WorldWideScience

Sample records for cell cardiopoiesis discovery

  1. Discovery and rediscoveries of Golgi cells

    NARCIS (Netherlands)

    E. Galliano (Elisa); P. Mazzarello (Paolo); E. D'Angelo (Egidio)

    2010-01-01

    textabstractWhen Camillo Golgi invented the black reaction in 1873 and first described the fine anatomical structure of the nervous system, he described a 'big nerve cell' that later took his name, the Golgi cell of cerebellum ('Golgi'schen Zellen', Gustaf Retzius, 1892). The Golgi cell was then

  2. Discovery and rediscoveries of Golgi cells.

    Science.gov (United States)

    Galliano, Elisa; Mazzarello, Paolo; D'Angelo, Egidio

    2010-10-01

    When Camillo Golgi invented the black reaction in 1873 and first described the fine anatomical structure of the nervous system, he described a ‘big nerve cell’ that later took his name, the Golgi cell of cerebellum (‘Golgi’schen Zellen’, Gustaf Retzius, 1892). The Golgi cell was then proposed as the prototype of type-II interneurons, which form complex connections and exert their actions exclusively within the local network. Santiago Ramón y Cajal (who received the Nobel Prize with Golgi in 1906) proceeded to a detailed description of Golgi cell morphological characteristics, but functional insight remained very limited for many years. The first rediscovery happened in the 1960s, when neurophysiological analysis in vivo revealed that Golgi cells are inhibitory interneurons. This finding promoted the development of two major cerebellar theories, the ‘beam theory’ of John Eccles and the ‘motor learning theory’ of David Marr, in which the Golgi cells regulate the spatial organisation and the gain of input signals to be processed and learned by the cerebellar circuit. However, the matter was not set and a series of pioneering observations using single unit recordings and electronmicroscopy raised new issues that could not be fully explored until the 1990s. Then, the advent of new electrophysiological and imaging techniques in vitro and in vivo demonstrated the cellular and network activities of these neurons. Now we know that Golgi cells, through complex systems of chemical and electrical synapses, effectively control the spatio-temporal organisation of cerebellar responses. The Golgi cells regulate the timing and number of spikes emitted by granule cells and coordinate their coherent activity. Moreover, the Golgi cells regulate the induction of long-term synaptic plasticity along the mossy fibre pathway. Eventually, the Golgi cells transform the granular layer of cerebellum into an adaptable spatio-temporal filter capable of performing several kinds

  3. Stem cells and the pancreas: from discovery to clinical approach

    Directory of Open Access Journals (Sweden)

    Angelica Dessì

    2016-02-01

    Full Text Available The existence of stem cells within the adult pancreas is supported by the ability of this organ to regenerate its endocrine component in various conditions such as pregnancy and following partial pancreatectomy. Several studies have shown that progenitor or adult stem cells may reside within the pancreas and particularly in the pancreatic ducts, including acinar cells and islets of Langerhans. The discovery of human pluripotent stem cells in the pancreas, and the possibility of development of strategies for generating these, represented a turning point for the therapeutic interventions of type 1 diabetes.Proceedings of the 2nd International Course on Perinatal Pathology (part of the 11th International Workshop on Neonatology · October 26th-31st, 2015 · Cagliari (Italy · October 31st, 2015 · Stem cells: present and future Guest Editors: Gavino Faa, Vassilios Fanos, Antonio Giordano

  4. Automated cell type discovery and classification through knowledge transfer

    Science.gov (United States)

    Lee, Hao-Chih; Kosoy, Roman; Becker, Christine E.

    2017-01-01

    Abstract Motivation: Recent advances in mass cytometry allow simultaneous measurements of up to 50 markers at single-cell resolution. However, the high dimensionality of mass cytometry data introduces computational challenges for automated data analysis and hinders translation of new biological understanding into clinical applications. Previous studies have applied machine learning to facilitate processing of mass cytometry data. However, manual inspection is still inevitable and becoming the barrier to reliable large-scale analysis. Results: We present a new algorithm called Automated Cell-type Discovery and Classification (ACDC) that fully automates the classification of canonical cell populations and highlights novel cell types in mass cytometry data. Evaluations on real-world data show ACDC provides accurate and reliable estimations compared to manual gating results. Additionally, ACDC automatically classifies previously ambiguous cell types to facilitate discovery. Our findings suggest that ACDC substantially improves both reliability and interpretability of results obtained from high-dimensional mass cytometry profiling data. Availability and Implementation: A Python package (Python 3) and analysis scripts for reproducing the results are availability on https://bitbucket.org/dudleylab/acdc. Contact: brian.kidd@mssm.edu or joel.dudley@mssm.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:28158442

  5. Human embryonic stem cell technologies and drug discovery.

    Science.gov (United States)

    Jensen, Janne; Hyllner, Johan; Björquist, Petter

    2009-06-01

    Development of new drugs is costly and takes huge resources into consideration. The big pharmaceutical companies are currently facing increasing developmental costs and a lower success-rate of bringing new compounds to the market. Therefore, it is now of outmost importance that the drug-hunting companies minimize late attritions due to sub-optimal pharmacokinetic properties or unexpected toxicity when entering the clinical programs. To achieve this, a strong need to test new candidate drugs in assays of high human relevance in vitro as early as possible has been identified. The traditionally used cell systems are however remarkably limited in this sense, and new improved technologies are of greatest importance. The human embryonic stem cells (hESC) is one of the most powerful cell types known. They have not only the possibility to divide indefinitely; these cells can also differentiate into all mature cell types of the human body. This makes them potentially very valuable for pharmaceutical development, spanning from use as tools in early target studies, DMPK or safety assessment, as screening models to find new chemical entities modulating adult stem cell fate, or as the direct use in cell therapies. This review illustrates the use of hESC in the drug discovery process, today, as well as in a future perspective. This will specifically be exemplified with the most important cell type for pharmaceutical development-the hepatocyte. We discuss how hESC-derived hepatocyte-like cells could improve this process, and how these cells should be cultured if optimized functionality and usefulness should be achieved. J. Cell. Physiol. 219: 513-519, 2009. (c) 2009 Wiley-Liss, Inc.

  6. Automated cell type discovery and classification through knowledge transfer.

    Science.gov (United States)

    Lee, Hao-Chih; Kosoy, Roman; Becker, Christine E; Dudley, Joel T; Kidd, Brian A

    2017-06-01

    Recent advances in mass cytometry allow simultaneous measurements of up to 50 markers at single-cell resolution. However, the high dimensionality of mass cytometry data introduces computational challenges for automated data analysis and hinders translation of new biological understanding into clinical applications. Previous studies have applied machine learning to facilitate processing of mass cytometry data. However, manual inspection is still inevitable and becoming the barrier to reliable large-scale analysis. We present a new algorithm called utomated ell-type iscovery and lassification (ACDC) that fully automates the classification of canonical cell populations and highlights novel cell types in mass cytometry data. Evaluations on real-world data show ACDC provides accurate and reliable estimations compared to manual gating results. Additionally, ACDC automatically classifies previously ambiguous cell types to facilitate discovery. Our findings suggest that ACDC substantially improves both reliability and interpretability of results obtained from high-dimensional mass cytometry profiling data. A Python package (Python 3) and analysis scripts for reproducing the results are availability on https://bitbucket.org/dudleylab/acdc . brian.kidd@mssm.edu or joel.dudley@mssm.edu. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press.

  7. Cell type discovery and representation in the era of high-content single cell phenotyping.

    Science.gov (United States)

    Bakken, Trygve; Cowell, Lindsay; Aevermann, Brian D; Novotny, Mark; Hodge, Rebecca; Miller, Jeremy A; Lee, Alexandra; Chang, Ivan; McCorrison, Jamison; Pulendran, Bali; Qian, Yu; Schork, Nicholas J; Lasken, Roger S; Lein, Ed S; Scheuermann, Richard H

    2017-12-21

    A fundamental characteristic of multicellular organisms is the specialization of functional cell types through the process of differentiation. These specialized cell types not only characterize the normal functioning of different organs and tissues, they can also be used as cellular biomarkers of a variety of different disease states and therapeutic/vaccine responses. In order to serve as a reference for cell type representation, the Cell Ontology has been developed to provide a standard nomenclature of defined cell types for comparative analysis and biomarker discovery. Historically, these cell types have been defined based on unique cellular shapes and structures, anatomic locations, and marker protein expression. However, we are now experiencing a revolution in cellular characterization resulting from the application of new high-throughput, high-content cytometry and sequencing technologies. The resulting explosion in the number of distinct cell types being identified is challenging the current paradigm for cell type definition in the Cell Ontology. In this paper, we provide examples of state-of-the-art cellular biomarker characterization using high-content cytometry and single cell RNA sequencing, and present strategies for standardized cell type representations based on the data outputs from these cutting-edge technologies, including "context annotations" in the form of standardized experiment metadata about the specimen source analyzed and marker genes that serve as the most useful features in machine learning-based cell type classification models. We also propose a statistical strategy for comparing new experiment data to these standardized cell type representations. The advent of high-throughput/high-content single cell technologies is leading to an explosion in the number of distinct cell types being identified. It will be critical for the bioinformatics community to develop and adopt data standard conventions that will be compatible with these new

  8. Single?Cell Mass Spectrometry for Discovery Proteomics: Quantifying Translational Cell Heterogeneity in the 16?Cell Frog (Xenopus) Embryo

    OpenAIRE

    Lombard?Banek, Camille; Moody, Sally A.; Nemes, Peter

    2016-01-01

    Abstract We advance mass spectrometry from a cell population?averaging tool to one capable of quantifying the expression of diverse proteins in single embryonic cells. Our instrument combines capillary electrophoresis (CE), electrospray ionization, and a tribrid ultrahigh?resolution mass spectrometer (HRMS) to enable untargeted (discovery) proteomics with ca. 25?amol lower limit of detection. CE??ESI?HRMS enabled the identification of 500?800 nonredundant protein groups by measuring 20?ng, or

  9. Macro cell assisted cell discovery method for 5G mobile networks

    DEFF Research Database (Denmark)

    Marcano, Andrea; Christiansen, Henrik Lehrmann

    2016-01-01

    , and requires a new system design. The aspects concerning the impact of using mmWave frequencies on the medium access (MAC) layer are one of the topics that need to be further analyzed. In this article we focus on the cell discovery process of the MAC laywe for mmWave communications. A new approach assuming...... a joint search of the user equipment (UE) between the mmWave small cell (SC) and the macro cell (MC) is proposed. The performance of this method is analyzed and compared with existing methods. The results show that using the MC as aid during the search process can allow for up to 99% improvement in terms...

  10. The beautiful cell: high-content screening in drug discovery.

    Science.gov (United States)

    Bickle, Marc

    2010-09-01

    The term "high-content screening" has become synonymous with imaging screens using automated microscopes and automated image analysis. The term was coined a little over 10 years ago. Since then the technology has evolved considerably and has established itself firmly in the drug discovery and development industry. Both the instruments and the software controlling the instruments and analyzing the data have come to maturity, so the full benefits of high-content screening can now be realized. Those benefits are the capability of carrying out phenotypic multiparametric cellular assays in an unbiased, fully automated, and quantitative fashion. Automated microscopes and automated image analysis are being applied at all stages of the drug discovery and development pipeline. All major pharmaceutical companies have adopted the technology and it is in the process of being embraced broadly by the academic community. This review aims at describing the current capabilities and limits of the technology as well as highlighting necessary developments that are required to exploit fully the potential of high-content screening and analysis.

  11. Induced Pluripotent Stem Cells as a Model for Accelerated Patient- and Disease-specific Drug Discovery

    OpenAIRE

    Gunaseeli, I.; Doss, M.X.; Antzelevitch, C.; Hescheler, J.; Sachinidis, A.

    2010-01-01

    Human induced pluripotent stem (iPS) cells hold great promise for therapy of a number of degenerative diseases such as ischemic heart failure, Parkinson’s disease, Alzheimer’s disease, diabetes mellitus, sickle cell anemia and Huntington disease. They also have the potential to accelerate drug discovery in 3 ways. The first involves the delineation of chemical components for efficient reprogramming of patient’s blood cells or cells from biopsies, obviating the need for cellular delivery of re...

  12. Impact of New Camera Technologies on Discoveries in Cell Biology.

    Science.gov (United States)

    Stuurman, Nico; Vale, Ronald D

    2016-08-01

    New technologies can make previously invisible phenomena visible. Nowhere is this more obvious than in the field of light microscopy. Beginning with the observation of "animalcules" by Antonie van Leeuwenhoek, when he figured out how to achieve high magnification by shaping lenses, microscopy has advanced to this day by a continued march of discoveries driven by technical innovations. Recent advances in single-molecule-based technologies have achieved unprecedented resolution, and were the basis of the Nobel prize in Chemistry in 2014. In this article, we focus on developments in camera technologies and associated image processing that have been a major driver of technical innovations in light microscopy. We describe five types of developments in camera technology: video-based analog contrast enhancement, charge-coupled devices (CCDs), intensified sensors, electron multiplying gain, and scientific complementary metal-oxide-semiconductor cameras, which, together, have had major impacts in light microscopy. © 2016 Marine Biological Laboratory.

  13. Translational Prospects and Challenges in Human Induced Pluripotent Stem Cell Research in Drug Discovery

    Directory of Open Access Journals (Sweden)

    Masaki Hosoya

    2016-12-01

    Full Text Available Despite continuous efforts to improve the process of drug discovery and development, achieving success at the clinical stage remains challenging because of a persistent translational gap between the preclinical and clinical settings. Under these circumstances, the discovery of human induced pluripotent stem (iPS cells has brought new hope to the drug discovery field because they enable scientists to humanize a variety of pharmacological and toxicological models in vitro. The availability of human iPS cell-derived cells, particularly as an alternative for difficult-to-access tissues and organs, is increasing steadily; however, their use in the field of translational medicine remains challenging. Biomarkers are an essential part of the translational effort to shift new discoveries from bench to bedside as they provide a measurable indicator with which to evaluate pharmacological and toxicological effects in both the preclinical and clinical settings. In general, during the preclinical stage of the drug development process, in vitro models that are established to recapitulate human diseases are validated by using a set of biomarkers; however, their translatability to a clinical setting remains problematic. This review provides an overview of current strategies for human iPS cell-based drug discovery from the perspective of translational research, and discusses the importance of early consideration of clinically relevant biomarkers.

  14. Discovery of HeLa Cell Contamination in HES Cells: Call for Cell Line Authentication in Reproductive Biology Research.

    Science.gov (United States)

    Kniss, Douglas A; Summerfield, Taryn L

    2014-08-01

    Continuous cell lines are used frequently in reproductive biology research to study problems in early pregnancy events and parturition. It has been recognized for 50 years that many mammalian cell lines contain inter- or intraspecies contaminations with other cells. However, most investigators do not routinely test their culture systems for cross-contamination. The most frequent contributor to cross-contamination of cell lines is the HeLa cell isolated from an aggressive cervical adenocarcinoma. We report on the discovery of HeLa cell contamination of the human endometrial epithelial cell line HES isolated in our laboratory. Short tandem repeat analysis of 9 unique genetic loci demonstrated molecular identity between HES and HeLa cells. In addition, we verified that WISH cells, isolated originally from human amnion epithelium, were also contaminated with HeLa cells. Inasmuch as our laboratory did not culture HeLa cells at the time of HES cell derivations, the source of contamination was the WISH cell line. These data highlight the need for continued diligence in authenticating cell lines used in reproductive biology research. © The Author(s) 2014.

  15. Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Chanshuai Han

    2018-02-01

    Full Text Available Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop “first-of-their-kind” disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI and its partners are piloting an “Open Science” model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders.

  16. Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders.

    Science.gov (United States)

    Han, Chanshuai; Chaineau, Mathilde; Chen, Carol X-Q; Beitel, Lenore K; Durcan, Thomas M

    2018-01-01

    Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs) from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop "first-of-their-kind" disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI) and its partners are piloting an "Open Science" model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders.

  17. Challenges for red blood cell biomarker discovery through proteomics

    NARCIS (Netherlands)

    Barasa, B.A.|info:eu-repo/dai/nl/341538353; Slijper, M.|info:eu-repo/dai/nl/146303989

    2014-01-01

    Red blood cells are rather unique body cells, since they have lost all organelles when mature, which results in lack of potential to replace proteins that have lost their function. They maintain only a few pathways for obtaining energy and reducing power for the key functions they need to fulfill.

  18. Patient-derived stem cells: pathways to drug discovery for brain diseases

    Directory of Open Access Journals (Sweden)

    Alan eMackay-Sim

    2013-03-01

    Full Text Available The concept of drug discovery through stem cell biology is based on technological developments whose genesis is now coincident. The first is automated cell microscopy with concurrent advances in image acquisition and analysis, known as high content screening (HCS. The second is patient-derived stem cells for modelling the cell biology of brain diseases. HCS has developed from the requirements of the pharmaceutical industry for high throughput assays to screen thousands of chemical compounds in the search for new drugs. HCS combines new fluorescent probes with automated microscopy and computational power to quantify the effects of compounds on cell functions. Stem cell biology has advanced greatly since the discovery of genetic reprogramming of somatic cells into induced pluripotent stem cells (iPSCs. There is now a rush of papers describing their generation from patients with various diseases of the nervous system. Although the majority of these have been genetic diseases, iPSCs have been generated from patients with complex diseases (schizophrenia and sporadic Parkinson’s disease. Some genetic diseases are also modelled in embryonic stem cells generated from blastocysts rejected during in vitro fertilisation. Neural stem cells have been isolated from post-mortem brain of Alzheimer’s patients and neural stem cells generated from biopsies of the olfactory organ of patients is another approach. These olfactory neurosphere-derived cells demonstrate robust disease-specific phenotypes in patients with schizophrenia and Parkinson’s disease. High content screening is already in use to find small molecules for the generation and differentiation of embryonic stem cells and induced pluripotent stem cells. The challenges for using stem cells for drug discovery are to develop robust stem cell culture methods that meet the rigorous requirements for repeatable, consistent quantities of defined cell types at the industrial scale necessary for high

  19. The neural crest and neural crest cells: discovery and significance ...

    Indian Academy of Sciences (India)

    PRAKASH KUMAR

    ). Le Douarin N M 1986 Cell line segregation during peripheral nervous system ontogeny; Science 231 1515–1522. Le Douarin N M, Dupin E, Baroffio A and Dulac C 1992 New insights into the development of neural crest derivatives; Int. Rev.

  20. Cornell Fuel Cell Institute: Materials Discovery to Enable Fuel Cell Technologies

    Energy Technology Data Exchange (ETDEWEB)

    Abruna, H.D.; DiSalvo, Francis J.

    2012-06-29

    The discovery and understanding of new, improved materials to advance fuel cell technology are the objectives of the Cornell Fuel Cell Institute (CFCI) research program. CFCI was initially formed in 2003. This report highlights the accomplishments from 2006-2009. Many of the grand challenges in energy science and technology are based on the need for materials with greatly improved or even revolutionary properties and performance. This is certainly true for fuel cells, which have the promise of being highly efficient in the conversion of chemical energy to electrical energy. Fuel cells offer the possibility of efficiencies perhaps up to 90 % based on the free energy of reaction. Here, the challenges are clearly in the materials used to construct the heart of the fuel cell: the membrane electrode assembly (MEA). The MEA consists of two electrodes separated by an ionically conducting membrane. Each electrode is a nanocomposite of electronically conducting catalyst support, ionic conductor and open porosity, that together form three percolation networks that must connect to each catalyst nanoparticle; otherwise the catalyst is inactive. This report highlights the findings of the three years completing the CFCI funding, and incudes developments in materials for electrocatalyts, catalyst supports, materials with structured and functional porosity for electrodes, and novel electrolyte membranes. The report also discusses developments at understanding electrocatalytic mechanisms, especially on novel catalyst surfaces, plus in situ characterization techniques and contributions from theory. Much of the research of the CFCI continues within the Energy Materials Center at Cornell (emc2), a DOE funded, Office of Science Energy Frontier Research Center (EFRC).

  1. Gastric and colonic mantle cell lymphoma - incidental discovery.

    Science.gov (United States)

    Pitigoi, Dan; Stoica, Victor; Stoia, Razvan; Dobrea, Camelia; Becheanu, Gabriel; Diculescu, Mircea

    2009-03-01

    A 65-year old patient, with no medical history, was admitted for lower gastrointestinal bleeding. On clinical examination the patient seemed to be in good health. However the examination was completed with a rectosigmoidoscopy revealing the presence of mucosal erosions, ulcerations, multiple papulae. The histopathological examination raised the suspicion of a colonic lymphoma. Gastric biopsies suggested a gastric MALT type lymphoma associated to the colonic lymphoma, but the immunohistochemical profile corresponded to a mantle cell lymphoma. In spite of the general poor prognosis of mantle cell lymphoma, our patient had a good clinical and endoscopic response to the standard cyclophosphamide, vincristine, prednisone (CVP) therapy. The cases of gastric and colonic mantle lymphoma are rare, the response to therapy is poor; fortunately, our patient had a complete resolution after completion of the six cycles of chemotherapy.

  2. Drug discovery via human-derived stem cell organoids

    Directory of Open Access Journals (Sweden)

    Fangkun Liu

    2016-09-01

    Full Text Available Patient-derived cell lines and animal models have proven invaluable for the understanding of human intestinal diseases and for drug development although both inherently comprise disadvantages and caveats. Many genetically determined intestinal diseases occur in specific tissue microenvironments that are not adequately modeled by monolayer cell culture. Likewise, animal models incompletely recapitulate the complex pathologies of intestinal diseases of humans and fall short in predicting the effects of candidate drugs. Patient-derived stem cell organoids are new and effective models for the development of novel targeted therapies. With the use of intestinal organoids from patients with inherited diseases, the potency and toxicity of drug candidates can be evaluated better. Moreover, owing to the novel CRISPR/Cas9 genome-editing technologies, researchers can use organoids to precisely modulate human genetic status and identify pathogenesis-related genes of intestinal diseases. Therefore, here we discuss how patient-derived organoids should be grown and how advanced genome-editing tools may be applied to research on modeling of cancer and infectious diseases. We also highlight practical applications of organoids ranging from basic studies to drug screening and precision medicine.

