) speak about "Drug Discovery: Ingenuity or Serendipity?" All events will take place at the Hilton Riverside Hotel in New Orleans, except the Undergraduate Research Poster Sessions and Sci-Mix, both of which will be held in Hall A of the Ernest N. Morial Convention Center.

  9. "Communication by impact" and other forms of non-verbal communication: a review of transference, countertransference and projective identification.

    PubMed

    Böhmer, M W

    2010-07-01

    This article aims to review the importance, place and especially the emotional impact of non-verbal communication in psychiatry. The paper argues that while biological psychiatry is in the ascendency with increasing discoveries being made about the functioning of the brain and psycho-pharmacology, it is important to try and understand what is happening between psychiatrist and patient. The importance of being aware of the subtleties of this interaction is argued, as are the roles of phenomena such as transference, counter-transference and projective identification. The workings and use of these phenomena are explored as central in the doctor-patient interaction, as well as the consequences of failure to utilize and understand these phenomena. The author reviews - amongst others - the work of the analysts Casement, Gabbard, Goldstein, Ogden and Symington.

  10. Code Grey: Stained Surgical Instruments and Their Impact on One Canadian Health Authority.

    PubMed

    Kean, Rob; Johnson, Ron; Doyle, Michael

    2017-01-01

    In 2016, NL's largest RHA was faced with serious challenges stemming from the discovery of stained surgical instruments at its two largest hospitals. This discovery prompted a series of postponed surgeries, an extensive internal mobilization of labour and the purchase of millions of dollars of new equipment. In tackling these challenges, the organization not only acquired a better understanding of its surgical tools, but it also gained renewed appreciation for the resilience of its human resources. By describing this incident and the lessons learned, we hope to offer insight to providers in similar circumstances.

  11. Poor boy 3D seismic effort yields South Central Kentucky discovery

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

    Hanratty, M.

    1996-11-04

    Clinton County, Ky., is on the eastern flank of the Cincinnati arch and the western edge of the Appalachian basin and the Pine Mountain overthrust. Clinton County has long been known for high volume fractured carbonate wells. The discovery of these fractured reservoir, unfortunately, has historically been serendipitous. The author currently uses 2D seismic and satellite imagery to design 3D high resolution seismic shoots. This method has proven to be the most efficient and is the core of his program. The paper describes exploration methods, seismic acquisition, well data base, and seismic interpretation.

  12. Women's Careers in Biomedical Sciences: Implications for the Economy, Scientific Discovery, and Women's Health.

    PubMed

    Plank-Bazinet, Jennifer L; Heggeness, Misty L; Lund, P Kay; Clayton, Janine Austin

    2017-05-01

    While women have been well represented in medical school and biomedical doctoral degree programs, they do not comprise half of academic medicine faculty positions. Furthermore, there is a significant paucity of women in academic medicine leadership positions, as evidenced by the fact that only 16% of dean positions at United States Medical schools are filled by women. In this commentary, the authors review the state of women in academic medicine and argue that increased representation of women in the academic workforce will lead to economic gains, increased scientific discovery, and improvements to women's health.

  13. Designing an intuitive web application for drug discovery scientists.

    PubMed

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

    2018-06-01

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

  14. Women's Careers in Biomedical Sciences: Implications for the Economy, Scientific Discovery, and Women's Health

    PubMed Central

    Heggeness, Misty L.; Lund, P. Kay; Clayton, Janine Austin

    2017-01-01

    Abstract While women have been well represented in medical school and biomedical doctoral degree programs, they do not comprise half of academic medicine faculty positions. Furthermore, there is a significant paucity of women in academic medicine leadership positions, as evidenced by the fact that only 16% of dean positions at United States Medical schools are filled by women. In this commentary, the authors review the state of women in academic medicine and argue that increased representation of women in the academic workforce will lead to economic gains, increased scientific discovery, and improvements to women's health. PMID:27509297