  3. Discovery of a Splicing Regulator Required for Cell Cycle Progression

    Energy Technology Data Exchange (ETDEWEB)

    Suvorova, Elena S.; Croken, Matthew; Kratzer, Stella; Ting, Li-Min; Conde de Felipe, Magnolia; Balu, Bharath; Markillie, Lye Meng; Weiss, Louis M.; Kim, Kami; White, Michael W.

    2013-02-01

    In the G1 phase of the cell division cycle, eukaryotic cells prepare many of the resources necessary for a new round of growth including renewal of the transcriptional and protein synthetic capacities and building the machinery for chromosome replication. The function of G1 has an early evolutionary origin and is preserved in single and multicellular organisms, although the regulatory mechanisms conducting G1 specific functions are only understood in a few model eukaryotes. Here we describe a new G1 mutant from an ancient family of apicomplexan protozoans. Toxoplasma gondii temperature-sensitive mutant 12-109C6 conditionally arrests in the G1 phase due to a single point mutation in a novel protein containing a single RNA-recognition-motif (TgRRM1). The resulting tyrosine to asparagine amino acid change in TgRRM1 causes severe temperature instability that generates an effective null phenotype for this protein when the mutant is shifted to the restrictive temperature. Orthologs of TgRRM1 are widely conserved in diverse eukaryote lineages, and the human counterpart (RBM42) can functionally replace the missing Toxoplasma factor. Transcriptome studies demonstrate that gene expression is downregulated in the mutant at the restrictive temperature due to a severe defect in splicing that affects both cell cycle and constitutively expressed mRNAs. The interaction of TgRRM1 with factors of the tri-SNP complex (U4/U6 & U5 snRNPs) indicate this factor may be required to assemble an active spliceosome. Thus, the TgRRM1 family of proteins is an unrecognized and evolutionarily conserved class of splicing regulators. This study demonstrates investigations into diverse unicellular eukaryotes, like the Apicomplexa, have the potential to yield new insights into important mechanisms conserved across modern eukaryotic kingdoms.

  4. Single-Cell Mass Spectrometry for Discovery Proteomics: Quantifying Translational Cell Heterogeneity in the 16-Cell Frog (Xenopus) Embryo.

    Science.gov (United States)

    Lombard-Banek, Camille; Moody, Sally A; Nemes, Peter

    2016-02-12

    We advance mass spectrometry from a cell population-averaging tool to one capable of quantifying the expression of diverse proteins in single embryonic cells. Our instrument combines capillary electrophoresis (CE), electrospray ionization, and a tribrid ultrahigh-resolution mass spectrometer (HRMS) to enable untargeted (discovery) proteomics with ca. 25 amol lower limit of detection. CE-μESI-HRMS enabled the identification of 500-800 nonredundant protein groups by measuring 20 ng, or embryo, amounting to a total of 1709 protein groups identified between n=3 biological replicates. By quantifying ≈150 nonredundant protein groups between all blastomeres and replicate measurements, we found significant translational cell heterogeneity along multiple axes of the embryo at this very early stage of development when the transcriptional program of the embryo has yet to begin. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  5. Discovery of novel inducers of cellular differentiation using HL-60 promyelocytic cells.

    Science.gov (United States)

    Mata-Greenwood, E; Ito, A; Westenburg, H; Cui, B; Mehta, R G; Kinghorn, A D; Pezzuto, J M

    2001-01-01

    Non-physiological inducers of terminal differentiation have been used as novel therapies for the prevention and therapy of cancer. We have used cultured HL-60 promyelocytic cells to monitor differentiation, proliferation and cell death events as induced by a large set of extracts derived from plants. Screening of more than 1400 extracts led to the discovery of 34 with potent activity (ED50 Petiveria alliacea, and desmethylrocaglamide from Aglaia ponapensis. Zapotin demonstrated the most favorable biological profile in that induction of differentiation correlated with proliferation arrest, and a lack of cytotoxicity. We conclude that the HL-60 cell model is a useful system for the discovery of novel pharmacophores with potential to suppress the process of carcinogenesis, and that flavonoids may be especially useful in this capacity.

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

    Science.gov (United States)

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

    2012-01-03

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

  7. Evolving towards a human-cell based and multiscale approach to drug discovery for CNS disorders

    Directory of Open Access Journals (Sweden)

    Eric eSchadt

    2014-12-01

    Full Text Available A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer’s Disease (AD, and the psychiatric disorder schizophrenia (SZ, we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature

  8. An Innovative Cell Microincubator for Drug Discovery Based on 3D Silicon Structures

    Directory of Open Access Journals (Sweden)

    Francesca Aredia

    2016-01-01

    Full Text Available We recently employed three-dimensional (3D silicon microstructures (SMSs consisting in arrays of 3 μm-thick silicon walls separated by 50 μm-deep, 5 μm-wide gaps, as microincubators for monitoring the biomechanical properties of tumor cells. They were here applied to investigate the in vitro behavior of HT1080 human fibrosarcoma cells driven to apoptosis by the chemotherapeutic drug Bleomycin. Our results, obtained by fluorescence microscopy, demonstrated that HT1080 cells exhibited a great ability to colonize the narrow gaps. Remarkably, HT1080 cells grown on 3D-SMS, when treated with the DNA damaging agent Bleomycin under conditions leading to apoptosis, tended to shrink, reducing their volume and mimicking the normal behavior of apoptotic cells, and were prone to leave the gaps. Finally, we performed label-free detection of cells adherent to the vertical silicon wall, inside the gap of 3D-SMS, by exploiting optical low coherence reflectometry using infrared, low power radiation. This kind of approach may become a new tool for increasing automation in the drug discovery area. Our results open new perspectives in view of future applications of the 3D-SMS as the core element of a lab-on-a-chip suitable for screening the effect of new molecules potentially able to kill tumor cells.

  9. Human pluripotent stem cells as tools for neurodegenerative and neurodevelopmental disease modeling and drug discovery.

    Science.gov (United States)

    Corti, Stefania; Faravelli, Irene; Cardano, Marina; Conti, Luciano

    2015-06-01

    Although intensive efforts have been made, effective treatments for neurodegenerative and neurodevelopmental diseases have not been yet discovered. Possible reasons for this include the lack of appropriate disease models of human neurons and a limited understanding of the etiological and neurobiological mechanisms. Recent advances in pluripotent stem cell (PSC) research have now opened the path to the generation of induced pluripotent stem cells (iPSCs) starting from somatic cells, thus offering an unlimited source of patient-specific disease-relevant neuronal cells. In this review, the authors focus on the use of human PSC-derived cells in modeling neurological disorders and discovering of new drugs and provide their expert perspectives on the field. The advent of human iPSC-based disease models has fuelled renewed enthusiasm and enormous expectations for insights of disease mechanisms and identification of more disease-relevant and novel molecular targets. Human PSCs offer a unique tool that is being profitably exploited for high-throughput screening (HTS) platforms. This process can lead to the identification and optimization of molecules/drugs and thus move forward new pharmacological therapies for a wide range of neurodegenerative and neurodevelopmental conditions. It is predicted that improvements in the production of mature neuronal subtypes, from patient-specific human-induced pluripotent stem cells and their adaptation to culture, to HTS platforms will allow the increased exploitation of human pluripotent stem cells in drug discovery programs.

  10. Induced Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Neurodegenerative Diseases.

    Science.gov (United States)

    Cao, Lei; Tan, Lan; Jiang, Teng; Zhu, Xi-Chen; Yu, Jin-Tai

    2015-08-01

    Although most neurodegenerative diseases have been closely related to aberrant accumulation of aggregation-prone proteins in neurons, understanding their pathogenesis remains incomplete, and there is no treatment to delay the onset or slow the progression of many neurodegenerative diseases. The availability of induced pluripotent stem cells (iPSCs) in recapitulating the phenotypes of several late-onset neurodegenerative diseases marks the new era in in vitro modeling. The iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in these diseases and provides a novel human stem cell platform for screening new candidate therapeutics. Modeling human diseases using iPSCs has created novel opportunities for both mechanistic studies as well as for the discovery of new disease therapies. In this review, we introduce iPSC-based disease modeling in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In addition, we discuss the implementation of iPSCs in drug discovery associated with some new techniques.

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

    Science.gov (United States)

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

    2011-01-01

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

  12. Rita Levi-Montalcini and the discovery of NGF, the first nerve cell growth factor.

    Science.gov (United States)

    Aloe, Luigi

    2011-06-01

    The nerve growth factor (NGF) is a signaling protein, discovered by Rita Levi-Montalcini in the early 1950's for its effect on growth and differentiation of specific populations of neurons of the peripheral nervous system. Originally identified as neurite outgrowth-stimulating factor, later studies revealed that the purified molecule has a number of target cells in the central nervous system and on nonneuronal cells. Moreover, recent studies showed the potential therapeutic properties of NGF in neuropathies of the central and peripheral nervous system and diseases of the eye and skin. Here I briefly describe the discovery of NGF, the early studies of Rita LeviMontalcini, a pioneer in modern neuroscience, and my scientific and human experience working in her laboratory for over 40 years.

  13. Personalized Whole-Cell Kinetic Models of Metabolism for Discovery in Genomics and Pharmacodynamics

    DEFF Research Database (Denmark)

    Bordbar, Aarash; McCloskey, Douglas; Zielinski, Daniel C

    2015-01-01

    Understanding individual variation is fundamental to personalized medicine. Yet interpreting complex phenotype data, such as multi-compartment metabolomic profiles, in the context of genotype data for an individual is complicated by interactions within and between cells and remains an unresolved...... challenge. Here, we constructed multi-omic, data-driven, personalized whole-cell kinetic models of erythrocyte metabolism for 24 healthy individuals based on fasting-state plasma and erythrocyte metabolomics and whole-genome genotyping. We show that personalized kinetic rate constants, rather than......-induced anemia) and how genetic variation (inosine triphosphatase deficiency) may protect against this side effect. This study demonstrates the feasibility of personalized kinetic models, and we anticipate their use will accelerate discoveries in characterizing individual metabolic variation....

  14. 3D cell culture systems modeling tumor growth determinants in cancer target discovery.

    Science.gov (United States)

    Thoma, Claudio R; Zimmermann, Miriam; Agarkova, Irina; Kelm, Jens M; Krek, Wilhelm

    2014-04-01

    Phenotypic heterogeneity of cancer cells, cell biological context, heterotypic crosstalk and the microenvironment are key determinants of the multistep process of tumor development. They sign responsible, to a significant extent, for the limited response and resistance of cancer cells to molecular-targeted therapies. Better functional knowledge of the complex intra- and intercellular signaling circuits underlying communication between the different cell types populating a tumor tissue and of the systemic and local factors that shape the tumor microenvironment is therefore imperative. Sophisticated 3D multicellular tumor spheroid (MCTS) systems provide an emerging tool to model the phenotypic and cellular heterogeneity as well as microenvironmental aspects of in vivo tumor growth. In this review we discuss the cellular, chemical and physical factors contributing to zonation and cellular crosstalk within tumor masses. On this basis, we further describe 3D cell culture technologies for growth of MCTS as advanced tools for exploring molecular tumor growth determinants and facilitating drug discovery efforts. We conclude with a synopsis on technological aspects for on-line analysis and post-processing of 3D MCTS models. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Antibiotic Discovery: Combatting Bacterial Resistance in Cells and in Biofilm Communities

    Directory of Open Access Journals (Sweden)

    Anahit Penesyan

    2015-03-01

    Full Text Available Bacterial resistance is a rapidly escalating threat to public health as our arsenal of effective antibiotics dwindles. Therefore, there is an urgent need for new antibiotics. Drug discovery has historically focused on bacteria growing in planktonic cultures. Many antibiotics were originally developed to target individual bacterial cells, being assessed in vitro against microorganisms in a planktonic mode of life. However, towards the end of the 20th century it became clear that many bacteria live as complex communities called biofilms in their natural habitat, and this includes habitats within a human host. The biofilm mode of life provides advantages to microorganisms, such as enhanced resistance towards environmental stresses, including antibiotic challenge. The community level resistance provided by biofilms is distinct from resistance mechanisms that operate at a cellular level, and cannot be overlooked in the development of novel strategies to combat infectious diseases. The review compares mechanisms of antibiotic resistance at cellular and community levels in the light of past and present antibiotic discovery efforts. Future perspectives on novel strategies for treatment of biofilm-related infectious diseases are explored.

  16. Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery

    Science.gov (United States)

    Singh, Vimal K.; Kalsan, Manisha; Kumar, Neeraj; Saini, Abhishek; Chandra, Ramesh

    2015-01-01

    Recent progresses in the field of Induced Pluripotent Stem Cells (iPSCs) have opened up many gateways for the research in therapeutics. iPSCs are the cells which are reprogrammed from somatic cells using different transcription factors. iPSCs possess unique properties of self renewal and differentiation to many types of cell lineage. Hence could replace the use of embryonic stem cells (ESC), and may overcome the various ethical issues regarding the use of embryos in research and clinics. Overwhelming responses prompted worldwide by a large number of researchers about the use of iPSCs evoked a large number of peple to establish more authentic methods for iPSC generation. This would require understanding the underlying mechanism in a detailed manner. There have been a large number of reports showing potential role of different molecules as putative regulators of iPSC generating methods. The molecular mechanisms that play role in reprogramming to generate iPSCs from different types of somatic cell sources involves a plethora of molecules including miRNAs, DNA modifying agents (viz. DNA methyl transferases), NANOG, etc. While promising a number of important roles in various clinical/research studies, iPSCs could also be of great use in studying molecular mechanism of many diseases. There are various diseases that have been modeled by uing iPSCs for better understanding of their etiology which maybe further utilized for developing putative treatments for these diseases. In addition, iPSCs are used for the production of patient-specific cells which can be transplanted to the site of injury or the site of tissue degeneration due to various disease conditions. The use of iPSCs may eliminate the chances of immune rejection as patient specific cells may be used for transplantation in various engraftment processes. Moreover, iPSC technology has been employed in various diseases for disease modeling and gene therapy. The technique offers benefits over other similar techniques

  17. Target-directed discovery and production of pharmaceuticals in transgenic mutant plant cells

    Science.gov (United States)

    Brown, DP; Rogers, DT; Gunjan, SK; Gerhardt, GA; Littleton, JM

    2016-01-01

    Plants are a source of complex bioactive compounds, with value as pharmaceuticals, or leads for synthetic modification. Many of these secondary metabolites have evolved as defenses against competing organisms. and their pharmaceutical value is “accidental”, resulting from homology between target proteins in these competitors, and human molecular therapeutic targets. Here we show that it is possible to use mutation and selection of plant cells to re-direct their “evolution” toward metabolites that interact with the therapeutic target proteins themselves. This is achieved by expressing the human target protein in plant cells, and selecting mutants for survival based on the interaction of their metabolome with this target. This report describes the successful evolution of hairy root cultures of a Lobelia species toward increased biosynthesis of metabolites that inhibit the human dopamine transporter protein. Many of the resulting selected mutants are overproducing the active metabolite found in the wild-type plant, but others overproduce active metabolites that are not readily detectable in non-mutants. This technology can access the whole genomic capability of a plant species to biosynthesize metabolites with a specific target. It has potential value as a novel platform for plant drug discovery and production, or as a means of optimizing the therapeutic value of medicinal plant extracts. PMID:27637316

  18. Live Cell Discovery of Microbial Vitamin Transport and Enzyme-Cofactor Interactions

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, Lindsey N.; Koech, Phillip K.; Plymale, Andrew E.; Landorf, Elizabeth V.; Konopka, Allan; Collart, Frank; Lipton, Mary S.; Romine, Margaret F.; Wright, Aaron T.

    2016-02-02

    The rapid completion of microbial genomes is inducing a conundrum in functional gene discovery. Novel methods are critically needed to shorten the gap between characterizing a microbial genome and experimentally validating bioinformatically-predicted functions. Of particular importance are transport mechanisms, used to shuttle nutrients and metabolites across cell mem-branes, such as B vitamins, which are indispensable to metabolic reactions crucial to the survival of diverse microbes ranging from members of environmental microbial communities to human pathogens. Methods to accurately assign function and specificity for a wide range of experimentally unidentified and/or predicted membrane-embedded transport proteins, and characterization of intra-cellular enzyme-cofactor/nutrient associations are needed to enable a significantly improved understanding of microbial biochemis-try and physiology, how microbes associate with others, and how they sense and respond to environmental perturbations. Chemical probes derived from B vitamins B1, B2, and B7 have allowed us to experimentally address the aforementioned needs by identifying B vitamin transporters and intracellular protein-cofactor associations through live cell labeling of the filamentous anoxygenic pho-toheterotroph, Chloroflexus aurantiacus J-10-fl, known for both B vitamin biosynthesis and environmental salvage. Our probes provide a unique opportunity to directly link cellular activity and protein function back to ecosystem and/or host dynamics by iden-tifying B vitamin transport and disposition mechanisms required for survival.

  19. An optogenetic toolbox for unbiased discovery of functionally connected cells in neural circuits.

    Science.gov (United States)

    Förster, Dominique; Dal Maschio, Marco; Laurell, Eva; Baier, Herwig

    2017-07-24

    Optical imaging approaches have revolutionized our ability to monitor neural network dynamics, but by themselves are unable to link a neuron's activity to its functional connectivity. We present a versatile genetic toolbox, termed 'Optobow', for all-optical discovery of excitatory connections in vivo. By combining the Gal4-UAS system with Cre/lox recombination, we target the optogenetic actuator ChrimsonR and the sensor GCaMP6 to stochastically labeled, nonoverlapping and sparse subsets of neurons. Photostimulation of single cells using two-photon computer-generated holography evokes calcium responses in downstream neurons. Morphological reconstruction of neurite arbors, response latencies and localization of presynaptic markers suggest that some neuron pairs recorded here are directly connected, while others are two or more synapses apart from each other. With this toolbox, we discover wiring principles between specific cell types in the larval zebrafish tectum. Optobow should be useful for identification and manipulation of networks of interconnected neurons, even in dense neural tissues.Mechanisms of neural processing can only be understood by revealing patterns of connectivity among the cellular components of the circuit. Here the authors report a new genetic toolbox, 'Optobow', which enables simultaneous optogenetic activation of single neurons in zebrafish and measuring the activity of downstream neurons in the network.

  20. An in vivo-like tumor stem cell-related glioblastoma in vitro model for drug discovery

    DEFF Research Database (Denmark)

    Jensen, Stine Skov; Aaberg-Jessen, Charlotte; Nørregaard, Annette

    the effects of new drugs on tumor cells including tumor stem cells. Implantation of glioblastoma cells into organotypic brain slice cultures has previously been published as a model system, but not using a stem cell favourable environment. Organotypic corticostriatal rat brain slice cultures were prepared...... and cultured in a serum containing medium replaced after three days with a serum-free stem cell medium. Thereafter fluorescent DiI labelled glioblastoma spheroids from the cell line U87 and the tumor stem cell line SJ-1 established in our laboratory were implanted into the brain slices between cortex......The discovery of tumor stem cells being highly resistant against therapy makes new demands to model systems suitable for evaluation of the effects of new drugs on tumor stem cells. The aim of the present study was therefore to develop an in vivo-like in vitro glioblastoma model for testing...

  1. Stem cell therapy for heart failure: Ensuring regenerative proficiency.

    Science.gov (United States)

    Terzic, Andre; Behfar, Atta

    2016-07-01

    Patient-derived stem cells enable promising regenerative strategies, but display heterogenous cardiac reparative proficiency, leading to unpredictable therapeutic outcomes impeding practice adoption. Means to establish and certify the regenerative potency of emerging biotherapies are thus warranted. In this era of clinomics, deconvolution of variant cytoreparative performance in clinical trials offers an unprecedented opportunity to map pathways that segregate regenerative from non-regenerative states informing the evolution of cardio-regenerative quality systems. A maiden example of this approach is cardiopoiesis-mediated lineage specification developed to ensure regenerative performance. Successfully tested in pre-clinical and early clinical studies, the safety and efficacy of the cardiopoietic stem cell phenotype is undergoing validation in pivotal trials for chronic ischemic cardiomyopathy offering the prospect of a next-generation regenerative solution for heart failure. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Cell surface profiling using high-throughput flow cytometry: a platform for biomarker discovery and analysis of cellular heterogeneity.

    Directory of Open Access Journals (Sweden)

    Craig A Gedye

    Full Text Available Cell surface proteins have a wide range of biological functions, and are often used as lineage-specific markers. Antibodies that recognize cell surface antigens are widely used as research tools, diagnostic markers, and even therapeutic agents. The ability to obtain broad cell surface protein profiles would thus be of great value in a wide range of fields. There are however currently few available methods for high-throughput analysis of large numbers of cell surface proteins. We describe here a high-throughput flow cytometry (HT-FC platform for rapid analysis of 363 cell surface antigens. Here we demonstrate that HT-FC provides reproducible results, and use the platform to identify cell surface antigens that are influenced by common cell preparation methods. We show that multiple populations within complex samples such as primary tumors can be simultaneously analyzed by co-staining of cells with lineage-specific antibodies, allowing unprecedented depth of analysis of heterogeneous cell populations. Furthermore, standard informatics methods can be used to visualize, cluster and downsample HT-FC data to reveal novel signatures and biomarkers. We show that the cell surface profile provides sufficient molecular information to classify samples from different cancers and tissue types into biologically relevant clusters using unsupervised hierarchical clustering. Finally, we describe the identification of a candidate lineage marker and its subsequent validation. In summary, HT-FC combines the advantages of a high-throughput screen with a detection method that is sensitive, quantitative, highly reproducible, and allows in-depth analysis of heterogeneous samples. The use of commercially available antibodies means that high quality reagents are immediately available for follow-up studies. HT-FC has a wide range of applications, including biomarker discovery, molecular classification of cancers, or identification of novel lineage specific or stem cell

  3. Cell surface profiling using high-throughput flow cytometry: a platform for biomarker discovery and analysis of cellular heterogeneity.