  15. Practical analysis of specificity-determining residues in protein families.

    PubMed

    Chagoyen, Mónica; García-Martín, Juan A; Pazos, Florencio

    2016-03-01

    Determining the residues that are important for the molecular activity of a protein is a topic of broad interest in biomedicine and biotechnology. This knowledge can help understanding the protein's molecular mechanism as well as to fine-tune its natural function eventually with biotechnological or therapeutic implications. Some of the protein residues are essential for the function common to all members of a family of proteins, while others explain the particular specificities of certain subfamilies (like binding on different substrates or cofactors and distinct binding affinities). Owing to the difficulty in experimentally determining them, a number of computational methods were developed to detect these functional residues, generally known as 'specificity-determining positions' (or SDPs), from a collection of homologous protein sequences. These methods are mature enough for being routinely used by molecular biologists in directing experiments aimed at getting insight into the functional specificity of a family of proteins and eventually modifying it. In this review, we summarize some of the recent discoveries achieved through SDP computational identification in a number of relevant protein families, as well as the main approaches and software tools available to perform this type of analysis. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  16. RNA Interference for Functional Genomics and Improvement of Cotton (Gossypium sp.)

    PubMed Central

    Abdurakhmonov, Ibrokhim Y.; Ayubov, Mirzakamol S.; Ubaydullaeva, Khurshida A.; Buriev, Zabardast T.; Shermatov, Shukhrat E.; Ruziboev, Haydarali S.; Shapulatov, Umid M.; Saha, Sukumar; Ulloa, Mauricio; Yu, John Z.; Percy, Richard G.; Devor, Eric J.; Sharma, Govind C.; Sripathi, Venkateswara R.; Kumpatla, Siva P.; van der Krol, Alexander; Kater, Hake D.; Khamidov, Khakimdjan; Salikhov, Shavkat I.; Jenkins, Johnie N.; Abdukarimov, Abdusattor; Pepper, Alan E.

    2016-01-01

    RNA interference (RNAi), is a powerful new technology in the discovery of genetic sequence functions, and has become a valuable tool for functional genomics of cotton (Gossypium sp.). The rapid adoption of RNAi has replaced previous antisense technology. RNAi has aided in the discovery of function and biological roles of many key cotton genes involved in fiber development, fertility and somatic embryogenesis, resistance to important biotic and abiotic stresses, and oil and seed quality improvements as well as the key agronomic traits including yield and maturity. Here, we have comparatively reviewed seminal research efforts in previously used antisense approaches and currently applied breakthrough RNAi studies in cotton, analyzing developed RNAi methodologies, achievements, limitations, and future needs in functional characterizations of cotton genes. We also highlighted needed efforts in the development of RNAi-based cotton cultivars, and their safety and risk assessment, small and large-scale field trials, and commercialization. PMID:26941765

  17. RNA Interference for Functional Genomics and Improvement of Cotton (Gossypium sp.).

    PubMed

    Abdurakhmonov, Ibrokhim Y; Ayubov, Mirzakamol S; Ubaydullaeva, Khurshida A; Buriev, Zabardast T; Shermatov, Shukhrat E; Ruziboev, Haydarali S; Shapulatov, Umid M; Saha, Sukumar; Ulloa, Mauricio; Yu, John Z; Percy, Richard G; Devor, Eric J; Sharma, Govind C; Sripathi, Venkateswara R; Kumpatla, Siva P; van der Krol, Alexander; Kater, Hake D; Khamidov, Khakimdjan; Salikhov, Shavkat I; Jenkins, Johnie N; Abdukarimov, Abdusattor; Pepper, Alan E

    2016-01-01

    RNA interference (RNAi), is a powerful new technology in the discovery of genetic sequence functions, and has become a valuable tool for functional genomics of cotton (Gossypium sp.). The rapid adoption of RNAi has replaced previous antisense technology. RNAi has aided in the discovery of function and biological roles of many key cotton genes involved in fiber development, fertility and somatic embryogenesis, resistance to important biotic and abiotic stresses, and oil and seed quality improvements as well as the key agronomic traits including yield and maturity. Here, we have comparatively reviewed seminal research efforts in previously used antisense approaches and currently applied breakthrough RNAi studies in cotton, analyzing developed RNAi methodologies, achievements, limitations, and future needs in functional characterizations of cotton genes. We also highlighted needed efforts in the development of RNAi-based cotton cultivars, and their safety and risk assessment, small and large-scale field trials, and commercialization.