    Science.gov (United States)

    Gedye, Craig A; Hussain, Ali; Paterson, Joshua; Smrke, Alannah; Saini, Harleen; Sirskyj, Danylo; Pereira, Keira; Lobo, Nazleen; Stewart, Jocelyn; Go, Christopher; Ho, Jenny; Medrano, Mauricio; Hyatt, Elzbieta; Yuan, Julie; Lauriault, Stevan; Meyer, Mona; Kondratyev, Maria; van den Beucken, Twan; Jewett, Michael; Dirks, Peter; Guidos, Cynthia J; Danska, Jayne; Wang, Jean; Wouters, Bradly; Neel, Benjamin; Rottapel, Robert; Ailles, Laurie E

    2014-01-01

    Cell surface proteins have a wide range of biological functions, and are often used as lineage-specific markers. Antibodies that recognize cell surface antigens are widely used as research tools, diagnostic markers, and even therapeutic agents. The ability to obtain broad cell surface protein profiles would thus be of great value in a wide range of fields. There are however currently few available methods for high-throughput analysis of large numbers of cell surface proteins. We describe here a high-throughput flow cytometry (HT-FC) platform for rapid analysis of 363 cell surface antigens. Here we demonstrate that HT-FC provides reproducible results, and use the platform to identify cell surface antigens that are influenced by common cell preparation methods. We show that multiple populations within complex samples such as primary tumors can be simultaneously analyzed by co-staining of cells with lineage-specific antibodies, allowing unprecedented depth of analysis of heterogeneous cell populations. Furthermore, standard informatics methods can be used to visualize, cluster and downsample HT-FC data to reveal novel signatures and biomarkers. We show that the cell surface profile provides sufficient molecular information to classify samples from different cancers and tissue types into biologically relevant clusters using unsupervised hierarchical clustering. Finally, we describe the identification of a candidate lineage marker and its subsequent validation. In summary, HT-FC combines the advantages of a high-throughput screen with a detection method that is sensitive, quantitative, highly reproducible, and allows in-depth analysis of heterogeneous samples. The use of commercially available antibodies means that high quality reagents are immediately available for follow-up studies. HT-FC has a wide range of applications, including biomarker discovery, molecular classification of cancers, or identification of novel lineage specific or stem cell markers.

  4. Volatility Discovery

    DEFF Research Database (Denmark)

    Dias, Gustavo Fruet; Scherrer, Cristina; Papailias, Fotis

    The price discovery literature investigates how homogenous securities traded on different markets incorporate information into prices. We take this literature one step further and investigate how these markets contribute to stochastic volatility (volatility discovery). We formally show...... that the realized measures from homogenous securities share a fractional stochastic trend, which is a combination of the price and volatility discovery measures. Furthermore, we show that volatility discovery is associated with the way that market participants process information arrival (market sensitivity......). Finally, we compute volatility discovery for 30 actively traded stocks in the U.S. and report that Nyse and Arca dominate Nasdaq....

  5. Discovery of Novel Small Molecules that Activate Satellite Cell Proliferation and Enhance Repair of Damaged Muscle.

    Science.gov (United States)

    Billin, Andrew N; Bantscheff, Marcus; Drewes, Gerard; Ghidelli-Disse, Sonja; Holt, Jason A; Kramer, Henning F; McDougal, Alan J; Smalley, Terry L; Wells, Carrow I; Zuercher, William J; Henke, Brad R

    2016-02-19

    Skeletal muscle progenitor stem cells (referred to as satellite cells) represent the primary pool of stem cells in adult skeletal muscle responsible for the generation of new skeletal muscle in response to injury. Satellite cells derived from aged muscle display a significant reduction in regenerative capacity to form functional muscle. This decrease in functional recovery has been attributed to a decrease in proliferative capacity of satellite cells. Hence, agents that enhance the proliferative abilities of satellite cells may hold promise as therapies for a variety of pathological settings, including repair of injured muscle and age- or disease-associated muscle wasting. Through phenotypic screening of isolated murine satellite cells, we identified a series of 2,4-diaminopyrimidines (e.g., 2) that increased satellite cell proliferation. Importantly, compound 2 was effective in accelerating repair of damaged skeletal muscle in an in vivo mouse model of skeletal muscle injury. While these compounds were originally prepared as c-Jun N-terminal kinase 1 (JNK-1) inhibitors, structure-activity analyses indicated JNK-1 inhibition does not correlate with satellite cell activity. Screening against a broad panel of kinases did not result in identification of an obvious molecular target, so we conducted cell-based proteomics experiments in an attempt to identify the molecular target(s) responsible for the potentiation of the satellite cell proliferation. These data provide the foundation for future efforts to design improved small molecules as potential therapeutics for muscle repair and regeneration.

  6. Using Osteoclast Differentiation as a Model for Gene Discovery in an Undergraduate Cell Biology Laboratory

    Science.gov (United States)

    Birnbaum, Mark J.; Picco, Jenna; Clements, Meghan; Witwicka, Hanna; Yang, Meiheng; Hoey, Margaret T.; Odgren, Paul R.

    2010-01-01

    A key goal of molecular/cell biology/biotechnology is to identify essential genes in virtually every physiological process to uncover basic mechanisms of cell function and to establish potential targets of drug therapy combating human disease. This article describes a semester-long, project-oriented molecular/cellular/biotechnology laboratory…

  7. Recent Advances in Disease Modeling and Drug Discovery for Diabetes Mellitus Using Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Mohammed Kawser Hossain

    2016-02-01

    Full Text Available Diabetes mellitus (DM is a widespread metabolic disease with a progressive incidence of morbidity and mortality worldwide. Despite extensive research, treatment options for diabetic patients remains limited. Although significant challenges remain, induced pluripotent stem cells (iPSCs have the capacity to differentiate into any cell type, including insulin-secreting pancreatic β cells, highlighting its potential as a treatment option for DM. Several iPSC lines have recently been derived from both diabetic and healthy donors. Using different reprogramming techniques, iPSCs were differentiated into insulin-secreting pancreatic βcells. Furthermore, diabetes patient-derived iPSCs (DiPSCs are increasingly being used as a platform to perform cell-based drug screening in order to develop DiPSC-based cell therapies against DM. Toxicity and teratogenicity assays based on iPSC-derived cells can also provide additional information on safety before advancing drugs to clinical trials. In this review, we summarize recent advances in the development of techniques for differentiation of iPSCs or DiPSCs into insulin-secreting pancreatic β cells, their applications in drug screening, and their role in complementing and replacing animal testing in clinical use. Advances in iPSC technologies will provide new knowledge needed to develop patient-specific iPSC-based diabetic therapies.

  8. Discovery of a novel gene involved in autolysis of Clostridium cells.

    Science.gov (United States)

    Yang, Liejian; Bao, Guanhui; Zhu, Yan; Dong, Hongjun; Zhang, Yanping; Li, Yin

    2013-06-01

    Cell autolysis plays important physiological roles in the life cycle of clostridial cells. Understanding the genetic basis of the autolysis phenomenon of pathogenic Clostridium or solvent producing Clostridium cells might provide new insights into this important species. Genes that might be involved in autolysis of Clostridium acetobutylicum, a model clostridial species, were investigated in this study. Twelve putative autolysin genes were predicted in C. acetobutylicum DSM 1731 genome through bioinformatics analysis. Of these 12 genes, gene SMB_G3117 was selected for testing the in tracellular autolysin activity, growth profile, viable cell numbers, and cellular morphology. We found that overexpression of SMB_G3117 gene led to earlier ceased growth, significantly increased number of dead cells, and clear electrolucent cavities, while disruption of SMB_G3117 gene exhibited remarkably reduced intracellular autolysin activity. These results indicate that SMB_G3117 is a novel gene involved in cellular autolysis of C. acetobutylicum.

  9. Discovery of a Benzamide Derivative That Protects Pancreatic β-Cells against Endoplasmic Reticulum Stress.

    Science.gov (United States)

    Duan, Hongliang; Li, Yu; Arora, Daleep; Xu, Depeng; Lim, Hui-Ying; Wang, Weidong

    2017-07-27

    Endoplasmic reticulum (ER) stress-mediated pancreatic insulin-producing β-cell dysfunction and death are critical elements in the onset and progression of both type 1 and type 2 diabetes. Here, through cell-based high throughput screening we identified benzamide derivatives as a novel class of β-cell protective agents against ER stress-induced dysfunction and death. Through structure-activity relationship optimization, a 3-(N-piperidinyl)methylbenzamide derivative 13d markedly protects β-cells against ER stress-induced dysfunction and death with near 100% maximum rescue activity and an EC 50 of 0.032 μM. Compound 13d alleviates ER stress in β-cells by suppressing ER stress-mediated activation of all three branches of unfolded protein response (UPR) and apoptotic genes. Finally, we show that 13d significantly lowers blood glucose levels and increases concomitant β-cell survival and number in a streptozotocin-induced diabetic mouse model. Identification of β-cell-protective small molecules against ER stress provides a new promising modality for the treatment of diabetes.

  10. Combination of Small Molecule Microarray and Confocal Microscopy Techniques for Live Cell Staining Fluorescent Dye Discovery

    Directory of Open Access Journals (Sweden)

    Attila Bokros

    2013-08-01

    Full Text Available Discovering new fluorochromes is significantly advanced by high-throughput screening (HTS methods. In the present study a combination of small molecule microarray (SMM prescreening and confocal laser scanning microscopy (CLSM was developed in order to discover novel cell staining fluorescent dyes. Compounds with high native fluorescence were selected from a 14,585-member library and further tested on living cells under the microscope. Eleven compartment-specific, cell-permeable (or plasma membrane-targeted fluorochromes were identified. Their cytotoxicity was tested and found that between 1–10 micromolar range, they were non-toxic even during long-term incubations.

  11. Single-Cell Genomics: A Stepping Stone for Future Immunology Discoveries.

    Science.gov (United States)

    Giladi, Amir; Amit, Ido

    2018-01-11

    The immunology field has invested great efforts and ingenuity to characterize the various immune cell types and elucidate their functions. However, accumulating evidence indicates that current technologies and classification schemes are limited in their ability to account for the functional heterogeneity of immune processes. Single-cell genomics hold the potential to revolutionize the way we characterize complex immune cell assemblies and study their spatial organization, dynamics, clonal distribution, pathways, function, and crosstalks. In this Perspective, we consider recent and forthcoming technological and analytical advances in single-cell genomics and the potential impact of those advances on the future of immunology research and immunotherapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Induced Pluripotent Stem Cells: Applications in regenerative medicine, disease modelling and drug discovery

    Directory of Open Access Journals (Sweden)

    Vimal kishor Singh

    2015-02-01

    Full Text Available Recent progresses in the field of Induced Pluripotent Stem Cells (iPSCs have opened up many gateways for the research in therapeutics. iPSCs are the cells which are reprogrammed from somatic cells using different transcription factors. IPSCs possess unique properties of self renewal and differentiation to many types of cell lineage. Hence could replace the use of embryonic stem cells, and may overcome the various ethical issues regarding the use of embryos in research and clinics. Overwhelming responses prompted worldwide by a large number of researchers about the use of iPSCs evoked a large number of peple to establish more authentic methods for iPSC generation. This would require understanding the underlying mechanism in a detailed manner. There have been a large number of reports showing potential role of different molecules as putative regulators of iPSC generating methods. The molecular mechanisms that play role in reprogramming to generate iPSCs from different types of somatic cell sources involves a plethora of molecules including miRNAs, DNA modifying agents (viz. DNA methyl transferases, NANOG, etc. While promising a number of important roles in various clinical/research studies, iPSCs could also be of great use in studying molecular mechanism of many diseases. There are various diseases that have been modelled by uing iPSCs for better understanding of their etiology which maybe further utilized for developing putative treatments for these diseases. In addition, iPSCs are used for the production of patient-specific cells which can be transplanted to the site of injury or the site of tissue degeneration due to various disease conditions. The use of iPSCs may eliminate the chances of immune rejection as patient specific cells may be used for transplantation in various engraftment processes. Moreover, iPSC technology has been employed in various diseases for disease modelling and gene therapy. The technique offers benefits over other

  13. Differential pathway dependency discovery associated with drug response across cancer cell lines* | Office of Cancer Genomics

    Science.gov (United States)

    The effort to personalize treatment plans for cancer patients involves the identification of drug treatments that can effectively target the disease while minimizing the likelihood of adverse reactions. In this study, the gene-expression profile of 810 cancer cell lines and their response data to 368 small molecules from the Cancer Therapeutics Research Portal (CTRP) are analyzed to identify pathways with significant rewiring between genes, or differential gene dependency, between sensitive and non-sensitive cell lines.

  14. Discovery of CTCF-sensitive Cis-spliced fusion RNAs between adjacent genes in human prostate cells.

    Science.gov (United States)

    Qin, Fujun; Song, Zhenguo; Babiceanu, Mihaela; Song, Yansu; Facemire, Loryn; Singh, Ritambhara; Adli, Mazhar; Li, Hui

    2015-02-01

    Genes or their encoded products are not expected to mingle with each other unless in some disease situations. In cancer, a frequent mechanism that can produce gene fusions is chromosomal rearrangement. However, recent discoveries of RNA trans-splicing and cis-splicing between adjacent genes (cis-SAGe) support for other mechanisms in generating fusion RNAs. In our transcriptome analyses of 28 prostate normal and cancer samples, 30% fusion RNAs on average are the transcripts that contain exons belonging to same-strand neighboring genes. These fusion RNAs may be the products of cis-SAGe, which was previously thought to be rare. To validate this finding and to better understand the phenomenon, we used LNCaP, a prostate cell line as a model, and identified 16 additional cis-SAGe events by silencing transcription factor CTCF and paired-end RNA sequencing. About half of the fusions are expressed at a significant level compared to their parental genes. Silencing one of the in-frame fusions resulted in reduced cell motility. Most out-of-frame fusions are likely to function as non-coding RNAs. The majority of the 16 fusions are also detected in other prostate cell lines, as well as in the 14 clinical prostate normal and cancer pairs. By studying the features associated with these fusions, we developed a set of rules: 1) the parental genes are same-strand-neighboring genes; 2) the distance between the genes is within 30kb; 3) the 5' genes are actively transcribing; and 4) the chimeras tend to have the second-to-last exon in the 5' genes joined to the second exon in the 3' genes. We then randomly selected 20 neighboring genes in the genome, and detected four fusion events using these rules in prostate cancer and non-cancerous cells. These results suggest that splicing between neighboring gene transcripts is a rather frequent phenomenon, and it is not a feature unique to cancer cells.

  15. Discovery of molecular markers to discriminate corneal endothelial cells in the human body.

    Science.gov (United States)

    Yoshihara, Masahito; Ohmiya, Hiroko; Hara, Susumu; Kawasaki, Satoshi; Hayashizaki, Yoshihide; Itoh, Masayoshi; Kawaji, Hideya; Tsujikawa, Motokazu; Nishida, Kohji

    2015-01-01

    The corneal endothelium is a monolayer of hexagonal corneal endothelial cells (CECs) on the inner surface of the cornea. CECs are critical in maintaining corneal transparency through their barrier and pump functions. CECs in vivo have a limited capacity in proliferation, and loss of a significant number of CECs results in corneal edema called bullous keratopathy which can lead to severe visual loss. Corneal transplantation is the most effective method to treat corneal endothelial dysfunction, where it suffers from donor shortage. Therefore, regeneration of CECs from other cell types attracts increasing interests, and specific markers of CECs are crucial to identify actual CECs. However, the currently used markers are far from satisfactory because of their non-specific expression in other cell types. Here, we explored molecular markers to discriminate CECs from other cell types in the human body by integrating the published RNA-seq data of CECs and the FANTOM5 atlas representing diverse range of cell types based on expression patterns. We identified five genes, CLRN1, MRGPRX3, HTR1D, GRIP1 and ZP4 as novel markers of CECs, and the specificities of these genes were successfully confirmed by independent experiments at both the RNA and protein levels. Notably none of them have been documented in the context of CEC function. These markers could be useful for the purification of actual CECs, and also available for the evaluation of the products derived from other cell types. Our results demonstrate an effective approach to identify molecular markers for CECs and open the door for the regeneration of CECs in vitro.

  16. Beyond Discovery

    DEFF Research Database (Denmark)

    Korsgaard, Steffen; Sassmannshausen, Sean Patrick

    2017-01-01

    In this chapter we explore four alternatives to the dominant discovery view of entrepreneurship; the development view, the construction view, the evolutionary view, and the Neo-Austrian view. We outline the main critique points of the discovery presented in these four alternatives, as well as the...

  17. First haemorheological experiment on NASA space shuttle 'Discovery' STS 51-C: aggregation of red cells.

    Science.gov (United States)

    Dintenfass, L; Osman, P D; Jedrzejczyk, H

    1985-01-01

    The 'secret' D.O.D. Mission on flight STS 51-C also carried nearly 100 kg of automated instrumentation of the Australian experiment on aggregation of red cells ("ARC"). The automated Slit-Capillary Photo Viscometer contained blood samples from subjects with history of coronary heart disease, cancer of the colon, insulin-dependent diabetes, etc., as well as normals. The experiment ran for nine hours, according to the program of its microcomputers. When shuttle landed and instrumentation recovered and opened in the presence of NASA quality control officers, it was obvious that experiment was a success. Tentative and preliminary results can be summarized as follows: red cells did not change shape under zero gravity; red cells do aggregate under zero gravity, although the size of aggregates is smaller than on the ground; the morphology of aggregates of red cells appears to be of rouleaux type under zero gravity, notwithstanding the fact that pathological blood was used. These results will have to be confirmed in the future flights. The background and history of development of the project are described, and put into context of our general haemorheological studies.

  18. Probing the O-glycoproteome of Gastric Cancer Cell Lines for Biomarker Discovery

    DEFF Research Database (Denmark)

    Vieira Campos, Diana Alexandra; Freitas, Daniela; Gomes, Joana

    2015-01-01

    Circulating O-glycoproteins shed from cancer cells represent important serum biomarkers for diagnostic and prognostic purposes. We have recently shown that selective detection of cancer-associated aberrant glycoforms of circulating O-glycoprotein biomarkers can increase specificity of cancer biom...

  19. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome.

    Science.gov (United States)

    Griffin, John H; Leung, Joey; Bruner, Rebecca J; Caligiuri, Michael A; Briesewitz, Roger

    2003-06-24

    Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disease of unknown etiology. Recently, it has been reported that imatinib mesylate (Gleevec), an inhibitor of Bcr-Abl kinase useful in the treatment of chronic myeloid leukemia, is also effective in treating HES; however, the molecular target of imatinib in HES is unknown. This report identifies a genetic rearrangement in the eosinophilic cell line EOL-1 that results in the expression of a fusion protein comprising an N-terminal region encoded by a gene of unknown function with the GenBank accession number NM_030917 and a C-terminal region derived from the intracellular domain of the platelet-derived growth factor receptor alpha (PDGFRalpha). The fusion gene was also detected in blood cells from two patients with HES. We propose naming NM_030917 Rhe for Rearranged in hypereosinophilia. Rhe-PDGFRalpha fusions result from an apparent interstitial deletion that links Rhe to exon 12 of PDGFRalpha on chromosome 4q12. The fusion kinase Rhe-PDGFRalpha is constitutively phosphorylated and supports IL-3-independent growth when expressed in BaF3 cells. Proliferation and viability of EOL-1 and BaF3 cells expressing Rhe-PDGFRalpha are ablated by the PDGFRalpha inhibitors imatinib, vatalanib, and THRX-165724.

  20. Red Blood Cell Proteomics: Challenges in biomarker discovery for clinical applications

    NARCIS (Netherlands)

    Barasa, B.A.

    2017-01-01

    Introduction This thesis describes the application of mass-spectrometry-based approaches on the cytosolic red blood cell (RBC) proteome in gaining improved understanding and insight into the metabolic effects and mechanisms of rare hereditary RBC defects that result in hemolytic anemia. Whilst the

  1. Sciatica leading to the discovery of a renal cell carcinoma | Lakmichi ...

    African Journals Online (AJOL)

    Metastatic renal cell cancer is not exceptional in kidney cancer (30% of patients with kidneyl cancer). Its prognosis is particularly severe. However, sciatic neuralgia (sciatica) remains an exceptional revealing clinical sign of this disease. The authors report the case of a patient admitted with right sciatica as chief complain, ...