  18. Discovering discovery patterns with Predication-based Semantic Indexing.

    PubMed

    Cohen, Trevor; Widdows, Dominic; Schvaneveldt, Roger W; Davies, Peter; Rindflesch, Thomas C

    2012-12-01

    In this paper we utilize methods of hyperdimensional computing to mediate the identification of therapeutically useful connections for the purpose of literature-based discovery. Our approach, named Predication-based Semantic Indexing, is utilized to identify empirically sequences of relationships known as "discovery patterns", such as "drug x INHIBITS substance y, substance y CAUSES disease z" that link pharmaceutical substances to diseases they are known to treat. These sequences are derived from semantic predications extracted from the biomedical literature by the SemRep system, and subsequently utilized to direct the search for known treatments for a held out set of diseases. Rapid and efficient inference is accomplished through the application of geometric operators in PSI space, allowing for both the derivation of discovery patterns from a large set of known TREATS relationships, and the application of these discovered patterns to constrain search for therapeutic relationships at scale. Our results include the rediscovery of discovery patterns that have been constructed manually by other authors in previous research, as well as the discovery of a set of previously unrecognized patterns. The application of these patterns to direct search through PSI space results in better recovery of therapeutic relationships than is accomplished with models based on distributional statistics alone. These results demonstrate the utility of efficient approximate inference in geometric space as a means to identify therapeutic relationships, suggesting a role of these methods in drug repurposing efforts. In addition, the results provide strong support for the utility of the discovery pattern approach pioneered by Hristovski and his colleagues. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Discovering discovery patterns with predication-based Semantic Indexing

    PubMed Central

    Cohen, Trevor; Widdows, Dominic; Schvaneveldt, Roger W.; Davies, Peter; Rindflesch, Thomas C.

    2012-01-01

    In this paper we utilize methods of hyperdimensional computing to mediate the identification of therapeutically useful connections for the purpose of literature-based discovery. Our approach, named Predication-based Semantic Indexing, is utilized to identify empirically sequences of relationships known as “discovery patterns”, such as “drug x INHIBITS substance y, substance y CAUSES disease z” that link pharmaceutical substances to diseases they are known to treat. These sequences are derived from semantic predications extracted from the biomedical literature by the SemRep system, and subsequently utilized to direct the search for known treatments for a held out set of diseases. Rapid and efficient inference is accomplished through the application of geometric operators in PSI space, allowing for both the derivation of discovery patterns from a large set of known TREATS relationships, and the application of these discovered patterns to constrain search for therapeutic relationships at scale. Our results include the rediscovery of discovery patterns that have been constructed manually by other authors in previous research, as well as the discovery of a set of previously unrecognized patterns. The application of these patterns to direct search through PSI space results in better recovery of therapeutic relationships than is accomplished with models based on distributional statistics alone. These results demonstrate the utility of efficient approximate inference in geometric space as a means to identify therapeutic relationships, suggesting a role of these methods in drug repurposing efforts. In addition, the results provide strong support for the utility of the discovery pattern approach pioneered by Hristovski and his colleagues. PMID:22841748