  2. Discovery of Molecular Markers to Discriminate Corneal Endothelial Cells in the Human Body

    NARCIS (Netherlands)

    Yoshihara, Masahito; Ohmiya, Hiroko; Hara, Susumu; Kawasaki, Satoshi; Hayashizaki, Yoshihide; Itoh, Masayoshi; Kawaji, Hideya; Tsujikawa, Motokazu; Nishida, Kohji; Forrest, Alistair R. R.; Rehli, Michael; Baillie, J. Kenneth; de Hoon, Michiel J. L.; Haberle, Vanja; Lassmann, Timo; Kulakovskiy, Ivan V.; Lizio, Marina; Andersson, Robin; Mungall, Christopher J.; Meehan, Terrence F.; Schmeier, Sebastian; Bertin, Nicolas; Jørgensen, Mette; Dimont, Emmanuel; Arner, Erik; Schmidl, Christian; Schaefer, Ulf; Medvedeva, Yulia A.; Plessy, Charles; Vitezic, Morana; Severin, Jessica; Semple, Colin A.; Ishizu, Yuri; Francescatto, Margherita; Alam, Intikhab; Albanese, Davide; Altschuler, Gabriel M.; Archer, John A. C.; Arner, Peter; Babina, Magda; Baker, Sarah; Balwierz, Piotr J.; Beckhouse, Anthony G.; Pradhan-Bhatt, Swati; Blake, Judith A.; Blumenthal, Antje; Bodega, Beatrice; Bonetti, Alessandro; Briggs, James; Brombacher, Frank; Burroughs, A. Maxwell; Califano, Andrea; Cannistraci, Carlo V.; Carbajo, Daniel; Chen, Yun; Chierici, Marco; Ciani, Yari; Clevers, Hans C.; Dalla, Emiliano; Davis, Carrie A.; Detmar, Michael; Diehl, Alexander D.; Dohi, Taeko; Drabløs, Finn; Edge, Albert S. B.; Edinger, Matthias; Ekwall, Karl; Endoh, Mitsuhiro; Enomoto, Hideki; Fagiolini, Michela; Fairbairn, Lynsey; Fang, Hai; Farach-Carson, Mary C.; Faulkner, Geoffrey J.; Favorov, Alexander V.; Fisher, Malcolm E.; Frith, Martin C.; Fujita, Rie; Fukuda, Shiro; Furlanello, Cesare; Furuno, Masaaki; Furusawa, Jun-ichi; Geijtenbeek, Teunis B.; Gibson, Andrew; Gingeras, Thomas; Goldowitz, Daniel; Gough, Julian; Guhl, Sven; Guler, Reto; Gustincich, Stefano; Ha, Thomas J.; Hamaguchi, Masahide; Hara, Mitsuko; Harbers, Matthias; Harshbarger, Jayson; Hasegawa, Akira; Hasegawa, Yuki; Hashimoto, Takehiro; Herlyn, Meenhard; Hitchens, Kelly J.; Ho Sui, Shannan J.; Hofmann, Oliver M.; Hoof, Ilka; Hori, Fumi; Huminiecki, Lukasz; Iida, Kei; Ikawa, Tomokatsu; Jankovic, Boris R.; Jia, Hui; Joshi, Anagha; Jurman, Giuseppe; Kaczkowski, Bogumil; Kai, Chieko; Kaida, Kaoru; Kaiho, Ai; Kajiyama, Kazuhiro; Kanamori-Katayama, Mutsumi; Kasianov, Artem S.; Kasukawa, Takeya; Katayama, Shintaro; Kato, Sachi; Kawaguchi, Shuji; Kawamoto, Hiroshi; Kawamura, Yuki I.; Kawashima, Tsugumi; Kempfle, Judith S.; Kenna, Tony J.; Kere, Juha; Khachigian, Levon M.; Kitamura, Toshio; Klinken, S. Peter; Knox, Alan J.; Kojima, Miki; Kojima, Soichi; Kondo, Naoto; Koseki, Haruhiko; Koyasu, Shigeo; Krampitz, Sarah; Kubosaki, Atsutaka; Kwon, Andrew T.; Laros, Jeroen F. J.; Lee, Weonju; Lennartsson, Andreas; Li, Kang; Lilje, Berit; Lipovich, Leonard; Mackay-sim, Alan; Manabe, Ri-ichiroh; Mar, Jessica C.; Marchand, Benoit; Mathelier, Anthony; Mejhert, Niklas; Meynert, Alison; Mizuno, Yosuke; Morais, David A. de Lima; Morikawa, Hiromasa; Morimoto, Mitsuru; Moro, Kazuyo; Motakis, Efthymios; Motohashi, Hozumi; Mummery, Christine L.; Murata, Mitsuyoshi; Nagao-Sato, Sayaka; Nakachi, Yutaka; Nakahara, Fumio; Nakamura, Toshiyuki; Nakamura, Yukio; Nakazato, Kenichi; van Nimwegen, Erik; Ninomiya, Noriko; Nishiyori, Hiromi; Noma, Shohei; Nozaki, Tadasuke; Ogishima, Soichi; Ohkura, Naganari; Ohno, Hiroshi; Ohshima, Mitsuhiro; Okada-Hatakeyama, Mariko; Okazaki, Yasushi; Orlando, Valerio; Ovchinnikov, Dmitry A.; Pain, Arnab; Passier, Robert; Patrikakis, Margaret; Persson, Helena; Piazza, Silvano; Prendergast, James G. D.; Rackham, Owen J. L.; Ramilowski, Jordan A.; Rashid, Mamoon; Ravasi, Timothy; Rizzu, Patrizia; Roncador, Marco; Roy, Sugata; Rye, Morten B.; Saijyo, Eri; Sajantila, Antti; Saka, Akiko; Sakaguchi, Shimon; Sakai, Mizuho; Sato, Hiroki; Satoh, Hironori; Savvi, Suzana; Saxena, Alka; Schneider, Claudio; Schultes, Erik A.; Schulze-Tanzil, Gundula G.; Schwegmann, Anita; Sengstag, Thierry; Sheng, Guojun; Shimoji, Hisashi; Shimoni, Yishai; Shin, Jay W.; Simon, Christophe; Sugiyama, Daisuke; Sugiyama, Takaaki; Suzuki, Masanori; Swoboda, Rolf K.; 't Hoen, Peter A. C.; Tagami, Michihira; Takahashi, Naoko; Takai, Jun; Tanaka, Hiroshi; Tatsukawa, Hideki; Tatum, Zuotian; Thompson, Mark; Toyoda, Hiroo; Toyoda, Tetsuro; Valen, Eivind; van de Wetering, Marc; van den Berg, Linda M.; Verardo, Roberto; Vijayan, Dipti; Vorontsov, Ilya E.; Wasserman, Wyeth W.; Watanabe, Shoko; Wells, Christine A.; Winteringham, Louise N.; Wolvetang, Ernst; Wood, Emily J.; Yamaguchi, Yoko; Yamamoto, Masayuki; Yoneda, Misako; Yonekura, Yohei; Yoshida, Shigehiro; Zabierowski, Suzan E.; Zhang, Peter G.; Zhao, Xiaobei; Zucchelli, Silvia; Summers, Kim M.; Suzuki, Harukazu; Daub, Carsten O.; Kawai, Jun; Heutink, Peter; Hide, Winston; Freeman, Tom C.; Lenhard, Boris; Bajic, Vladimir B.; Taylor, Martin S.; Makeev, Vsevolod J.; Sandelin, Albin; Hume, David A.; Carninci, Piero

    2015-01-01

    The corneal endothelium is a monolayer of hexagonal corneal endothelial cells (CECs) on the inner surface of the cornea. CECs are critical in maintaining corneal transparency through their barrier and pump functions. CECs in vivo have a limited capacity in proliferation, and loss of a significant

  3. Deriving human ENS lineages for cell therapy and drug discovery in Hirschsprung disease.

    Science.gov (United States)

    Fattahi, Faranak; Steinbeck, Julius A; Kriks, Sonja; Tchieu, Jason; Zimmer, Bastian; Kishinevsky, Sarah; Zeltner, Nadja; Mica, Yvonne; El-Nachef, Wael; Zhao, Huiyong; de Stanchina, Elisa; Gershon, Michael D; Grikscheit, Tracy C; Chen, Shuibing; Studer, Lorenz

    2016-03-03

    The enteric nervous system (ENS) is the largest component of the autonomic nervous system, with neuron numbers surpassing those present in the spinal cord. The ENS has been called the 'second brain' given its autonomy, remarkable neurotransmitter diversity and complex cytoarchitecture. Defects in ENS development are responsible for many human disorders including Hirschsprung disease (HSCR). HSCR is caused by the developmental failure of ENS progenitors to migrate into the gastrointestinal tract, particularly the distal colon. Human ENS development remains poorly understood owing to the lack of an easily accessible model system. Here we demonstrate the efficient derivation and isolation of ENS progenitors from human pluripotent stem (PS) cells, and their further differentiation into functional enteric neurons. ENS precursors derived in vitro are capable of targeted migration in the developing chick embryo and extensive colonization of the adult mouse colon. The in vivo engraftment and migration of human PS-cell-derived ENS precursors rescue disease-related mortality in HSCR mice (Ednrb(s-l/s-l)), although the mechanism of action remains unclear. Finally, EDNRB-null mutant ENS precursors enable modelling of HSCR-related migration defects, and the identification of pepstatin A as a candidate therapeutic target. Our study establishes the first, to our knowledge, human PS-cell-based platform for the study of human ENS development, and presents cell- and drug-based strategies for the treatment of HSCR.

  4. Global discovery of erythroid long noncoding RNAs reveals novel regulators of red cell maturation

    NARCIS (Netherlands)

    Alvarez-Dominguez, Juan R; Hu, Wenqian; Yuan, Bingbing; Shi, Jiahai; Park, Staphany S; Gromatzky, Austin A; van Oudenaarden, Alexander; Lodish, Harvey F

    2014-01-01

    Erythropoiesis is regulated at multiple levels to ensure the proper generation of mature red cells under multiple physiological conditions. To probe the contribution of long noncoding RNAs (lncRNAs) to this process, we examined >1 billion RNA-seq reads of polyadenylated and nonpolyadenylated RNA

  5. Discovery of Black Dye Crystal Structure Polymorphs: Implications for Dye Conformational Variation in Dye-Sensitized Solar Cells.

    Science.gov (United States)

    Cole, Jacqueline M; Low, Kian Sing; Gong, Yun

    2015-12-23

    We present the discovery of a new crystal structure polymorph (1) and pseudopolymorph (2) of the Black Dye, one of the world's leading dyes for dye-sensitized solar cells, DSSCs (10.4% device performance efficiency). This reveals that Black Dye molecules can adopt multiple low-energy conformers. This is significant since it challenges existing models of the Black Dye···TiO2 adsorption process that renders a DSSC working electrode; these have assumed a single molecular conformation that refers to the previously reported Black Dye crystal structure (3). The marked structural differences observed between 1, 2, and 3 make the need for modeling multiple conformations more acute. Additionally, the ordered form of the Black Dye (1) provides a more appropriate depiction of its anionic structure, especially regarding its anchoring group and NCS bonding descriptions. The tendency toward NCS ligand isomerism, evidenced via the disordered form 2, has consequences for electron injection and electron recombination in Black Dye embedded DSSC devices. Dyes 2 and 3 differ primarily by the absence or presence of a solvent of crystallization, respectively; solvent environment effects on the dye are thereby elucidated. This discovery of multiple Black Dye conformers from diffraction, with atomic-level definition, complements recently reported nanoscopic evidence for multiple dye conformations existing at a dye···TiO2 interface, for a chemically similar DSSC dye; those results emanated from imaging and spectroscopy, but were unresolved at the submolecular level. Taken together, these findings lead to the general notion that multiple dye conformations should be explicitly considered when modeling dye···TiO2 interfaces in DSSCs, at least for ruthenium-based dye complexes.

  6. A cell-based high throughput screening assay for the discovery of cGAS-STING pathway agonists.

    Science.gov (United States)

    Liu, Bowei; Tang, Liudi; Zhang, Xiaohui; Ma, Julia; Sehgal, Mohit; Cheng, Junjun; Zhang, Xuexiang; Zhou, Yan; Du, Yanming; Kulp, John; Guo, Ju-Tao; Chang, Jinhong

    2017-11-01

    Stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that serves as a molecular hub for activation of interferon and inflammatory cytokine response by multiple cellular DNA sensors. Not surprisingly, STING has been demonstrated to play an important role in host defense against microorganisms and pharmacologic activation of STING is considered as an attractive strategy to treat viral diseases and boost antitumor immunity. In light of this we established a HepAD38-derived reporter cell line that expresses firefly luciferase in response to the activation of cyclic GMP-AMP synthase (cGAS)-STING pathway for high throughput screening (HTS) of small molecular human STING agonists. This cell-based reporter assay required only 4 h treatment with a reference STING agonist to induce a robust luciferase signal and was demonstrated to have an excellent performance in HTS format. By screening 16,000 compounds, a dispiro diketopiperzine (DSDP) compound was identified to induce cytokine response in a manner dependent on the expression of functional human STING, but not mouse STING. Moreover, we showed that DSDP induced an interferon-dominant cytokine response in human skin fibroblasts and peripheral blood mononuclear cells, which in turn potently suppressed the replication of yellow fever virus, dengue virus and Zika virus. We have thus established a robust cell-based assay system suitable for rapid discovery and mechanistic analyses of cGAS-STING pathway agonists. Identification of DSDP as a human STING agonist enriches the pipelines of STING-targeting drug development for treatment of viral infections and cancers. Copyright © 2017. Published by Elsevier B.V.

  7. Discovery of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells

    Directory of Open Access Journals (Sweden)

    Bernardas Morkunas

    2016-07-01

    Full Text Available Pyocyanin is a small molecule produced by Pseudomonas aeruginosa that plays a crucial role in the pathogenesis of infections by this notorious opportunistic pathogen. The inhibition of pyocyanin production has been identified as an attractive antivirulence strategy for the treatment of P. aeruginosa infections. Herein, we report the discovery of an inhibitor of pyocyanin production in cultures of wild-type P. aeruginosa which is based around a 4-alkylquinolin-2(1H-one scaffold. To the best of our knowledge, this is the first reported example of pyocyanin inhibition by a compound based around this molecular framework. The compound may therefore be representative of a new structural sub-class of pyocyanin inhibitors, which could potentially be exploited in in a therapeutic context for the development of critically needed new antipseudomonal agents. In this context, the use of wild-type cells in this study is notable, since the data obtained are of direct relevance to native situations. The compound could also be of value in better elucidating the role of pyocyanin in P. aeruginosa infections. Evidence suggests that the active compound reduces the level of pyocyanin production by inhibiting the cell–cell signalling mechanism known as quorum sensing. This could have interesting implications; quorum sensing regulates a range of additional elements associated with the pathogenicity of P. aeruginosa and there is a wide range of other potential applications where the inhibition of quorum sensing is desirable.

  8. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome

    OpenAIRE

    Griffin, John H.; Leung, Joey; Bruner, Rebecca J.; Caligiuri, Michael A.; Briesewitz, Roger

    2003-01-01

    Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disease of unknown etiology. Recently, it has been reported that imatinib mesylate (Gleevec), an inhibitor of Bcr-Abl kinase useful in the treatment of chronic myeloid leukemia, is also effective in treating HES; however, the molecular target of imatinib in HES is unknown. This report identifies a genetic rearrangement in the eosinophilic cell line EOL-1 that results in the expression of a fusion protein comprising an N...

  9. Discovery of Small Molecules That Induce Lysosomal Cell Death in Cancer Cell Lines Using an Image-Based Screening Platform

    NARCIS (Netherlands)

    Pagliero, Romina J; D'Astolfo, Diego S; Lelieveld, Daphne; Pratiwi, Riyona D; Aits, Sonja; Jaattela, Marja; Martin, Nathaniel I; Klumperman, Judith; Egan, David A

    2016-01-01

    The lysosomal cell death (LCD) pathway is a caspase 3-independent cell death pathway that has been suggested as a possible target for cancer therapy, making the development of sensitive and specific high-throughput (HT) assays to identify LCD inducers highly desirable. In this study, we report a

  10. Brown-Like Adipocyte Progenitors Derived from Human iPS Cells: A New Tool for Anti-obesity Drug Discovery and Cell-Based Therapy?

    Science.gov (United States)

    Yao, Xi; Salingova, Barbara; Dani, Christian

    2018-04-10

    Alternative strategies are urgently required to fight obesity and associated metabolic disorders including diabetes and cardiovascular diseases. Brown and brown-like adipocytes (BAs) store fat, but in contrast to white adipocytes, activated BAs are equipped to dissipate energy stored. Therefore, BAs represent promising cell targets to counteract obesity. However, the scarcity of BAs in adults is a major limitation for a BA-based therapy of obesity, and the notion to increase the BA mass by transplanting BA progenitors (BAPs) in obese patients recently emerged. The next challenge is to identify an abundant and reliable source of BAPs. In this chapter, we describe the capacity of human-induced pluripotent stem cells (hiPSCs) to generate BAPs able to differentiate at a high efficiency with no gene transfer. This cell model represents an unlimited source of human BAPs that in a near future may be a suitable tool for both therapeutic transplantation and for the discovery of novel efficient and safe anti-obesity drugs. The generation of a relevant cell model, such as hiPSC-BAs in 3D adipospheres enriched with macrophages and endothelial cells to better mimic the microenvironment within the adipose tissue, will be the next critical step.

  11. Discovery of a new human T-cell lymphotropic virus (HTLV-3 in Central Africa

    Directory of Open Access Journals (Sweden)

    Mahieux Renaud

    2005-05-01

    Full Text Available Abstract Human T-cell Leukemia virus type 1 (HTLV-1 and type 2 (HTLV-2 are pathogenic retroviruses that infect humans and cause severe hematological and neurological diseases. Both viruses have simian counterparts (STLV-1 and STLV-2. STLV-3 belongs to a third group of lymphotropic viruses which infect numerous African monkeys species. Among 240 Cameroonian plasma tested for the presence of HTLV-1 and/or HTLV-2 antibodies, 48 scored positive by immunofluorescence. Among those, 27 had indeterminate western-blot pattern. PCR amplification of pol and tax regions, using HTLV-1, -2 and STLV-3 highly conserved primers, demonstrated the presence of a new human retrovirus in one DNA sample. tax (180 bp and pol (318 bp phylogenetic analyses demonstrated the strong relationships between the novel human strain (Pyl43 and STLV-3 isolates from Cameroon. The virus, that we tentatively named HTLV-3, originated from a 62 years old Bakola Pygmy living in a remote settlement in the rain forest of Southern Cameroon. The plasma was reactive on MT2 cells but was negative on C19 cells. The HTLV 2.4 western-blot exhibited a strong reactivity to p19 and a faint one to MTA-1. On the INNO-LIA strip, it reacted faintly with the generic p19 (I/II, but strongly to the generic gp46 (I/II and to the specific HTLV-2 gp46. The molecular relationships between Pyl43 and STLV-3 are thus not paralleled by the serological results, as most of the STLV-3 infected monkeys have an "HTLV-2 like" WB pattern. In the context of the multiple interspecies transmissions which occurred in the past, and led to the present-day distribution of the PTLV-1, it is thus very tempting to speculate that this newly discovered human retrovirus HTLV-3 might be widespread, at least in the African continent.

  12. Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2.

    Science.gov (United States)

    Sweis, Ramzi F; Wang, Zhi; Algire, Mikkel; Arrowsmith, Cheryl H; Brown, Peter J; Chiang, Gary G; Guo, Jun; Jakob, Clarissa G; Kennedy, Steven; Li, Fengling; Maag, David; Shaw, Bailin; Soni, Nirupama B; Vedadi, Masoud; Pappano, William N

    2015-06-11

    A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure-activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line.

  13. DERIVING HUMAN ENS LINEAGES FOR CELL THERAPY AND DRUG DISCOVERY IN HIRSCHSPRUNG'S DISEASE

    Science.gov (United States)

    Fattahi, Faranak; Steinbeck, Julius A; Kriks, Sonja; Tchieu, Jason; Zimmer, Bastian; Kishinevsky, Sarah; Zeltner, Nadja; Mica, Yvonne; El-Nachef, Wael; Zhao, Huiyong; de Stanchina, Elisa; Gershon, Michael D.; Grikscheit, Tracy C.; Chen, Shuibing; Studer, Lorenz

    2015-01-01

    The enteric nervous system (ENS) is the largest component of the autonomic nervous system with neuron numbers surpassing those present in the spinal cord1. The ENS has been called the “second brain”1 given its autonomy, remarkable neurotransmitter diversity and complex cytoarchitecture. Defects in ENS development are responsible for many human disorders including Hirschsprung's disease (HSCR). HSCR is a caused by the developmental failure of ENS progenitors to migrate into the GI tract in particular the distal colon2. Human ENS development remains poorly understood due to the lack of an easily accessible model system. Here we demonstrate the efficient derivation and isolation of ENS progenitors from human pluripotent stem cells (hPSCs) and their further differentiation into functional enteric neurons. In vitro derived ENS precursors are capable of targeted migration in the developing chick embryo and extensive colonization of the adult mouse colon. In vivo engraftment and migration of hPSC-derived ENS precursors rescues disease-related mortality in HSCR mice (EDNRBs-l/s-l), though mechanism of action remains unclear. Finally, EDNRB null mutant ENS precursors enable modeling of HSCR-related migration defects and the identification of Pepstatin A as candidate therapeutics. Our study establishes the first hPSC-based platform for the study of human ENS development and presents cell and drug-based strategies for the treatment of HSCR. PMID:26863197

  14. Discovery of novel proteasome inhibitors using a high-content cell-based screening system.

    Directory of Open Access Journals (Sweden)

    Irena Lavelin

    2009-12-01

    Full Text Available The regulated degradation of damaged or misfolded proteins, as well as down-regulation of key signaling proteins, within eukaryotic and bacterial cells is catalyzed primarily by large, ATP-dependent multimeric proteolytic complexes, termed proteasomes. Inhibition of proteasomal activity affects a wide variety of physiological and pathological processes, and was found to be particularly effective for cancer therapy. We report here on the development of a novel high throughput assay for proteasome inhibition using a unique, highly sensitive live-cell screening, based on the cytoplasm-to-nucleus translocation of a fluorescent proteasome inhibition reporter (PIR protein, consisting of nuclear localization signal-deficient p53 derivative. We further show here that mdm2, a key negative regulator of p53 plays a key role in the accumulation of PIR in the nucleus upon proteasome inhibition. Using this assay, we have screened the NCI Diversity Set library, containing 1,992 low molecular weight synthetic compounds, and identified four proteasome inhibitors. The special features of the current screen, compared to those of other approaches are discussed.

  15. Discovery of Power-Law Growth in the Self-Renewal of Heterogeneous Glioma Stem Cell Populations.

    Science.gov (United States)

    Sugimori, Michiya; Hayakawa, Yumiko; Boman, Bruce M; Fields, Jeremy Z; Awaji, Miharu; Kozano, Hiroko; Tamura, Ryoi; Yamamoto, Seiji; Ogata, Toru; Yamada, Mitsuhiko; Endo, Shunro; Kurimoto, Masanori; Kuroda, Satoshi

    2015-01-01

    glioma stem cell populations. That the data always fit a power-law suggests that: (i) clone sizes follow continuous, non-random, and scale-free hierarchy; (ii) precise biologic rules that reflect self-organizing emergent behaviors govern the generation of neurospheres. That the power-law behavior and the original GS heterogeneity are maintained over multiple passages indicates that these rules are invariant. These self-organizing mechanisms very likely underlie tumor heterogeneity during tumor growth. Discovery of this power-law behavior provides a mechanism that could be targeted in the development of new, more effective, anti-cancer agents.

  16. Discovery of Power-Law Growth in the Self-Renewal of Heterogeneous Glioma Stem Cell Populations.

    Directory of Open Access Journals (Sweden)

    Michiya Sugimori

    glioma stem cell populations. That the data always fit a power-law suggests that: (i clone sizes follow continuous, non-random, and scale-free hierarchy; (ii precise biologic rules that reflect self-organizing emergent behaviors govern the generation of neurospheres. That the power-law behavior and the original GS heterogeneity are maintained over multiple passages indicates that these rules are invariant. These self-organizing mechanisms very likely underlie tumor heterogeneity during tumor growth. Discovery of this power-law behavior provides a mechanism that could be targeted in the development of new, more effective, anti-cancer agents.

  17. Platelets are versatile cells: New discoveries in hemostasis, thrombosis, immune responses, tumor metastasis and beyond.

    Science.gov (United States)

    Xu, Xiaohong Ruby; Zhang, Dan; Oswald, Brigitta Elaine; Carrim, Naadiya; Wang, Xiaozhong; Hou, Yan; Zhang, Qing; Lavalle, Christopher; McKeown, Thomas; Marshall, Alexandra H; Ni, Heyu

    2016-12-01

    Platelets are small anucleate blood cells generated from megakaryocytes in the bone marrow and cleared in the reticuloendothelial system. At the site of vascular injury, platelet adhesion, activation and aggregation constitute the first wave of hemostasis. Blood coagulation, which is initiated by the intrinsic or extrinsic coagulation cascades, is the second wave of hemostasis. Activated platelets can also provide negatively-charged surfaces that harbor coagulation factors and markedly potentiate cell-based thrombin generation. Recently, deposition of plasma fibronectin, and likely other plasma proteins, onto the injured vessel wall has been identified as a new "protein wave of hemostasis" that may occur even earlier than the first wave of hemostasis, platelet accumulation. Although no experimental evidence currently exists, it is conceivable that platelets may also contribute to this protein wave of hemostasis by releasing their granule fibronectin and other proteins that may facilitate fibronectin self- and non-self-assembly on the vessel wall. Thus, platelets may contribute to all three waves of hemostasis and are central players in this critical physiological process to prevent bleeding. Low platelet counts in blood caused by enhanced platelet clearance and/or impaired platelet production are usually associated with hemorrhage. Auto- and allo-immune thrombocytopenias such as idiopathic thrombocytopenic purpura and fetal and neonatal alloimmune thrombocytopenia may cause life-threatening bleeding such as intracranial hemorrhage. When triggered under pathological conditions such as rupture of an atherosclerotic plaque, excessive platelet activation and aggregation may result in thrombosis and vessel occlusion. This may lead to myocardial infarction or ischemic stroke, the major causes of mortality and morbidity worldwide. Platelets are also involved in deep vein thrombosis and thromboembolism, another leading cause of mortality. Although fibrinogen has been

  18. Discovery and Characterization of Super-Enhancer Associated Dependencies in Diffuse Large B-Cell Lymphoma

    Science.gov (United States)

    Chapuy, Bjoern; McKeown, Michael R.; Lin, Charles Y.; Monti, Stefano; Roemer, Margaretha G.M.; Qi, Jun; Rahl, Peter B.; Sun, Heather H.; Yeda, Kelly T.; Doench, John G; Reichert, Elaine; Kung, Andrew L.; Rodig, Scott J.; Young, Richard A.; Shipp, Margaret A.; Bradner, James E.

    2014-01-01

    Summary Diffuse Large B-Cell Lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of BET bromodomain proteins in DLBCL, using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of BRD4 at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease. PMID:24332044

  19. Discovery of a low order drug-cell response surface for applications in personalized medicine

    International Nuclear Information System (INIS)

    Ding, Xianting; Liu, Wenjia; Li, Yiyang; Weiss, Andrea; Van den Bergh, Hubert; Nowak-Sliwinska, Patrycja; Wong, Ieong; Ho, Chih-Ming; Griffioen, Arjan W; Xu, Hongquan

    2014-01-01

    The cell is a complex system involving numerous components, which may often interact in a non-linear dynamic manner. Diseases at the cellular level are thus likely to involve multiple cellular constituents and pathways. As some drugs, or drug combinations, may act synergistically on these multiple pathways, they might be more effective than the respective single target agents. Optimizing a drug mixture for a given disease in a particular patient is particularly challenging due to both the difficulty in the selection of the drug mixture components to start out with, and the all-important doses of these drugs to be applied. For n concentrations of m drugs, in principle, n m combinations will have to be tested. As this may lead to a costly and time-consuming investigation for each individual patient, we have developed a Feedback System Control (FSC) technique which can rapidly select the optimal drug–dose combination from the often millions of possible combinations. By testing this FSC technique in a number of experimental systems representing different disease states, we found that the response of cells to multiple drugs is well described by a low order, rather smooth, drug-mixture-input/drug-effect-output multidimensional surface. The main consequences of this are that optimal drug combinations can be found in a surprisingly small number of tests, and that translation from in vitro to in vivo is simplified. This points to the possibility of personalized optimal drug mixtures in the near future. This unexpectedly simple input–output relationship may also lead to a simple solution for handling the issue of human diversity in cancer therapeutics. (paper)

  20. Drug Discovery Models and Toxicity Testing Using Embryonic and Induced Pluripotent Stem-Cell-Derived Cardiac and Neuronal Cells

    Directory of Open Access Journals (Sweden)

    Rahul S. Deshmukh

    2012-01-01

    Full Text Available Development of induced pluripotent stem cells (iPSCs using forced expression of specific sets of transcription factors has changed the field of stem cell research extensively. Two important limitations for research application of embryonic stem cells (ESCs, namely, ethical and immunological issues, can be circumvented using iPSCs. Since the development of first iPSCs, tremendous effort has been directed to the development of methods to increase the efficiency of the process and to reduce the extent of genomic modifications associated with the reprogramming procedure. The established lineage-specific differentiation protocols developed for ESCs are being applied to iPSCs, as they have great potential in regenerative medicine for cell therapy, disease modeling either for drug development or for fundamental science, and, last but not least, toxicity testing. This paper reviews efforts aimed at practical development of iPSC differentiation to neural/cardiac lineages and further the use of these iPSCs-derived cells for drug development and toxicity testing.

  1. Discovery, Annotation, and Functional Analysis of Long Noncoding RNAs Controlling Cell Cycle Gene Expression and Proliferation in Breast Cancer Cells

    Science.gov (United States)

    Sun, Miao; Gadad, Shrikanth S.; Kim, Dae-Seok; Kraus, W. Lee

    2015-01-01

    SUMMARY We describe a computational approach that integrates GRO-seq and RNA-seq data to annotate long noncoding RNAs (lncRNAs), with increased sensitivity for low abundance lncRNAs. We used this approach to characterize the lncRNA transcriptome in MCF-7 human breast cancer cells, including >700 previously unannotated lncRNAs. We then used information about the (1) transcription of lncRNA genes from GRO-seq, (2) steady-state levels of lncRNA transcripts in cell lines and patient samples from RNA-seq, and (3) histone modifications and factor binding at lncRNA gene promoters from ChIP-seq to explore lncRNA gene structure and regulation, as well as lncRNA transcript stability, regulation, and function. Functional analysis of selected lncRNAs with altered expression in breast cancers revealed roles in cell proliferation, regulation of an E2F-dependent cell cycle gene expression program, and estrogen-dependent mitogenic growth. Collectively, our studies demonstrate the use of an integrated genomic and molecular approach to identify and characterize growth-regulating lncRNAs in cancers. PMID:26236012

  2. Predicting Causal Relationships from Biological Data: Applying Automated Casual Discovery on Mass Cytometry Data of Human Immune Cells

    KAUST Repository

    Triantafillou, Sofia

    2017-03-31

    Learning the causal relationships that define a molecular system allows us to predict how the system will respond to different interventions. Distinguishing causality from mere association typically requires randomized experiments. Methods for automated causal discovery from limited experiments exist, but have so far rarely been tested in systems biology applications. In this work, we apply state-of-the art causal discovery methods on a large collection of public mass cytometry data sets, measuring intra-cellular signaling proteins of the human immune system and their response to several perturbations. We show how different experimental conditions can be used to facilitate causal discovery, and apply two fundamental methods that produce context-specific causal predictions. Causal predictions were reproducible across independent data sets from two different studies, but often disagree with the KEGG pathway databases. Within this context, we discuss the caveats we need to overcome for automated causal discovery to become a part of the routine data analysis in systems biology.

  3. Optogenetics enlightens neuroscience drug discovery.

    Science.gov (United States)

    Song, Chenchen; Knöpfel, Thomas

    2016-02-01

    Optogenetics - the use of light and genetics to manipulate and monitor the activities of defined cell populations - has already had a transformative impact on basic neuroscience research. Now, the conceptual and methodological advances associated with optogenetic approaches are providing fresh momentum to neuroscience drug discovery, particularly in areas that are stalled on the concept of 'fixing the brain chemistry'. Optogenetics is beginning to translate and transit into drug discovery in several key domains, including target discovery, high-throughput screening and novel therapeutic approaches to disease states. Here, we discuss the exciting potential of optogenetic technologies to transform neuroscience drug discovery.

  4. A Multidisciplinary Biospecimen Bank of Renal Cell Carcinomas Compatible with Discovery Platforms at Mayo Clinic, Scottsdale, Arizona.

    Directory of Open Access Journals (Sweden)

    Thai H Ho

    Full Text Available To address the need to study frozen clinical specimens using next-generation RNA, DNA, chromatin immunoprecipitation (ChIP sequencing and protein analyses, we developed a biobank work flow to prospectively collect biospecimens from patients with renal cell carcinoma (RCC. We describe our standard operating procedures and work flow to annotate pathologic results and clinical outcomes. We report quality control outcomes and nucleic acid yields of our RCC submissions (N=16 to The Cancer Genome Atlas (TCGA project, as well as newer discovery platforms, by describing mass spectrometry analysis of albumin oxidation in plasma and 6 ChIP sequencing libraries generated from nephrectomy specimens after histone H3 lysine 36 trimethylation (H3K36me3 immunoprecipitation. From June 1, 2010, through January 1, 2013, we enrolled 328 patients with RCC. Our mean (SD TCGA RNA integrity numbers (RINs were 8.1 (0.8 for papillary RCC, with a 12.5% overall rate of sample disqualification for RIN <7. Banked plasma had significantly less albumin oxidation (by mass spectrometry analysis than plasma kept at 25 °C (P<.001. For ChIP sequencing, the FastQC score for average read quality was at least 30 for 91% to 95% of paired-end reads. In parallel, we analyzed frozen tissue by RNA sequencing; after genome alignment, only 0.2% to 0.4% of total reads failed the default quality check steps of Bowtie2, which was comparable to the disqualification ratio (0.1% of the 786-O RCC cell line that was prepared under optimal RNA isolation conditions. The overall correlation coefficients for gene expression between Mayo Clinic vs TCGA tissues ranged from 0.75 to 0.82. These data support the generation of high-quality nucleic acids for genomic analyses from banked RCC. Importantly, the protocol does not interfere with routine clinical care. Collections over defined time points during disease treatment further enhance collaborative efforts to integrate genomic information with outcomes.

  5. Discovery of novel cell wall-active compounds using P ywaC, a sensitive reporter of cell wall stress, in the model gram-positive bacterium Bacillus subtilis.

    Science.gov (United States)

    Czarny, T L; Perri, A L; French, S; Brown, E D

    2014-06-01

    The emergence of antibiotic resistance in recent years has radically reduced the clinical efficacy of many antibacterial treatments and now poses a significant threat to public health. One of the earliest studied well-validated targets for antimicrobial discovery is the bacterial cell wall. The essential nature of this pathway, its conservation among bacterial pathogens, and its absence in human biology have made cell wall synthesis an attractive pathway for new antibiotic drug discovery. Herein, we describe a highly sensitive screening methodology for identifying chemical agents that perturb cell wall synthesis, using the model of the Gram-positive bacterium Bacillus subtilis. We report on a cell-based pilot screen of 26,000 small molecules to look for cell wall-active chemicals in real time using an autonomous luminescence gene cluster driven by the promoter of ywaC, which encodes a guanosine tetra(penta)phosphate synthetase that is expressed under cell wall stress. The promoter-reporter system was generally much more sensitive than growth inhibition testing and responded almost exclusively to cell wall-active antibiotics. Follow-up testing of the compounds from the pilot screen with secondary assays to verify the mechanism of action led to the discovery of 9 novel cell wall-active compounds. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  6. Data Discovery

    Directory of Open Access Journals (Sweden)

    Gerhard Weikum

    2013-07-01

    Full Text Available Discovery of documents, data sources, facts, and opinions is at the very heart of digital information and knowledge services. Being able to search, discover, compile, and analyse relevant information for a user’s specific tasks is of utmost importance in science (e.g., computational life sciences, digital humanities, etc., business (e.g., market and media analytics, customer relationship management, etc. , and society at large (e.g., consumer information, traffic logistics, health discussions, etc..

  7. Cosmic Discovery

    Science.gov (United States)

    Harwit, Martin

    1984-04-01

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

  8. Assay development and multivariate scoring for high-content discovery of chemoprotectants of endoplasmic-reticulum-stress-mediated amylin-induced cytotoxicity in pancreatic beta cells.

    Science.gov (United States)

    Law, Courtney J; Ashcroft, Harriet A; Zheng, Weifan; Sexton, Jonathan Z

    2014-09-01

    The underlying pathogenesis of type-II diabetes mellitus is in the dysfunction and selective loss of pancreatic islet β-cells, which ultimately leads to underproduction of endogenous insulin. Amylin, a 37-amino-acid human hormone that is cosecreted with insulin, helps regulate gastric emptying and maintain blood glucose homeostasis through improved postprandial satiety. It is hypothesized that amylin protofibrils cause selective loss of pancreatic β-cells in a manner similar to amyloid β aggregation in Alzheimer's disease. β-Cell death occurs in vitro when isolated human or rodent β-cells are exposed to micromolar concentrations of amylin, but the exact mechanism of selective β-cell loss in vivo remains unknown. Therefore, pursuing small-molecule drug discovery for chemoprotectants of amylin-induced β-cell toxicity is a viable phenotypic target that can lead to potential pharmacotherapies for the preservation of β-cell mass, delaying insulin dependence and allowing additional opportunities for lifestyle intervention. Additionally, chronic endoplasmic reticulum (ER) stress induced by chronic hyperglycemia and hyperlipidemia is a potentiating factor of amylin-induced β-cell loss. Herein, we describe a high-content/high-throughput screening (HTS) assay for the discovery of small molecules that are chemoprotective of amylin-induced, ER-stress-potentiated β-cell loss. We also put forth a general method for construction of a robust well-level multivariate scoring system using partial least squares regression analysis to improve high-content assay performance and to streamline the association of complex high-content data into HTS activity databases where univariate responses are typical.

  9. Predicting Causal Relationships from Biological Data: Applying Automated Causal Discovery on Mass Cytometry Data of Human Immune Cells.

    Science.gov (United States)

    Triantafillou, Sofia; Lagani, Vincenzo; Heinze-Deml, Christina; Schmidt, Angelika; Tegner, Jesper; Tsamardinos, Ioannis

    2017-10-05

    Learning the causal relationships that define a molecular system allows us to predict how the system will respond to different interventions. Distinguishing causality from mere association typically requires randomized experiments. Methods for automated  causal discovery from limited experiments exist, but have so far rarely been tested in systems biology applications. In this work, we apply state-of-the art causal discovery methods on a large collection of public mass cytometry data sets, measuring intra-cellular signaling proteins of the human immune system and their response to several perturbations. We show how different experimental conditions can be used to facilitate causal discovery, and apply two fundamental methods that produce context-specific causal predictions. Causal predictions were reproducible across independent data sets from two different studies, but often disagree with the KEGG pathway databases. Within this context, we discuss the caveats we need to overcome for automated causal discovery to become a part of the routine data analysis in systems biology.

  10. Predicting Causal Relationships from Biological Data: Applying Automated Causal Discovery on Mass Cytometry Data of Human Immune Cells

    KAUST Repository

    Triantafillou, Sofia

    2017-09-29

    Learning the causal relationships that define a molecular system allows us to predict how the system will respond to different interventions. Distinguishing causality from mere association typically requires randomized experiments. Methods for automated  causal discovery from limited experiments exist, but have so far rarely been tested in systems biology applications. In this work, we apply state-of-the art causal discovery methods on a large collection of public mass cytometry data sets, measuring intra-cellular signaling proteins of the human immune system and their response to several perturbations. We show how different experimental conditions can be used to facilitate causal discovery, and apply two fundamental methods that produce context-specific causal predictions. Causal predictions were reproducible across independent data sets from two different studies, but often disagree with the KEGG pathway databases. Within this context, we discuss the caveats we need to overcome for automated causal discovery to become a part of the routine data analysis in systems biology.

  11. Cardiac Regenerative Medicine: The Potential of a New Generation of Stem Cells.

    Science.gov (United States)

    Cambria, Elena; Steiger, Julia; Günter, Julia; Bopp, Annina; Wolint, Petra; Hoerstrup, Simon P; Emmert, Maximilian Y

    2016-07-01

    Cardiac stem cell therapy holds great potential to prompt myocardial regeneration in patients with ischemic heart disease. The selection of the most suitable cell type is pivotal for its successful application. Various cell types, including crude bone marrow mononuclear cells, skeletal myoblast, and hematopoietic and endothelial progenitors, have already advanced into the clinical arena based on promising results from different experimental and preclinical studies. However, most of these so-called first-generation cell types have failed to fully emulate the promising preclinical data in clinical trials, resulting in heterogeneous outcomes and a critical lack of translation. Therefore, different next-generation cell types are currently under investigation for the treatment of the diseased myocardium. This review article provides an overview of current stem cell therapy concepts, including the application of cardiac stem (CSCs) and progenitor cells (CPCs) and lineage commitment via guided cardiopoiesis from multipotent cells such as mesenchymal stem cells (MSCs) or pluripotent cells such as embryonic and induced pluripotent stem cells. Furthermore, it introduces new strategies combining complementary cell types, such as MSCs and CSCs/CPCs, which can yield synergistic effects to boost cardiac regeneration.

  12. Discovery of TUG-770

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Hansen, Steffen Vissing Fahnøe; Urban, Christian

    2013-01-01

    Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical...... and pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days of chronic dosing....

  13. Discovery Mondays

    CERN Multimedia

    2003-01-01

    Many people don't realise quite how much is going on at CERN. Would you like to gain first-hand knowledge of CERN's scientific and technological activities and their many applications? Try out some experiments for yourself, or pick the brains of the people in charge? If so, then the «Lundis Découverte» or Discovery Mondays, will be right up your street. Starting on May 5th, on every first Monday of the month you will be introduced to a different facet of the Laboratory. CERN staff, non-scientists, and members of the general public, everyone is welcome. So tell your friends and neighbours and make sure you don't miss this opportunity to satisfy your curiosity and enjoy yourself at the same time. You won't have to listen to a lecture, as the idea is to have open exchange with the expert in question and for each subject to be illustrated with experiments and demonstrations. There's no need to book, as Microcosm, CERN's interactive museum, will be open non-stop from 7.30 p.m. to 9 p.m. On the first Discovery M...

  14. Exosomes in urine biomarker discovery.

    Science.gov (United States)

    Huebner, Alyssa R; Somparn, Poorichaya; Benjachat, Thitima; Leelahavanichkul, Asada; Avihingsanon, Yingyos; Fenton, Robert A; Pisitkun, Trairak

    2015-01-01

    Nanovesicles present in urine the so-called urinary exosomes have been found to be secreted by every epithelial cell type lining the urinary tract system in human. Urinary exosomes are an appealing source for biomarker discovery as they contain molecular constituents of their cell of origin, including proteins and genetic materials, and they can be isolated in a non-invasive manner. Following the discovery of urinary exosomes in 2004, many studies have been performed using urinary exosomes as a starting material to identify biomarkers in various renal, urogenital, and systemic diseases. Here, we describe the discovery of urinary exosomes and address the issues on the collection, isolation, and normalization of urinary exosomes as well as delineate the systems biology approach to biomarker discovery using urinary exosomes.

  15. An in vivo-like tumor stem cell-related glioblastoma in vitro model for drug discovery

    DEFF Research Database (Denmark)

    Jensen, Stine Skov; Aaberg-Jessen, Charlotte; Nørregaard, Annette

    the effects of new drugs on tumor cells including tumor stem cells. Implantation of glioblastoma cells into organotypic brain slice cultures has previously been published as a model system, but not using a stem cell favourable environment. Organotypic corticostriatal rat brain slice cultures were prepared...... and cultured in a serum containing medium replaced after three days with a serum-free stem cell medium. Thereafter fluorescent DiI labelled glioblastoma spheroids from the cell line U87 and the tumor stem cell line SJ-1 established in our laboratory were implanted into the brain slices between cortex...... growth of the U87 implants, but no invasion of cells into the brain tissue, neither in vitro nor in vivo. In contrast, SJ-1 was clearly invasive both in vitro and in vivo, but not very expansive. The co-cultures and brains with xenografts were immunohistochemically stained with anti-human vimentin...

  16. The programmed cell death GLuc PCA library – a powerful tool for pathway discovery and drug screening

    Science.gov (United States)

    Gilad, Yuval; Kimchi, Adi

    2014-01-01

    A programmed cell death library based on the Gaussia luciferase protein-fragment complementation assay (GLuc PCA) enables detection of protein–protein interactions (PPI) within the cell death network and quantitative assessments of these interactions. Among future applications for the GLuc PCA cell death library is its potential use as a platform for PPI-targeted drug screening. PMID:27308378

  17. Hepatocellular carcinoma-targeted drug discovery through image-based phenotypic screening in co-cultures of HCC cells with hepatocytes.

    Science.gov (United States)

    Jang, Jae-Woo; Song, Yeonhwa; Kim, Kang Mo; Kim, Jin-Sun; Choi, Eun Kyung; Kim, Joon; Seo, Haengran

    2016-10-18

    Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide and is associated with substantial mortality. Because HCCs have strong resistance to conventional chemotherapeutic agents, novel therapeutic strategies are needed to improve survival in HCC patients. Here, we developed a fluorescence image-based phenotypic screening system in vitro to identify HCC-specific drugs in co-cultures of HCC cells with hepatocytes. To this end, we identified two distinctive markers of HCC, CHALV1 and AFP, which are highly expressed in HCC cell lines and liver cancer patient-derived materials. We applied these markers to an HCC-specific drug screening system. Through pilot screening, we identified three anti-folate compounds that had HCC-specific cytotoxicity. Among them, pyrimethamine exhibited the greatest HCC-specific cytotoxicity. Interestingly, pyrimethamine significantly increased the size and number of lysosomes and subsequently induced the release of cathepsin B from the lysosome to the cytosol, which triggered caspase-3-dependent apoptosis in Huh7 (HCC) but not Fa2N-4 cells (immortalized hepatocytes). Importantly, Fa2N-4 cells had strong resistance to pyrimethamine relative to Huh7 cells in 2D and 3D culture systems. These results demonstrate that this in vitro image-based phenotypic screening platform has the potential to be widely adopted in drug discovery research, since we promptly estimated anticancer activity and hepatotoxicity and elucidated functional roles of pyrimethamine during the apoptosis process in HCC.