  20. Fragment-based approaches to anti-HIV drug discovery: state of the art and future opportunities.

    PubMed

    Huang, Boshi; Kang, Dongwei; Zhan, Peng; Liu, Xinyong

    2015-12-01

    The search for additional drugs to treat HIV infection is a continuing effort due to the emergence and spread of HIV strains resistant to nearly all current drugs. The recent literature reveals that fragment-based drug design/discovery (FBDD) has become an effective alternative to conventional high-throughput screening strategies for drug discovery. In this critical review, the authors describe the state of the art in FBDD strategies for the discovery of anti-HIV drug-like compounds. The article focuses on fragment screening techniques, direct fragment-based design and early hit-to-lead progress. Rapid progress in biophysical detection and in silico techniques has greatly aided the application of FBDD to discover candidate agents directed at a variety of anti-HIV targets. Growing evidence suggests that structural insights on key proteins in the HIV life cycle can be applied in the early phase of drug discovery campaigns, providing valuable information on the binding modes and efficiently prompting fragment hit-to-lead progression. The combination of structural insights with improved methodologies for FBDD, including the privileged fragment-based reconstruction approach, fragment hybridization based on crystallographic overlays, fragment growth exploiting dynamic combinatorial chemistry, and high-speed fragment assembly via diversity-oriented synthesis followed by in situ screening, offers the possibility of more efficient and rapid discovery of novel drugs for HIV-1 prevention or treatment. Though the use of FBDD in anti-HIV drug discovery is still in its infancy, it is anticipated that anti-HIV agents developed via fragment-based strategies will be introduced into the clinic in the future.

  1. 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.

  2. Teaching Quantum Mechanics on an Introductory Level.

    ERIC Educational Resources Information Center

    Muller, Rainer; Wiesner, Hartmut

    2002-01-01

    Presents a new research-based course on quantum mechanics in which the conceptual issues of quantum mechanics are taught at an introductory level. Involves students in the discovery of how quantum phenomena deviate from classical everyday experiences. (Contains 31 references.) (Author/YDS)

  3. 45 CFR 681.18 - What type of discovery is authorized and how is it conducted?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... SCIENCE FOUNDATION PROGRAM FRAUD CIVIL REMEDIES ACT REGULATIONS Hearing Procedures § 681.18 What type of... authenticity of any relevant document or of the truth of any relevant fact; (3) Written interrogatories; and (4...

  4. 45 CFR 681.18 - What type of discovery is authorized and how is it conducted?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... SCIENCE FOUNDATION PROGRAM FRAUD CIVIL REMEDIES ACT REGULATIONS Hearing Procedures § 681.18 What type of... authenticity of any relevant document or of the truth of any relevant fact; (3) Written interrogatories; and (4...

  5. 45 CFR 681.18 - What type of discovery is authorized and how is it conducted?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... SCIENCE FOUNDATION PROGRAM FRAUD CIVIL REMEDIES ACT REGULATIONS Hearing Procedures § 681.18 What type of... authenticity of any relevant document or of the truth of any relevant fact; (3) Written interrogatories; and (4...

  6. 45 CFR 681.18 - What type of discovery is authorized and how is it conducted?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... SCIENCE FOUNDATION PROGRAM FRAUD CIVIL REMEDIES ACT REGULATIONS Hearing Procedures § 681.18 What type of... authenticity of any relevant document or of the truth of any relevant fact; (3) Written interrogatories; and (4...

  7. 45 CFR 681.18 - What type of discovery is authorized and how is it conducted?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... SCIENCE FOUNDATION PROGRAM FRAUD CIVIL REMEDIES ACT REGULATIONS Hearing Procedures § 681.18 What type of... authenticity of any relevant document or of the truth of any relevant fact; (3) Written interrogatories; and (4...

  8. [The Roentgen's discovery -first press releases, research articles and textbooks in Kraków].

    PubMed

    Urbanik, Monika

    2013-01-01

    The author presents Kraków's publications from the pioneering years of radiology. She also emphasises the great role of the publications in the development of this field in Kraków's medical environment

  9. Visual Compositions and Language Development.

    ERIC Educational Resources Information Center

    Sinatra, Richard

    1981-01-01

    Presents an approach for improving verbal development by using organized slide shows to produce visual/verbal interaction in classroom. Suggests strength of visual involvement is that it provides a procedure for language discovery while achieving cooperation between right and left brain processing. (Author/BK)

  10. Moral Imagination and the Philosophy of School Leadership.

    ERIC Educational Resources Information Center

    Maxcy, Spencer J.; Caldas, Stephen J.

    1991-01-01

    Reviews four models of moral imagination applied to school leadership (as discovery, moral authority, faculty of mind, and super science) and discusses their inherent difficulties. Replacing "moral imagination" with "critical imagination," coupled with "democratic value deliberation," yields a richer leadership that…

  11. Cognitive and Motivational Consequences of Tutoring and Discovery Learning

    DTIC Science & Technology

    1998-06-01

    for the Behavioral and Social Sciences t*J Approved for public release; distribution is unlimited. [flEIC QUAUTy INSPECTED U.S. Army Research...Institute for the Behavioral and Social Sciences A Directorate of the U.S. Total Army Personnel Command EDGAR M. JOHNSON Director Research...and Social Sciences. NOTE: The views, opinions, and findings in this Research Note are those of the author(s) and should not be construed as an

  12. ["Unintended consequences of scientific discoveries" or: "Heterogeny of purposes" as phenomena of the history of science].

    PubMed

    Wittkau-Horgby, A

    2001-01-01

    This paper deals with an old observation in respect to man's action--the problem of unintended consequences of human action. It presents the scientific approaches to this phenomenon in the 18th century and focusses then on the problem of unintended consequences of scientific discoveries. Using the prominent examples of Copernicus and Darwin the author shows that the actual outcomes and final effects of scientific discoveries must not necessarily be the originally intended ones. On the contrary, especially those results of scientific discoveries which have affected the sphere of world view (Weltanschauung) like the research works of Copernicus and Darwin were originally meant to be only scientific studies. The final results in respect to the world view were on Copernicus' side not even realized and on Darwin's side neither intended nor welcomed. The conclusion of this analysis is that due to the fact that both scientists did not have the intention to change the world view they can only partly be regarded to be responsible for the fundamental changes they finally caused.

  13. Viruses in the 21st Century: From the Curiosity-Driven Discovery of Giant Viruses to New Concepts and Definition of Life.

    PubMed

    Forterre, Patrick

    2017-08-15

    The curiosity-driven discovery of giant DNA viruses infecting amoebas has triggered an intense debate about the origin, nature, and definition of viruses. This discovery was delayed by the current paradigm confusing viruses with small virions. Several new definitions and concepts have been proposed either to reconcile the unique features of giant viruses with previous paradigms or to propose a completely new vision of the living world. I briefly review here how several other lines of research in virology converged during the last 2 decades with the discovery of giant viruses to change our traditional perception of the viral world. This story emphasizes the power of multidisciplinary curiosity-driven research, from the hospital to the field and the laboratory. Notably, some philosophers have now also joined biologists in their quest to make sense of the abundance and diversity of viruses and related capsidless mobile elements in the biosphere. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  14. [Criteria for the classification as a "domestic-setting corpse"--a literature search and review to define the term].

    PubMed

    Merz, Marius; Birngruber, Christoph G; Heidorn, Frank; Ramsthaler, Frank; Risse, Manfred; Kreutz, Kerstin; Krähahn, Jonathan; Verhoff, Marcel A

    2011-01-01

    In German medical and media circles (daily routine, specialist literature, press, novels), the term "domestic-setting corpse" is frequently used, but the term is only vaguely defined. The authors thus decided to perform an in-depth study of the literature, including historic textbooks and all German- and English-language medicolegal journals, going as far back as their first issues, in an attempt to more clearly define the term. Inclusion criteria used in the search were a post-mortem interval of at least 24 hours prior to discovery and discovery of the corpse in a domestic setting. In the literature, 37 cases that complied with the above-mentioned inclusion criteria were found. These cases frequently described "advanced decomposition", often "unclear cause of death" and "problems in identification". These characteristics can thus be considered as being additional pointers in the definition. However, we suggest that the two general defining characteristics of a "domestic-setting corpse" are a post-mortem interval of more than 24 hours before discovery and the discovery of the corpse in a domestic setting.