  18. Model-driven discovery of long-chain fatty acid metabolic reprogramming in heterogeneous prostate cancer cells.

    Science.gov (United States)

    Marín de Mas, Igor; Aguilar, Esther; Zodda, Erika; Balcells, Cristina; Marin, Silvia; Dallmann, Guido; Thomson, Timothy M; Papp, Balázs; Cascante, Marta

    2018-01-01

    Epithelial-mesenchymal-transition promotes intra-tumoral heterogeneity, by enhancing tumor cell invasiveness and promoting drug resistance. We integrated transcriptomic data for two clonal subpopulations from a prostate cancer cell line (PC-3) into a genome-scale metabolic network model to explore their metabolic differences and potential vulnerabilities. In this dual cell model, PC-3/S cells express Epithelial-mesenchymal-transition markers and display high invasiveness and low metastatic potential, while PC-3/M cells present the opposite phenotype and higher proliferative rate. Model-driven analysis and experimental validations unveiled a marked metabolic reprogramming in long-chain fatty acids metabolism. While PC-3/M cells showed an enhanced entry of long-chain fatty acids into the mitochondria, PC-3/S cells used long-chain fatty acids as precursors of eicosanoid metabolism. We suggest that this metabolic reprogramming endows PC-3/M cells with augmented energy metabolism for fast proliferation and PC-3/S cells with increased eicosanoid production impacting angiogenesis, cell adhesion and invasion. PC-3/S metabolism also promotes the accumulation of docosahexaenoic acid, a long-chain fatty acid with antiproliferative effects. The potential therapeutic significance of our model was supported by a differential sensitivity of PC-3/M cells to etomoxir, an inhibitor of long-chain fatty acid transport to the mitochondria.

  19. Label-free drug discovery

    Directory of Open Access Journals (Sweden)

    Ye eFang

    2014-03-01

    Full Text Available Current drug discovery is dominated by label-dependent molecular approaches, which screen drugs in the context of a predefined and target-based hypothesis in vitro. Given that target-based discovery has not transformed the industry, phenotypic screen that identifies drugs based on a specific phenotype of cells, tissues, or animals has gained renewed interest. However, owing to the intrinsic complexity in drug-target interactions, there is often a significant gap between the phenotype screened and the ultimate molecular mechanism of action sought. This paper presents a label-free strategy for early drug discovery. This strategy combines label-free cell phenotypic profiling with computational approaches, and holds promise to bridge the gap by offering a kinetic and holistic representation of the functional consequences of drugs in disease relevant cells that is amenable to mechanistic deconvolution.

  20. Discovery of cell-type specific DNA motif grammar in cis-regulatory elements using random Forest.

    Science.gov (United States)

    Wang, Xin; Lin, Peijie; Ho, Joshua W K

    2018-01-19

    It has been observed that many transcription factors (TFs) can bind to different genomic loci depending on the cell type in which a TF is expressed in, even though the individual TF usually binds to the same core motif in different cell types. How a TF can bind to the genome in such a highly cell-type specific manner, is a critical research question. One hypothesis is that a TF requires co-binding of different TFs in different cell types. If this is the case, it may be possible to observe different combinations of TF motifs - a motif grammar - located at the TF binding sites in different cell types. In this study, we develop a bioinformatics method to systematically identify DNA motifs in TF binding sites across multiple cell types based on published ChIP-seq data, and address two questions: (1) can we build a machine learning classifier to predict cell-type specificity based on motif combinations alone, and (2) can we extract meaningful cell-type specific motif grammars from this classifier model. We present a Random Forest (RF) based approach to build a multi-class classifier to predict the cell-type specificity of a TF binding site given its motif content. We applied this RF classifier to two published ChIP-seq datasets of TF (TCF7L2 and MAX) across multiple cell types. Using cross-validation, we show that motif combinations alone are indeed predictive of cell types. Furthermore, we present a rule mining approach to extract the most discriminatory rules in the RF classifier, thus allowing us to discover the underlying cell-type specific motif grammar. Our bioinformatics analysis supports the hypothesis that combinatorial TF motif patterns are cell-type specific.

  1. Execution of "ARC" experiment on space shuttle "Discovery" STS 51-C: some results on aggregation of red blood cells under zero gravity.

    Science.gov (United States)

    Dintenfass, L

    1986-01-01

    A project on "Aggregation of Red Cells" has been accepted by NASA in 1977. An automated slit-capillary photo-viscometer has been designed during 1979-1984, and its last version met NASA's space hazards requirements. The 'heart' of instrument is a set of two highly polished glass plates, spaced by a gap of 12.5 micrometers. An original drum-like infusion pump allows utilization of up to eight blood samples. During a sequential process, blood flows through the slit, and then stops to allow formation of aggregates. Micro- and macro-photography is carried out, and 500 photographs are obtained. Blood from normal donors and patients with history of ischaemic heart disease, colon cancer, juvenile-onset diabetes, hyperlipidaemia, etc., is anticoagulated and adjusted to haematocrit of 0.30 using native plasma. Samples are divided, and infused into the 'flight' and 'ground' instruments. Prior to experiment temp. is 5 degrees C; temp. during experiment is 25 degrees C. Experiments took place on 24-25 January 1985, on the middeck of space shuttle 'Discovery'. Subsequent results showed that red blood cells do not change shape under zero gravity; that aggregation of red cells does take place; that aggregates in pathologic blood show morphology of normal rouleaux under zero gravity, while identical blood shows clumps of red cells on the ground. The latter observation suggests that zero gravity might affect cell-to-cell interaction, and perhaps microstructure of the cell membrane. These aspects must remain however tentative till a confirmation by subsequent experiments can be obtained.

  2. Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2).

    Science.gov (United States)

    Kinarivala, Nihar; Patel, Ronak; Boustany, Rose-Mary; Al-Ahmad, Abraham; Trippier, Paul C

    2017-12-14

    Neurodegenerative diseases share certain pathophysiological hallmarks that represent common targets for drug discovery. In particular, dysfunction of proteostasis and the resultant apoptotic death of neurons represent common pathways for pharmacological intervention. A library of aromatic carbamate derivatives based on the clinically available drug flupirtine was synthesized to determine a structure-activity relationship for neuroprotective activity. Several derivatives were identified that possess greater protective effect in human induced pluripotent stem cell-derived neurons, protecting up to 80% of neurons against etoposide-induced apoptosis at concentrations as low as 100 nM. The developed aromatic carbamates possess physicochemical properties desirable for CNS therapeutics. The primary known mechanisms of action of the parent scaffold are not responsible for the observed neuroprotective activity. Herein, we demonstrate that neuroprotective aromatic carbamates function to increase the Bcl-2/Bax ratio to an antiapoptotic state and activate autophagy through induction of beclin 1.

  3. Experiment on "Discovery" STS 51-C: aggregation of red cells and thrombocytes in heart disease, hyperlipidaemia and other conditions.

    Science.gov (United States)

    Dintenfass, L

    1989-01-01

    The aim of this experiment was to study aggregation of red cells in the blood of patients with ischaemic heart disease, diabetes, hyperlipidaemia, and (silent) cancer, and in two normal donors. Reconstituted blood using IgG was also used. The instrument, the automated slit-capillary photo-viscometer (100 kg weight) was set on the middeck of the Space Shuttle. An analogous instrument was at the Kennedy Space Center. Blood was obtained from donors, anticoagulated, and adjusted to haematocrit of 30% using native plasma. Experiments took place at 25 degrees C, during which blood was forced to flow in the slit formed by two parallel glass plates. Macro and microphotography was carried out at specific intervals controlled by a computer. During stasis, lasting 6 minutes, aggregates (or clumps) of the red cells were formed. Results indicated that red cell aggregates do form under zero-G; that such aggregates are smaller than the ones obtained at one-G; that morphology is different, the zero-G showing rouleaux while one-G showing usual sludge-like clumps of red cells in all severe disorders. Platelets appeared to remain monodisperse under zero-G. Assuming that these data can be confirmed, one could suggest that zero-G affects cell-cell interaction, and may consequently influence the internal microstructure of the cell membrane and of the receptors, as well as their activity. Gravitational studies may thus open a new door on immunology and haematology in general.

  4. Library synthesis, screening, and discovery of modified Zinc(II)-Bis(dipicolylamine) probe for enhanced molecular imaging of cell death.

    Science.gov (United States)

    Plaunt, Adam J; Harmatys, Kara M; Wolter, William R; Suckow, Mark A; Smith, Bradley D

    2014-04-16

    Zinc(II)-bis(dipicolylamine) (Zn-BDPA) coordination complexes selectively target the surfaces of dead and dying mammalian cells, and they have promise as molecular probes for imaging cell death. A necessary step toward eventual clinical imaging applications is the development of next-generation Zn-BDPA complexes with enhanced affinity for the cell death membrane biomarker, phosphatidylserine (PS). This study employed an iterative cycle of library synthesis and screening, using a novel rapid equilibrium dialysis assay, to discover a modified Zn-BDPA structure with high and selective affinity for vesicles containing PS. The lead structure was converted into a deep-red fluorescent probe and its targeting and imaging performance was compared with an unmodified control Zn-BDPA probe. The evaluation process included a series of FRET-based vesicle titration studies, cell microscopy experiments, and rat tumor biodistribution measurements. In all cases, the modified probe exhibited comparatively higher affinity and selectivity for the target membranes of dead and dying cells. The results show that this next-generation deep-red fluorescent Zn-BDPA probe is well suited for preclinical molecular imaging of cell death in cell cultures and animal models. Furthermore, it should be possible to substitute the deep-red fluorophore with alternative reporter groups that enable clinically useful, deep-tissue imaging modalities, such as MRI and nuclear imaging.

  5. Discovery of dehydroabietic acid sulfonamide based derivatives as selective matrix metalloproteinases inactivators that inhibit cell migration and proliferation.

    Science.gov (United States)

    Huang, Ri-Zhen; Liang, Gui-Bin; Huang, Xiao-Chao; Zhang, Bin; Zhou, Mei-Mei; Liao, Zhi-Xin; Wang, Heng-Shan

    2017-09-29

    A series of dehydroabietic acid (DHAA) dipeptide derivatives containing the sulfonamide moiety were designed, synthesized and evaluated for inhibition of MMPs as well as the effects of in vitro cell migration. These compounds exhibited relatively good inhibition activity against MMPs with IC 50 values in low micromolar range. A docking study of the most active compound 8k revealed key interactions between 8k and MMP-3 in which the sulfonamide moiety and the dipeptide group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU. In particular, compound 8k appeared to be the most potent compound against the HepG2 cell line, at least partly, by inhibition of the activity of MMP-3 and apoptosis induction. The treatment of HepG2 cells with compound 8k resulted in inhibition of in vitro cell migration through wound healing assay and G1 phase of cell cycle arrested. In addition, 8k-induced apoptosis was significantly facilitated in HepG2 cells. Thus, we conclude that DHAA dipeptide derivatives containing the sulfonamide moiety may be the potential MMPs inhibitors with the ability to suppress cells migration. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Colworth prize lecture 2016: exploiting new biological targets from a whole-cell phenotypic screening campaign for TB drug discovery.

    Science.gov (United States)

    Moynihan, Patrick Joseph; Besra, Gurdyal S

    2017-10-01

    Mycobacterium tuberculosis is the aetiological agent of tuberculosis (TB) and is the leading bacterial cause of mortality and morbidity in the world. One third of the world's population is infected with TB, and in conjunction with HIV represents a serious problem that urgently needs addressing. TB is a disease of poverty and mostly affects young adults in their productive years, primarily in the developing world. The most recent report from the World Health Organisation states that 8 million new cases of TB were reported and that ~1.5 million people died from TB. The efficacy of treatment is threatened by the emergence of multi-drug and extensively drug-resistant strains of M. tuberculosis. It can be argued that, globally, M. tuberculosis is the single most important infectious agent affecting mankind. Our research aims to establish an academic-industrial partnership with the goal of discovering new drug targets and hit-to-lead new chemical entities for TB drug discovery.

  7. Discovery of a novel, monocationic, small-molecule inhibitor of scrapie prion accumulation in cultured sheep microglia and Rov cells.

    Science.gov (United States)

    Stanton, James B; Schneider, David A; Dinkel, Kelcey D; Balmer, Bethany F; Baszler, Timothy V; Mathison, Bruce A; Boykin, David W; Kumar, Arvind

    2012-01-01

    Prion diseases, including sheep scrapie, are neurodegenerative diseases with the fundamental pathogenesis involving conversion of normal cellular prion protein (PrP(C)) to disease-associated prion protein (PrP(Sc)). Chemical inhibition of prion accumulation is widely investigated, often using rodent-adapted prion cell culture models. Using a PrP(Sc)-specific ELISA we discovered a monocationic phenyl-furan-benzimidazole (DB772), which has previously demonstrated anti-pestiviral activity and represents a chemical category previously untested for anti-prion activity, that inhibited PrP(Sc) accumulation and prion infectivity in primary sheep microglial cell cultures (PRNP 136VV/154RR/171QQ) and Rov9 cultures (VRQ-ovinized RK13 cells). We investigated potential mechanisms of this anti-prion activity by evaluating PrP(C) expression with quantitative RT-PCR and PrP ELISA, comparing the concentration-dependent anti-prion and anti-pestiviral effects of DB772, and determining the selectivity index. Results demonstrate at least an approximate two-log inhibition of PrP(Sc) accumulation in the two cell systems and confirmed that the inhibition of PrP(Sc) accumulation correlates with inhibition of prion infectivity. PRNP transcripts and total PrP protein concentrations within cell lysates were not decreased; thus, decreased PrP(C) expression is not the mechanism of PrP(Sc) inhibition. PrP(Sc) accumulation was multiple logs more resistant than pestivirus to DB772, suggesting that the anti-PrP(Sc) activity was independent of anti-pestivirus activity. The anti-PrP(Sc) selectivity index in cell culture was approximately 4.6 in microglia and 5.5 in Rov9 cells. The results describe a new chemical category that inhibits ovine PrP(Sc) accumulation in primary sheep microglia and Rov9 cells, and can be used for future studies into the treatment and mechanism of prion diseases.

  8. Cholangiocarcinomas: New Insights from the Discovery of Stem Cell Niches in Peribiliary Glands of the Biliary Tree

    Directory of Open Access Journals (Sweden)

    Vincenzo Cardinale

    2014-01-01

    Full Text Available Peribiliary glands (PBGs are located in the large intrahepatic and extrahepatic bile ducts. Although they were described many years ago, their functions have been elucidated only in the last couple of years when our group demonstrated that PBGs are niches of multipotent stem/progenitor cells of endodermal origin. These cells express genes of multipotency and can be rapidly differentiated in vitro into hepatocytes, cholangiocytes, and endocrine pancreatic cells. PBGs share common features, in terms of stem/progenitor cell niches, with pancreatic duct glands and colon crypts, glandular structures representing in the adult life the endodermal remnants of fetal life. PBG stem/progenitor cells participate in the renewal of surface biliary epithelium and are active players in chronic pathologies of the biliary tree as well as in cholangiocarcinomas (CCA. Specifically, a large amount of recent evidence indicates that the pure mucin-CCA originates from PBGs; this could explain the similarities with pancreatic ductal adenocarcinoma and colorectal cancer, which also originate from transformed gland cells. In this paper, we summarized our recent findings concerning structure and functions of PBGs with the implications for liver pathophysiology and, specifically, for cancers of the biliary tree.

  9. Milestones and recent discoveries on cell death mediated by mitochondria and their interactions with biologically active amines.

    Science.gov (United States)

    Grancara, Silvia; Ohkubo, Shinji; Artico, Marco; Ciccariello, Mauro; Manente, Sabrina; Bragadin, Marcantonio; Toninello, Antonio; Agostinelli, Enzo

    2016-10-01

    Mitochondria represent cell "powerhouses," being involved in energy transduction from the electrochemical gradient to ATP synthesis. The morphology of their cell types may change, according to various metabolic processes or osmotic pressure. A new morphology of the inner membrane and mitochondrial cristae, significantly different from the previous one, has been proposed for the inner membrane and mitochondrial cristae, based on the technique of electron tomography. Mitochondrial Ca(2+) transport (the transporter has been isolated) generates reactive oxygen species and induces the mitochondrial permeability transition of both inner and outer mitochondrial membranes, leading to induction of necrosis and apoptosis. In the mitochondria of several cell types (liver, kidney, and heart), mitochondrial oxidative stress is an essential step in the induction of cell death, although not in brain, in which the phenomenon is caused by a different mechanism. Mitochondrial permeability transition drives both apoptosis and necrosis, whereas mitochondrial outer membrane permeability is characteristic of apoptosis. Adenine nucleotide translocase remains the most important component involved in membrane permeability, with the opening of the transition pore, although other proteins, such as ATP synthase or phosphate carriers, have been proposed. Intrinsic cell death is triggered by the release from mitochondria of proteic factors, such as cytochrome c, apoptosis inducing factor, and Smac/DIABLO, with the activation of caspases upon mitochondrial permeability transition or mitochondrial outer membrane permeability induction. Mitochondrial permeability transition induces the permeability of the inner membrane in sites in contact with the outer membrane; mitochondrial outer membrane permeability forms channels on the outer membrane by means of various stimuli involving Bcl-2 family proteins. The biologically active amines, spermine, and agmatine, have specific functions on mitochondria

  10. Discovery of LPMO activity on hemicelluloses shows the importance of oxidative processes in plant cell wall degradation

    DEFF Research Database (Denmark)

    Agger, Jane W.; Isaksen, Trine; Várnai, Anikó

    2014-01-01

    of LPMOs, and considering the complexity and copolymeric nature of the plant cell wall, it has been speculated that some LPMOs may act on other substrates, in particular the hemicelluloses that tether to cellulose microfibrils. We demonstrate that an LPMO from Neurospora crassa, NcLPMO9C, indeed degrades...... various hemicelluloses, in particular xyloglucan. This activity was discovered using a glycan microarray-based screening method for detection of substrate specificities of carbohydrate-active enzymes, and further explored using defined oligomeric hemicelluloses, isolated polymeric hemicelluloses and cell...

  11. From discovery to approval of an advanced therapy medicinal product-containing stem cells, in the EU.

    Science.gov (United States)

    Pellegrini, Graziella; Lambiase, Alessandro; Macaluso, Claudio; Pocobelli, Augusto; Deng, Sophie; Cavallini, Gian Maria; Esteki, Roza; Rama, Paolo

    2016-06-01

    In 1997, the human corneal epithelium was reconstructed in vitro and transplanted on patients. Later, it became a routine treatment, before regulations considered advanced therapy medicinal products and drugs on the same lines. Manufacturing, before and after good manufacturing practice setting, was established in different facilities and the clinical application in several hospitals. Advanced therapy medicinal products, including stem cells, are unique products with different challenges than other drugs: some uncertainties, in addition to benefit, cannot be avoided. This review will focus on all recent developments in the stem cell-based corneal therapy.

  12. Discovery of a novel, monocationic, small-molecule inhibitor of scrapie prion accumulation in cultured sheep microglia and Rov cells.

    Directory of Open Access Journals (Sweden)

    James B Stanton

    Full Text Available Prion diseases, including sheep scrapie, are neurodegenerative diseases with the fundamental pathogenesis involving conversion of normal cellular prion protein (PrP(C to disease-associated prion protein (PrP(Sc. Chemical inhibition of prion accumulation is widely investigated, often using rodent-adapted prion cell culture models. Using a PrP(Sc-specific ELISA we discovered a monocationic phenyl-furan-benzimidazole (DB772, which has previously demonstrated anti-pestiviral activity and represents a chemical category previously untested for anti-prion activity, that inhibited PrP(Sc accumulation and prion infectivity in primary sheep microglial cell cultures (PRNP 136VV/154RR/171QQ and Rov9 cultures (VRQ-ovinized RK13 cells. We investigated potential mechanisms of this anti-prion activity by evaluating PrP(C expression with quantitative RT-PCR and PrP ELISA, comparing the concentration-dependent anti-prion and anti-pestiviral effects of DB772, and determining the selectivity index. Results demonstrate at least an approximate two-log inhibition of PrP(Sc accumulation in the two cell systems and confirmed that the inhibition of PrP(Sc accumulation correlates with inhibition of prion infectivity. PRNP transcripts and total PrP protein concentrations within cell lysates were not decreased; thus, decreased PrP(C expression is not the mechanism of PrP(Sc inhibition. PrP(Sc accumulation was multiple logs more resistant than pestivirus to DB772, suggesting that the anti-PrP(Sc activity was independent of anti-pestivirus activity. The anti-PrP(Sc selectivity index in cell culture was approximately 4.6 in microglia and 5.5 in Rov9 cells. The results describe a new chemical category that inhibits ovine PrP(Sc accumulation in primary sheep microglia and Rov9 cells, and can be used for future studies into the treatment and mechanism of prion diseases.

  13. Literature-Related Discovery: A Review

    Science.gov (United States)

    2007-11-05

    disaggregation; Guar Gum for decrease in plasma fibrinogen and viscosity; Cell hydration to improve cell deformity and increase arm blood flow. This...discoveries to insure that they were indeed unique. Some potential discoveries include: The use of plasmin to deter cell adhesion for use in non...2006] have generated a semantic space approach that bears some similarities to LSI. It is based on the Hyperspace Analogue to Language (HAL

  14. 76 FR 51374 - Direct Discovery of HLA Associated Influenza Epitopes Isolated From Human Cells for Vaccine and...

    Science.gov (United States)

    2011-08-18

    ..., MD 20892, Telephone: 301-827-0793; E-mail: [email protected] . For Financial and... requires extensive infrastructure for growing cells, purifying HLA from culture supernatants, and for mass... allow FDA to acquire the proteomic expertise, training, and tissue culture support to establish a...

  15. Bio-Activity and Dereplication-Based Discovery of Ophiobolins and Other Fungal Secondary Metabolites Targeting Leukemia Cells

    DEFF Research Database (Denmark)

    Bladt, Tanja Thorskov; Dürr, Claudia; Knudsen, Peter Boldsen

    2013-01-01

    The purpose of this study was to identify and characterize fungal natural products (NPs) with in vitro bioactivity towards leukemia cells. We based our screening on a combined analytical and bio-guided approach of LC-DAD-HRMS dereplication, explorative solid-phase extraction (E-SPE), and a co...