  15. NMR approaches in structure-based lead discovery: recent developments and new frontiers for targeting multi-protein complexes.

    PubMed

    Dias, David M; Ciulli, Alessio

    2014-01-01

    Nuclear magnetic resonance (NMR) spectroscopy is a pivotal method for structure-based and fragment-based lead discovery because it is one of the most robust techniques to provide information on protein structure, dynamics and interaction at an atomic level in solution. Nowadays, in most ligand screening cascades, NMR-based methods are applied to identify and structurally validate small molecule binding. These can be high-throughput and are often used synergistically with other biophysical assays. Here, we describe current state-of-the-art in the portfolio of available NMR-based experiments that are used to aid early-stage lead discovery. We then focus on multi-protein complexes as targets and how NMR spectroscopy allows studying of interactions within the high molecular weight assemblies that make up a vast fraction of the yet untargeted proteome. Finally, we give our perspective on how currently available methods could build an improved strategy for drug discovery against such challenging targets. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. Service Discovery Oriented Management System Construction Method

    NASA Astrophysics Data System (ADS)

    Li, Huawei; Ren, Ying

    2017-10-01

    In order to solve the problem that there is no uniform method for design service quality management system in large-scale complex service environment, this paper proposes a distributed service-oriented discovery management system construction method. Three measurement functions are proposed to compute nearest neighbor user similarity at different levels. At present in view of the low efficiency of service quality management systems, three solutions are proposed to improve the efficiency of the system. Finally, the key technologies of distributed service quality management system based on service discovery are summarized through the factor addition and subtraction of quantitative experiment.

  17. Unusual flavoenzyme catalysis in marine bacteria

    PubMed Central

    Teufel, Robin; Agarwal, Vinayak; Moore, Bradley S.

    2016-01-01

    Ever since the discovery of the flavin cofactor more than 80 years ago, flavin-dependent enzymes have emerged as ubiquitous and versatile redox catalysts in primary metabolism. Yet, the recent advances in the discovery and characterization of secondary metabolic pathways exposed new roles for flavin-mediated catalysis in the generation of structurally complex natural products. Here, we review a selection of key biosynthetic flavoenzymes from marine bacterial secondary metabolism and illustrate how their functional and mechanistic investigation expanded our view of the cofactor's chemical repertoire and led to the discovery of a previously unknown flavin redox state. PMID:26803009

  18. 100 years of Drosophila research and its impact on vertebrate neuroscience: a history lesson for the future.

    PubMed

    Bellen, Hugo J; Tong, Chao; Tsuda, Hiroshi

    2010-07-01

    Discoveries in fruit flies have greatly contributed to our understanding of neuroscience. The use of an unparalleled wealth of tools, many of which originated between 1910–1960, has enabled milestone discoveries in nervous system development and function. Such findings have triggered and guided many research efforts in vertebrate neuroscience. After 100 years, fruit flies continue to be the choice model system for many neuroscientists. The combinational use of powerful research tools will ensure that this model organism will continue to lead to key discoveries that will impact vertebrate neuroscience.

  19. Protein Complex Production from the Drug Discovery Standpoint.

    PubMed

    Moarefi, Ismail

    2016-01-01

    Small molecule drug discovery critically depends on the availability of meaningful in vitro assays to guide medicinal chemistry programs that are aimed at optimizing drug potency and selectivity. As it becomes increasingly evident, most disease relevant drug targets do not act as a single protein. In the body, they are instead generally found in complex with protein cofactors that are highly relevant for their correct function and regulation. This review highlights selected examples of the increasing trend to use biologically relevant protein complexes for rational drug discovery to reduce costly late phase attritions due to lack of efficacy or toxicity.

  20. 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

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