  16. Discovery of the rare HLA-B*39:77 allele in an unrelated Taiwanese bone marrow stem cell donor using the sequence-based typing method.

    Science.gov (United States)

    Yang, K L; Lee, S K; Lin, P Y

    2013-08-01

    We detected a rare HLA-B locus allele, B*39:77, in a Taiwanese unrelated marrow stem cell donor in our routine HLA sequence-based typing (SBT) exercise for a possible haematopoietic stem cell donation. In exons 2, 3 and 4, the DNA sequence of B*39:77 is identical to the sequence of B*39:01:01:01 except one nucleotide at nucleotide position 733 (G->A) in exon 4. The nucleotide variation caused one amino acid alteration at residue 221 (Gly->Ser). B*39:77 was probably derived from a nucleotide substitution event involving B*39:01:01:01. The probable HLA-A, -B, -C, -DRB1 and -DQB1 haplotype in association with B*39:77 may be deduced as A*02:01-B*39:77-C*07:02-DRB1*08:03-DQB1*06:01. Our discovery of B*39:77 in Taiwanese adds further polymorphism of B*39 variants in Taiwanese population. © 2013 John Wiley & Sons Ltd.

  17. Discovery of a novel HIV-1 integrase inhibitor from natural compounds through structure based virtual screening and cell imaging.

    Science.gov (United States)

    Gu, Wan-Gang; Zhang, Xuan; Ip, Denis Tsz-Ming; Yang, Liu-Meng; Zheng, Yong-Tang; Wan, David Chi-Cheong

    2014-09-17

    The interaction between HIV-1 integrase and LEDGF/P75 has been validated as a target for anti-HIV drug development. Based on the crystal structure of integrase in complex with LEDGF/P75, a library containing 80 thousand natural compounds was filtered with virtual screening. 11 hits were selected for cell based assays. One compound, 3-(1,3-benzothiazol-2-yl)-8-{[bis(2-hydroxyethyl)amino]methyl}-7-hydroxy-2H-chromen-2-one (D719) inhibited integrase nuclear translocation in cell imaging. The binding mode of D719 was analyzed with molecular simulation. The anti-HIV activity of D719 was assayed by measuring the p24 antigen production in acute infection. The structure characteristics of D719 may provide valuable information for integrase inhibitor design. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  18. High-throughput discovery of T cell epitopes in type 1 diabetes using DNA barcode labelledpeptide-MHC multimers

    DEFF Research Database (Denmark)

    Lyngaa, Rikke Birgitte; Bentzen, Amalie Kai; Overgaard, A. Julie

    2016-01-01

    applying a novel technology where the selection of MHC-multimer binding T cells is followed by amplification and sequencing of MHC multimer-associated DNA barcodes revealing their recognition. This technique enables simultaneous detection of >1000 specificities. Identifying post translational modifications...... as T cell targets in other autoimmune diseases. We used netMHC prediction algorithm to identify 764 epitopes from Insulin, GAD65, IA-2 and ZnT8 restricted to HLA-A2, A24, B8 and B15. Among these 91 peptide sequences were susceptible for citrullination. We evaluate the MHC-affinity of both...... the citrullinated and non-citrullinated library, to identify potential neo-epitopes and to understand the impact of citrullination on MHC affinity. In parallel we will analyse peripheral blood lymphocytes from 50 T1D patients for immune reactivity against the full library. The large library screen will be conducted...

  19. Transcriptomic-Wide Discovery of Direct and Indirect HuR RNA Targets in Activated CD4+ T Cells.

    Directory of Open Access Journals (Sweden)

    Patsharaporn Techasintana

    Full Text Available Due to poor correlation between steady state mRNA levels and protein product, purely transcriptomic profiling methods may miss genes posttranscriptionally regulated by RNA binding proteins (RBPs and microRNAs (miRNAs. RNA immunoprecipitation (RIP methods developed to identify in vivo targets of RBPs have greatly elucidated those mRNAs which may be regulated via transcript stability and translation. The RBP HuR (ELAVL1 and family members are major stabilizers of mRNA. Many labs have identified HuR mRNA targets; however, many of these analyses have been performed in cell lines and oftentimes are not independent biological replicates. Little is known about how HuR target mRNAs behave in conditional knock-out models. In the present work, we performed HuR RIP-Seq and RNA-Seq to investigate HuR direct and indirect targets using a novel conditional knock-out model of HuR genetic ablation during CD4+ T activation and Th2 differentiation. Using independent biological replicates, we generated a high coverage RIP-Seq data set (>160 million reads that was analyzed using bioinformatics methods specifically designed to find direct mRNA targets in RIP-Seq data. Simultaneously, another set of independent biological replicates were sequenced by RNA-Seq (>425 million reads to identify indirect HuR targets. These direct and indirect targets were combined to determine canonical pathways in CD4+ T cell activation and differentiation for which HuR plays an important role. We show that HuR may regulate genes in multiple canonical pathways involved in T cell activation especially the CD28 family signaling pathway. These data provide insights into potential HuR-regulated genes during T cell activation and immune mechanisms.

  20. Synthesis of Tolmetin Hydrazide-Hydrazones and Discovery of a Potent Apoptosis Inducer in Colon Cancer Cells.

    Science.gov (United States)

    Küçükgüzel, Ş Güniz; Koç, Derya; Çıkla-Süzgün, Pelin; Özsavcı, Derya; Bingöl-Özakpınar, Özlem; Mega-Tiber, Pınar; Orun, Oya; Erzincan, Pınar; Sağ-Erdem, Safiye; Şahin, Fikrettin

    2015-10-01

    Tolmetin hydrazide and a novel series of tolmetin hydrazide-hydrazones 4a-l were synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, (1)H NMR) methods. N'-[(2,6-Dichlorophenyl)methylidene]-2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetohydrazide (4g) was evaluated in vitro using the MTT colorimetric method against the colon cancer cell lines HCT-116 (ATCC, CCL-247) and HT-29 (ATCC, HTB-38) to determine growth inhibition and cell viability at different doses. Compound 4g exhibited anti-cancer activity with an IC50 value of 76 μM against colon cancer line HT-29 (ATCC, HTB-38) and did not display cytotoxicity toward control NIH3T3 mouse embryonic fibroblast cells compared to tolmetin. In addition, this compound was evaluated for caspase-3, caspase-8, caspase-9, and annexin-V activation in the apoptotic pathway, which plays a key role in the treatment of cancer. We demonstrated that the anti-cancer activity of this compound was due to the activation of caspase-8 and caspase-9 involved in the apoptotic pathway. In addition, in this study, we investigated the catalytical effect of COX on the HT-29 cancer line, the apoptotic mechanism, and the moleculer binding of tolmetin and compound 4g on the COX enzyme active site. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Bio-Activity and Dereplication-Based Discovery of Ophiobolins and Other Fungal Secondary Metabolites Targeting Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Tanja Thorskov Bladt

    2013-11-01

    Full Text Available The purpose of this study was to identify and characterize fungal natural products (NPs with in vitro bioactivity towards leukemia cells. We based our screening on a combined analytical and bio-guided approach of LC-DAD-HRMS dereplication, explorative solid-phase extraction (E-SPE, and a co-culture platform of CLL and stromal cells. A total of 289 fungal extracts were screened and we tracked the activity to single compounds in seven of the most active extracts. The novel ophiobolin U was isolated together with the known ophiobolins C, H, K as well as 6-epiophiobolins G, K and N from three fungal strains in the Aspergillus section Usti. Ophiobolins A, B, C and K displayed bioactivity towards leukemia cells with induction of apoptosis at nanomolar concentrations. The remaining ophiobolins were mainly inactive or only slightly active at micromolar concentrations. Dereplication of those ophiobolin derivatives possessing different activity in combination with structural analysis allowed a correlation of the chemical structure and conformation with the extent of bioactivity, identifying the hydroxy group at C3 and an aldehyde at C21, as well as the A/B-cis ring structure, as indispensible for the strong activity of the ophiobolins. The known compounds penicillic acid, viridicatumtoxin, calbistrin A, brefeldin A, emestrin A, and neosolaniol monoacetate were identified from the extracts and also found generally cytotoxic.

  2. A class discovery and class prediction approach to histopathological classification of mammographic screen detected columnar cell lesions of the breast.

    Science.gov (United States)

    Pathmanathan, Nirmala; Salisbury, Elizabeth L; Provan, Pamela J; Bilous, A Michael; Byth, Karen; Milliken, Jane S; Clarke, Christine L; Balleine, Rosemary L

    2010-01-01

    Columnar cell lesions (CCLs) of the breast have been increasingly recognised in biopsies taken to investigate mammographic screen detected microcalcification. The aim of this study was to identify distinct CCL subtypes by systematic analysis of histopathology. Hierarchical cluster analysis was performed based on the profile of histopathological features in 102 screen detected CCLs. Features assessed included nuclear morphology, acinar dilatation, epithelial cell hyperplasia, cell crowding, apical snout formation and intraluminal secretion. The stability of this classification was tested in an independent cohort of 32 cases. The histopathology of screen detected CCLs was extremely variable. Hierarchical cluster analysis identified two subclasses: Class 1 (34/102, 33%) characterised by absence of nuclear atypia and less pronounced hyperplasia; and Class 2 (68/102, 67%) that were generally more atypical. Ki-67 scores were significantly lower for Class 1 CCLs (p Class 1 cases were clearly distinguished from Class 2, indicating that these were stable phenotypes amongst screen detected CCLs. The histopathological features of CCLs diagnosed at screening are extremely heterogeneous. Using a systematic approach, we have devised a broad classification system that delineates a category of less atypical CCLs that could form a basis for future studies.

  3. Microscopy Opening Up New Cancer Discovery Avenues

    Science.gov (United States)

    Today’s high-powered microscopes are allowing researchers to study the fine details of individual cells and to peer into cells, opening up new avenues of discovery about the inner workings of cells, including the events that can cause healthy cells to tra

  4. MHC-I Ligand Discovery Using Targeted Database Searches of Mass Spectrometry Data: Implications for T-Cell Immunotherapies

    DEFF Research Database (Denmark)

    Murphy, J. Patrick; Konda, Prathyusha; Kowalewski, Daniel J.

    2017-01-01

    we offer a solution to this problem whereby we developed a targeted database search approach and accompanying tool SpectMHC, that is based on a priori-predicted MHC-I peptides. We first validated the approach using MS data from two different allotype-specific immunoprecipitates for the C57BL/6 mouse...... background. We then developed allotype-specific HLA databases to search previously published MS data sets of human peripheral blood mononuclear cells (PBMCs). This targeted search strategy improved peptide identifications for both mouse and human ligandomes by greater than 2-fold and is superior...

  5. Combinatorial discovery of new methanol-tolerant non-noble metal cathode electrocatalysts for direct methanol fuel cells.

    Science.gov (United States)

    Yu, Jong-Sung; Kim, Min-Sik; Kim, Jung Ho

    2010-12-14

    Combinatorial synthesis and screening were used to identify methanol-tolerant non-platinum cathode electrocatalysts for use in direct methanol fuel cells (DMFCs). Oxygen reduction consumes protons at the surface of DMFC cathode catalysts. In combinatorial screening, this pH change allows one to differentiate active catalysts using fluorescent acid-base indicators. Combinatorial libraries of carbon-supported catalyst compositions containing Ru, Mo, W, Sn, and Se were screened. Ternary and quaternary compositions containing Ru, Sn, Mo, Se were more active than the "standard" Alonso-Vante catalyst, Ru(3)Mo(0.08)Se(2), when tested in liquid-feed DMFCs. Physical characterization of the most active catalysts by powder X-ray diffraction, gas adsorption, and X-ray photoelectron spectroscopy revealed that the predominant crystalline phase was hexagonal close-packed (hcp) ruthenium, and showed a surface mostly covered with oxide. The best new catalyst, Ru(7.0)Sn(1.0)Se(1.0), was significantly more active than Ru(3)Se(2)Mo(0.08), even though the latter contained smaller particles.

  6. Topology Discovery Using Cisco Discovery Protocol

    OpenAIRE

    Rodriguez, Sergio R.

    2009-01-01

    In this paper we address the problem of discovering network topology in proprietary networks. Namely, we investigate topology discovery in Cisco-based networks. Cisco devices run Cisco Discovery Protocol (CDP) which holds information about these devices. We first compare properties of topologies that can be obtained from networks deploying CDP versus Spanning Tree Protocol (STP) and Management Information Base (MIB) Forwarding Database (FDB). Then we describe a method of discovering topology ...

  7. Discovery, Annotation, and Functional Analysis of Long Noncoding RNAs Controlling Cell-Cycle Gene Expression and Proliferation in Breast Cancer Cells.

    Science.gov (United States)

    Sun, Miao; Gadad, Shrikanth S; Kim, Dae-Seok; Kraus, W Lee

    2015-08-20

    We describe a computational approach that integrates GRO-seq and RNA-seq data to annotate long noncoding RNAs (lncRNAs), with increased sensitivity for low-abundance lncRNAs. We used this approach to characterize the lncRNA transcriptome in MCF-7 human breast cancer cells, including >700 previously unannotated lncRNAs. We then used information about the (1) transcription of lncRNA genes from GRO-seq, (2) steady-state levels of lncRNA transcripts in cell lines and patient samples from RNA-seq, and (3) histone modifications and factor binding at lncRNA gene promoters from ChIP-seq to explore lncRNA gene structure and regulation, as well as lncRNA transcript stability, regulation, and function. Functional analysis of selected lncRNAs with altered expression in breast cancers revealed roles in cell proliferation, regulation of an E2F-dependent cell-cycle gene expression program, and estrogen-dependent mitogenic growth. Collectively, our studies demonstrate the use of an integrated genomic and molecular approach to identify and characterize growth-regulating lncRNAs in cancers. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Advancements in Aptamer Discovery Technologies.

    Science.gov (United States)

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

    2016-09-20

    transforms solution-phase aptamers into "aptamer particles" that can be individually screened at high-throughput via fluorescence-activated cell sorting. Using PD, we have shown the feasibility of rapidly generating aptamers with exceptional affinities, even for proteins that have previously proven intractable to aptamer discovery. We are confident that these advanced aptamer-discovery methods will accelerate the discovery of aptamer reagents with excellent affinities and specificities, perhaps even exceeding those of the best monoclonal antibodies. Since aptamers are reproducible, renewable, stable, and can be distributed as sequence information, we anticipate that these affinity reagents will become even more valuable tools for both research and clinical applications.

  9. Academic Drug Discovery Centres

    DEFF Research Database (Denmark)

    Kirkegaard, Henriette Schultz; Valentin, Finn

    2014-01-01

    Academic drug discovery centres (ADDCs) are seen as one of the solutions to fill the innovation gap in early drug discovery, which has proven challenging for previous organisational models. Prior studies of ADDCs have identified the need to analyse them from the angle of their economic and organi......Academic drug discovery centres (ADDCs) are seen as one of the solutions to fill the innovation gap in early drug discovery, which has proven challenging for previous organisational models. Prior studies of ADDCs have identified the need to analyse them from the angle of their economic...... their performance....

  10. Discovery of a benzofuran derivative (MBPTA) as a novel ROCK inhibitor that protects against MPP⁺-induced oxidative stress and cell death in SH-SY5Y cells.

    Science.gov (United States)

    Chong, Cheong-Meng; Shen, Mingyun; Zhou, Zhong-Yan; Pan, Peichen; Hoi, Pui-Man; Li, Shang; Liang, Wang; Ai, Nana; Zhang, Lun-Qing; Li, Cheuk-Wing; Yu, Huidong; Hou, Tingjun; Lee, Simon Ming-Yuen

    2014-09-01

    Parkinson disease (PD) is a neurodegenerative disease with multifactorial etiopathogenesis. The discovery of drug candidates that act on new targets of PD is required to address the varied pathological aspects and modify the disease process. In this study, a small compound, 2-(5-methyl-1-benzofuran-3-yl)-N-(5-propylsulfanyl-1,3,4-thiadiazol-2-yl) acetamide (MBPTA) was identified as a novel Rho-associated protein kinase inhibitor with significant protective effects against 1-methyl-4-phenylpyridinium ion (MPP(+))-induced damage in SH-SY5Y neuroblastoma cells. Further investigation showed that pretreatment of SH-SY5Y cells with MBPTA significantly suppressed MPP(+)-induced cell death by restoring abnormal changes in nuclear morphology, mitochondrial membrane potential, and numerous apoptotic regulators. MBPTA was able to inhibit MPP(+)-induced reactive oxygen species (ROS)/NO generation, overexpression of inducible NO synthase, and activation of NF-κB, indicating the critical role of MBPTA in regulating ROS/NO-mediated cell death. Furthermore, MBPTA was shown to activate PI3K/Akt survival signaling, and its cytoprotective effect was abolished by PI3K and Akt inhibitors. The structural comparison of a series of MBPTA analogs revealed that the benzofuran moiety probably plays a crucial role in the anti-oxidative stress action. Taken together, these results suggest that MBPTA protects against MPP(+)-induced apoptosis in a neuronal cell line through inhibition of ROS/NO generation and activation of PI3K/Akt signaling. Copyright © 2014. Published by Elsevier Inc.

  11. Service discovery at home

    NARCIS (Netherlands)

    Sundramoorthy, V.; Scholten, Johan; Jansen, P.G.; Hartel, Pieter H.

    2003-01-01

    Service discovery is a fairly new field that kicked off since the advent of ubiquitous computing and has been found essential in the making of intelligent networks by implementing automated discovery and remote control between devices. This paper provides an overview and comparison of several

  12. Service Discovery At Home

    NARCIS (Netherlands)

    Sundramoorthy, V.; Scholten, Johan; Jansen, P.G.; Hartel, Pieter H.

    Service discovery is a fady new field that kicked off since the advent of ubiquitous computing and has been found essential in the making of intelligent networks by implementing automated discovery and remote control between deviies. This paper provides an ovewiew and comparison of several prominent

  13. Learning from the failures of drug discovery in B-cell non-Hodgkin lymphomas and perspectives for the future: chronic lymphocytic leukemia and diffuse large B-cell lymphoma as two ends of a spectrum in drug development.

    Science.gov (United States)

    Kubuschok, Boris; Trepel, Martin

    2017-07-01

    Despite substantial recent advances, there is still an unmet need for better therapies in B-cell non Hodgkin lymphomas (B-NHL), especially in relapsed or refractory disease. Many novel targeted drugs have been developed based on a better molecular understanding of B-NHL. Areas covered: This article focuses on chronic lymphocytic leukemia (CLL) as a representative for indolent lymphomas and paradigmatic for the tremendous progress in treating B-NHL on the one hand and diffuse large B-cell lymphoma (DLBCL) as a representative for aggressive lymphomas and paradigmatic for many unsolved problems in lymphoma treatment or the other hand. We highlight salient points in current therapies targeting genetic, epigenetic, immunological and microenvironmental alterations. Possible reasons for drug failure in clinical trials like tumor heterogeneity, clonal evolution and drug resistance mechanisms are discussed. Based thereon, some perspectives for further drug discovery are given. Expert opinion: In view of the pathogenetic complexity of lymphomas, therapies targeting exclusively a single alteration may fail because resistance mechanisms are present either initially or evolve during treatment. Therefore, future therapies in B-NHL may have to target the greatest possible number of genetic, immunological or epigenetic alterations still allowing tolerability and to monitor these alterations during therapy.

  14. "Eureka, Eureka!" Discoveries in Science

    Science.gov (United States)

    Agarwal, Pankaj

    2011-01-01

    Accidental discoveries have been of significant value in the progress of science. Although accidental discoveries are more common in pharmacology and chemistry, other branches of science have also benefited from such discoveries. While most discoveries are the result of persistent research, famous accidental discoveries provide a fascinating…

  15. The Greatest Mathematical Discovery?

    Energy Technology Data Exchange (ETDEWEB)

    Bailey, David H.; Borwein, Jonathan M.

    2010-05-12

    What mathematical discovery more than 1500 years ago: (1) Is one of the greatest, if not the greatest, single discovery in the field of mathematics? (2) Involved three subtle ideas that eluded the greatest minds of antiquity, even geniuses such as Archimedes? (3) Was fiercely resisted in Europe for hundreds of years after its discovery? (4) Even today, in historical treatments of mathematics, is often dismissed with scant mention, or else is ascribed to the wrong source? Answer: Our modern system of positional decimal notation with zero, together with the basic arithmetic computational schemes, which were discovered in India about 500 CE.

  16. Fateful discovery almost forgotten

    CERN Multimedia

    1989-01-01

    "The discovery of the fission of uranium exactly half a century ago is at risk of passing unremarked because of the general ambivalence towards the consequences of this development. Can that be wise?" (4 pages)

  17. On the antiproton discovery

    International Nuclear Information System (INIS)

    Piccioni, O.

    1989-01-01

    The author of this article describes his own role in the discovery of the antiproton. Although Segre and Chamberlain received the Nobel Prize in 1959 for its discovery, the author claims that their experimental method was his idea which he communicated to them informally in December 1954. He describes how his application for citizenship (he was Italian), and other scientists' manipulation, prevented him from being at Berkeley to work on the experiment himself. (UK)

  18. Discovery-based strategies for studying platelet function.

    Science.gov (United States)

    Flaumenhaft, R; Dilks, J R

    2008-04-01

    The platelet is an anucleate cell, complicating efforts to study platelet function by traditional genetic means. Discovery-based strategies have lead to the identification of pharmacological agents capable of targeting specific proteins critical for platelet activation. This review will address the evolution of discovery-based strategies to identify probes that are at once useful reagents for studying platelet activation and effective therapeutics.

  19. Discovery of Fullerenes

    Indian Academy of Sciences (India)

    ... Journal of Science Education; Volume 2; Issue 1. Discovery of Fullerenes Giving a New Shape to Carbon Chemistry. Rathna Ananthaiah. Research News Volume 2 Issue 1 January 1997 pp 68-73. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/002/01/0068-0073 ...

  20. Landmark Discoveries in Neurosciences

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 17; Issue 11. Landmark Discoveries in Neurosciences. Niranjan Kambi Neeraj Jain. General Article Volume 17 Issue 11 November 2012 pp 1054-1064. Fulltext. Click here to view fulltext PDF. Permanent link:

  1. The discovery of fission

    International Nuclear Information System (INIS)

    McKay, H.A.C.

    1978-01-01

    In this article by the retired head of the Separation Processes Group of the Chemistry Division, Atomic Energy Research Establishment, Harwell, U.K., the author recalls what he terms 'an exciting drama, the unravelling of the nature of the atomic nucleus' in the years before the Second World War, including the discovery of fission. 12 references. (author)

  2. Antibacterial drug discovery in the resistance era.

    Science.gov (United States)

    Brown, Eric D; Wright, Gerard D

    2016-01-21

    The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era.

  3. On reliable discovery of molecular signatures

    Directory of Open Access Journals (Sweden)

    Björkegren Johan

    2009-01-01

    Full Text Available Abstract Background Molecular signatures are sets of genes, proteins, genetic variants or other variables that can be used as markers for a particular phenotype. Reliable signature discovery methods could yield valuable insight into cell biology and mechanisms of human disease. However, it is currently not clear how to control error rates such as the false discovery rate (FDR in signature discovery. Moreover, signatures for cancer gene expression have been shown to be unstable, that is, difficult to replicate in independent studies, casting doubts on their reliability. Results We demonstrate that with modern prediction methods, signatures that yield accurate predictions may still have a high FDR. Further, we show that even signatures with low FDR may fail to replicate in independent studies due to limited statistical power. Thus, neither stability nor predictive accuracy are relevant when FDR control is the primary goal. We therefore develop a general statistical hypothesis testing framework that for the first time provides FDR control for signature discovery. Our method is demonstrated to be correct in simulation studies. When applied to five cancer data sets, the method was able to discover molecular signatures with 5% FDR in three cases, while two data sets yielded no significant findings. Conclusion Our approach enables reliable discovery of molecular signatures from genome-wide data with current sample sizes. The statistical framework developed herein is potentially applicable to a wide range of prediction problems in bioinformatics.

  4. The neutron discovery

    International Nuclear Information System (INIS)

    Six, J.

    1987-01-01

    The neutron: who had first the idea, who discovered it, who established its main properties. To these apparently simple questions, multiple answers exist. The progressive discovery of the neutron is a marvellous illustration of some characteristics of the scientific research, where the unforeseen may be combined with the expected. This discovery is replaced in the context of the 1930's scientific effervescence that succeeded the revolutionary introduction of quantum mechanics. This book describes the works of Bothe, the Joliot-Curie and Chadwick which led to the neutron in an unexpected way. A historical analysis allows to give a new interpretation on the hypothesis suggested by the Joliot-Curie. Some texts of these days will help the reader to revive this fascinating story [fr

  5. Discovery of charm

    Energy Technology Data Exchange (ETDEWEB)

    Goldhaber, G.

    1984-11-01

    In my talk I will cover the period 1973 to 1976 which saw the discoveries of the J/psi and psi' resonances and most of the Psion spectroscopy, the tau lepton and the D/sup 0/,D/sup +/ charmed meson doublet. Occasionally I will refer briefly to more recent results. Since this conference is on the history of the weak-interactions I will deal primarily with the properties of naked charm and in particular the weakly decaying doublet of charmed mesons. Most of the discoveries I will mention were made with the SLAC-LBL Magnetic Detector or MARK I which we operated at SPEAR from 1973 to 1976. 27 references.

  6. Atlas of Astronomical Discoveries

    CERN Document Server

    Schilling, Govert

    2011-01-01

    Four hundred years ago in Middelburg, in the Netherlands, the telescope was invented. The invention unleashed a revolution in the exploration of the universe. Galileo Galilei discovered mountains on the Moon, spots on the Sun, and moons around Jupiter. Christiaan Huygens saw details on Mars and rings around Saturn. William Herschel discovered a new planet and mapped binary stars and nebulae. Other astronomers determined the distances to stars, unraveled the structure of the Milky Way, and discovered the expansion of the universe. And, as telescopes became bigger and more powerful, astronomers delved deeper into the mysteries of the cosmos. In his Atlas of Astronomical Discoveries, astronomy journalist Govert Schilling tells the story of 400 years of telescopic astronomy. He looks at the 100 most important discoveries since the invention of the telescope. In his direct and accessible style, the author takes his readers on an exciting journey encompassing the highlights of four centuries of astronomy. Spectacul...

  7. Discoveries of isotopes by fission

    Indian Academy of Sciences (India)

    also contributed to the discovery of new isotopes. More recently, most of the very neutron- rich isotopes have been discovered by projectile fission. After a brief summary of the discovery of fission process itself, these production mechanisms will be discussed. The paper concludes with an outlook on future discoveries of ...

  8. Recent Discoveries and Bible Translation.

    Science.gov (United States)

    Harrelson, Walter

    1990-01-01

    Discusses recent discoveries for "Bible" translation with a focus on the "Dead Sea Scrolls." Examines recent discoveries that provide direct support for alternative reading of biblical passages and those discoveries that have contributed additional insight to knowledge of cultural practices, especially legal and religious…

  9. Fateful discovery almost forgotten

    International Nuclear Information System (INIS)

    Anon.

    1989-01-01

    The paper reviews the discovery of the fission of uranium, which took place fifty years ago. A description is given of the work of Meitner and Frisch in interpreting the Fermi data on the bombardment of uranium nuclei with neutrons, i.e. proposing fission. The historical events associated with the development and exploitation of uranium fission are described, including the Manhattan Project, Hiroshima and Nagasaki, Shippingport, and Chernobyl. (U.K.)

  10. Discovery as a process

    Energy Technology Data Exchange (ETDEWEB)

    Loehle, C.

    1994-05-01

    The three great myths, which form a sort of triumvirate of misunderstanding, are the Eureka! myth, the hypothesis myth, and the measurement myth. These myths are prevalent among scientists as well as among observers of science. The Eureka! myth asserts that discovery occurs as a flash of insight, and as such is not subject to investigation. This leads to the perception that discovery or deriving a hypothesis is a moment or event rather than a process. Events are singular and not subject to description. The hypothesis myth asserts that proper science is motivated by testing hypotheses, and that if something is not experimentally testable then it is not scientific. This myth leads to absurd posturing by some workers conducting empirical descriptive studies, who dress up their study with a ``hypothesis`` to obtain funding or get it published. Methods papers are often rejected because they do not address a specific scientific problem. The fact is that many of the great breakthroughs in silence involve methods and not hypotheses or arise from largely descriptive studies. Those captured by this myth also try to block funding for those developing methods. The third myth is the measurement myth, which holds that determining what to measure is straightforward, so one doesn`t need a lot of introspection to do science. As one ecologist put it to me ``Don`t give me any of that philosophy junk, just let me out in the field. I know what to measure.`` These myths lead to difficulties for scientists who must face peer review to obtain funding and to get published. These myths also inhibit the study of science as a process. Finally, these myths inhibit creativity and suppress innovation. In this paper I first explore these myths in more detail and then propose a new model of discovery that opens the supposedly miraculous process of discovery to doser scrutiny.

  11. Discovery concepts for Mars

    Science.gov (United States)

    Luhmann, J. G.; Russell, C. T.; Brace, L. H.; Nagy, A. F.; Jakosky, B. M.; Barth, C. A.; Waite, J. H.

    1992-01-01

    Two focused Mars missions that would fit within the guidelines for the proposed Discovery line are discussed. The first mission would deal with the issue of the escape of the atmosphere (Mars') to space. A complete understanding of this topic is crucial to deciphering the evolution of the atmosphere, climate change, and volatile inventories. The second mission concerns the investigation of remanent magnetization of the crust and its relationship to the ionosphere and the atmosphere.

  12. Discovery and structure-activity relationship of novel 4-hydroxy-thiazolidine-2-thione derivatives as tumor cell specific pyruvate kinase M2 activators.

    Science.gov (United States)

    Li, Ridong; Ning, Xianling; Zhou, Shuo; Lin, Zhiqiang; Wu, Xingyu; Chen, Hong; Bai, Xinyu; Wang, Xin; Ge, Zemei; Li, Runtao; Yin, Yuxin

    2018-01-01

    Pyruvate kinase M2 isoform (PKM2) is a crucial protein responsible for aerobic glycolysis of cancer cells. Activation of PKM2 may alter aberrant metabolism in cancer cells. In this study, we discovered a 4-hydroxy-thiazolidine-2-thione compound 2 as a novel PKM2 activator from a random screening of an in-house compound library. Then a series of novel 4-hydroxy-thiazolidine-2-thione derivatives were designed and synthesized for screening as potent PKM2 activators. Among these, some compounds showed higher PKM2 activation activity than lead compound 2 and also exhibited significant anti-proliferative activities on human cancer cell lines at nanomolar concentration. The compound 5w was identified as the most potent antitumor agent, which showed excellent anti-proliferative effects with IC 50 values from 0.46 μM to 0.81 μM against H1299, HCT116, Hela and PC3 cell lines. 5w also showed less cytotoxicity in non-tumor cell line HELF compared with cancer cells. In addition, Preliminary pharmacological studies revealed that 5w arrests the cell cycle at the G2/M phase in HCT116 cell line. The best PKM2 activation by compound 5t was rationalized through docking studies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  13. Discovery, Synthesis, and Evaluation of 2,4-Diaminoquinazolines as a Novel Class of Pancreatic β-Cell-Protective Agents against Endoplasmic Reticulum (ER) Stress.

    Science.gov (United States)

    Duan, Hongliang; Lee, Jae Wook; Moon, Sung Won; Arora, Daleep; Li, Yu; Lim, Hui-Ying; Wang, Weidong

    2016-09-08

    Pancreatic insulin-producing β-cell dysfunction and death plays central roles in the onset and progression of both type 1 and type 2 diabetes. Current antidiabetic drugs cannot halt the ongoing progression of β-cell dysfunction and death. In diabetes, a major cause for the decline in β-cell function and survival is endoplasmic reticulum (ER) stress. Here, we identified quinazoline derivatives as a novel class of β-cell protective agents against ER stress-induced dysfunction and death. A series of quinazoline derivatives were synthesized from dichloroquiazoline utilizing a sequence of nucleophilic reactions. Through SAR optimization, 2,4-diaminoquinazoline compound 9c markedly protects β-cells against ER stress-induced dysfunction and death with 80% maximum rescue activity and an EC50 value of 0.56 μM. Importantly, 9c restores the ER stress-impaired glucose-stimulated insulin secretion response and survival in primary human islet β-cells. We showed that 9c protects β-cells by alleviating ER stress through the suppression of the induction of key genes of the unfolded protein response and apoptosis.

  14. Discovery of novel hedgehog antagonists from cell-based screening: Isosteric modification of p38 bisamides as potent inhibitors of SMO.

    Science.gov (United States)

    Yang, Bin; Hird, Alexander W; Russell, Daniel John; Fauber, Benjamin P; Dakin, Les A; Zheng, Xiaolan; Su, Qibin; Godin, Robert; Brassil, Patrick; Devereaux, Erik; Janetka, James W

    2012-07-15

    Cell-based subset screening of compounds using a Gli transcription factor reporter cell assay and shh stimulated cell differentiation assay identified a series of bisamide compounds as hedgehog pathway inhibitors with good potency. Using a ligand-based optimization strategy, heteroaryl groups were utilized as conformationally restricted amide isosteres replacing one of the amides which significantly increased their potency against SMO and the hedgehog pathway while decreasing activity against p38α kinase. We report herein the identification of advanced lead compounds such as imidazole 11c and 11f encompassing good p38α selectivity, low nanomolar potency in both cell assays, excellent physiochemical properties and in vivo pharmacokinetics. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. “Splicing up” drug discovery. Cell-Based Expression and Screening of Genetically-Encoded Libraries of Backbone Cyclized Polypeptides

    Science.gov (United States)

    Sancheti, Harshkumar; Camarero, Julio A.

    2012-01-01

    The present paper reviews the use of protein splicing for the biosynthesis of backbone cyclic polypeptides. This general method allows the in vivo and in vitro biosynthesis of cyclic polypeptides using recombinant DNA expression techniques. Biosynthetic access to backbone cyclic peptides opens the possibility to generate cell-based combinatorial libraries that can be screened inside living cells for their ability to attenuate or inhibit cellular processes thus providing a new way for finding therapeutic agents. PMID:19628015

  16. Re-education begins at home: an overview of the discovery of in vivo-active small molecule modulators of endogenous stem cells.

    Science.gov (United States)

    Um, JungIn; Lee, Ji-Hyung; Jung, Da-Woon; Williams, Darren R

    2018-04-01

    Degenerative diseases, such as Alzheimer's disease, heart disease and arthritis cause great suffering and are major socioeconomic burdens. An attractive treatment approach is stem cell transplantation to regenerate damaged or destroyed tissues. However, this can be problematic. For example, donor cells may not functionally integrate into the host tissue. An alternative methodology is to deliver bioactive agents, such as small molecules, directly into the diseased tissue to enhance the regenerative potential of endogenous stem cells. Areas covered: In this review, the authors discuss the necessity of developing these small molecules to treat degenerative diseases and survey progress in their application as therapeutics. They describe both the successes and caveats of developing small molecules that target endogenous stem cells to induce tissue regeneration. This article is based on literature searches which encompass databases for biomedical research and clinical trials. These small molecules are also categorized per their target disease and mechanism of action. Expert opinion: The development of small molecules targeting endogenous stem cells is a high-profile research area. Some compounds have made the successful transition to the clinic. Novel approaches, such as modulating the stem cell niche or targeted delivery to disease sites, should increase the likelihood of future successes in this field.

  17. Automated Supernova Discovery (Abstract)

    Science.gov (United States)

    Post, R. S.

    2015-12-01

    (Abstract only) We are developing a system of robotic telescopes for automatic recognition of Supernovas as well as other transient events in collaboration with the Puckett Supernova Search Team. At the SAS2014 meeting, the discovery program, SNARE, was first described. Since then, it has been continuously improved to handle searches under a wide variety of atmospheric conditions. Currently, two telescopes are used to build a reference library while searching for PSN with a partial library. Since data is taken every night without clouds, we must deal with varying atmospheric and high background illumination from the moon. Software is configured to identify a PSN, reshoot for verification with options to change the run plan to acquire photometric or spectrographic data. The telescopes are 24-inch CDK24, with Alta U230 cameras, one in CA and one in NM. Images and run plans are sent between sites so the CA telescope can search while photometry is done in NM. Our goal is to find bright PSNs with magnitude 17.5 or less which is the limit of our planned spectroscopy. We present results from our first automated PSN discoveries and plans for PSN data acquisition.

  18. Aggregation of red cells in disease: some deductions and speculations based on results of "ARC" experiment on the space shuttle "Discovery" STS 51-C.

    Science.gov (United States)

    Dintenfass, L

    1988-01-01

    Experiment on STS 51-C in January 1985, carried out on blood samples obtained from patients with heart disease, diabetes, hyperlipidaemia and cancer showed that, under zero gravity, the morphology of red cell aggregates aggregates was normal, in contradistinction to the parallel and simultaneous observations under 1 g, which showed large and unorientated clumps of red cells. As such clumps could be considered of disadvantage in the microcirculation and tissue perfusion, the zero gravity observations were significant in a number of ways. In particular, a preliminary deduction (subject to further zero g experimentation) was that cell-cell interaction and adhesion are affected by zero gravity, and that most likely the microarchitecture of the cell membrane is modified; and that probably the receptors, their position and/or activity, are affected by zero gravity. Of particular interest could be a possible change in the properties of the discrete surface areas which respond preferentially to specific macromolecules (or ligands). There is a dissonance between these in vitro results and theoretical deductions on flow in the microcirculations by Oka, and as well of deductions on space sickness by Dintenfass, both assuming a disabling effect of zero g on the in vivo microcirculation. This dissonance should be explored, as effect of zero g might be different on blood flow in vivo and in vitro. However, the data available from the in vitro experiment suggest that studies in immunology and oncology might be enriched by zero gravity findings; and that studies under zero gravity might open a new avenue of research in these important fields.

  19. Structure-based discovery of NANOG variant with enhanced properties to promote self-renewal and reprogramming of pluripotent stem cells.

    Science.gov (United States)

    Hayashi, Yohei; Caboni, Laura; Das, Debanu; Yumoto, Fumiaki; Clayton, Thomas; Deller, Marc C; Nguyen, Phuong; Farr, Carol L; Chiu, Hsiu-Ju; Miller, Mitchell D; Elsliger, Marc-André; Deacon, Ashley M; Godzik, Adam; Lesley, Scott A; Tomoda, Kiichiro; Conklin, Bruce R; Wilson, Ian A; Yamanaka, Shinya; Fletterick, Robert J

    2015-04-14

    NANOG (from Irish mythology Tír na nÓg) transcription factor plays a central role in maintaining pluripotency, cooperating with OCT4 (also known as POU5F1 or OCT3/4), SOX2, and other pluripotency factors. Although the physiological roles of the NANOG protein have been extensively explored, biochemical and biophysical properties in relation to its structural analysis are poorly understood. Here we determined the crystal structure of the human NANOG homeodomain (hNANOG HD) bound to an OCT4 promoter DNA, which revealed amino acid residues involved in DNA recognition that are likely to be functionally important. We generated a series of hNANOG HD alanine substitution mutants based on the protein-DNA interaction and evolutionary conservation and determined their biological activities. Some mutant proteins were less stable, resulting in loss or decreased affinity for DNA binding. Overexpression of the orthologous mouse NANOG (mNANOG) mutants failed to maintain self-renewal of mouse embryonic stem cells without leukemia inhibitory factor. These results suggest that these residues are critical for NANOG transcriptional activity. Interestingly, one mutant, hNANOG L122A, conversely enhanced protein stability and DNA-binding affinity. The mNANOG L122A, when overexpressed in mouse embryonic stem cells, maintained their expression of self-renewal markers even when retinoic acid was added to forcibly drive differentiation. When overexpressed in epiblast stem cells or human induced pluripotent stem cells, the L122A mutants enhanced reprogramming into ground-state pluripotency. These findings demonstrate that structural and biophysical information on key transcriptional factors provides insights into the manipulation of stem cell behaviors and a framework for rational protein engineering.

  20. Integrative bioinformatics and proteomics-based discovery of an eEF2K inhibitor (cefatrizine) with ER stress modulation in breast cancer cells.

    Science.gov (United States)

    Yao, Zhiqiang; Li, Juntang; Liu, Zhongyu; Zheng, Lu; Fan, Naijun; Zhang, Ying; Jia, Nan; Lv, Jingjing; Liu, Ningning; Zhu, Xiaoshan; Du, Jiangbo; Lv, Ci; Xie, Feng; Liu, Yigang; Wang, Xingke; Fei, Zhou; Gao, Chunfang

    2016-03-01

    Eukaryotic elongation factor-2 kinase (eEF2K), a unique calcium/calmodulin-dependent protein kinase, is well known to regulate apoptosis, autophagy and ER stress in many types of human cancers. Therefore, eEF2K would be regarded as a promising therapeutic target; however, the eEF2K-regulated mechanism and its targeted inhibitor still remain to be discovered in cancer. Herein, we constructed a protein-protein interaction (PPI) network of eEF2K and achieved an eEF2K-regulated ER stress subnetwork by bioinformatics prediction. Then, we found that the differential protein expressions involved in ER stress in the context of si-eEF2K-treated MCF-7 and MDA-MB-436 cells by iTRAQ-based analyses, respectively. Integrated into these aforementioned results, we constructed a core eEF2K-regulated ER stress subnetwork in breast cancer cells. Subsequently, we screened a series of candidate compounds targeting eEF2K and discovered a novel eEF2K inhibitor (cefatrizine) with an anti-proliferative activity toward breast cancer cells. Moreover, we found that cefatrizine induced ER stress in both MCF-7 and MDA-MB-436 cells. Interestingly, we demonstrated that the mechanism of cefatrizine-induced ER stress was in good agreement with our bioinformatics and proteomics-based results. In conclusion, these results demonstrate that a novel eEF2K inhibitor (cefatrizine) induces ER stress in breast cancer cells by integrating bioinformatics prediction, proteomics analyses and experimental validation, which would provide a clue for exploring more mechanisms of eEF2K and its targeted inhibitors in cancer therapy.

  1. Natural product discovery: past, present, and future.

    Science.gov (United States)

    Katz, Leonard; Baltz, Richard H

    2016-03-01

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

  2. Discovery of New Aminosubstituted Pyrrolopyrimidines with Antiproliferative Activity Against Breast Cancer Cells and Investigation of their Effect Towards the PI3Kα Enzyme.

    Science.gov (United States)

    Daniilides, Konstantinos; Lougiakis, Nikolaos; Evangelidis, Thomas; Kostakis, Ioannis K; Pouli, Nicole; Marakos, Panagiotis; Mikros, Emmanuel; Skaltsounis, Alexios-Leandros; Bach, Stephane; Baratte, Blandine; Ruchaud, Sandrine; Karamani, Valia; Papafotika, Alexandra; Christoforidis, Savvas; Argyros, Orestis; Kouvari, Eva; Tamvakopoulos, Constantin

    2017-01-01

    A series of novel 2,4-diaminosubstituted pyrrolo[3,2-d]pyrimidines was synthesized together with their corresponding 7-phenyl or 7-isopropyl counterparts. Among the target derivatives, the 7-substituted analogues exhibited interesting cytotoxic activity against a panel of PI3Kα related human breast cancer cell lines, namely MCF7, T47D, MDA-MB-231 and HCC1954. Selected compounds were tested for potential PI3Kα inhibitory activity as well as for their cytotoxic effect in prostate cancer cell lines (DU145 and PC3). Derivatives bearing a specific substitution pattern consisting of 7-phenyl as well as a 2-(4- aminocyclohexylamino) moiety (16c, 16f) display kinase inhibitory activity, elucidated on the basis of molecular simulation studies, which revealed their interaction with the DFG motif of the kinase. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Discovery of a novel B-cell lymphoma 6 (BCL6)-corepressor interaction inhibitor by utilizing structure-based drug design.

    Science.gov (United States)

    Yasui, Takeshi; Yamamoto, Takeshi; Sakai, Nozomu; Asano, Kouhei; Takai, Takafumi; Yoshitomi, Yayoi; Davis, Melinda; Takagi, Terufumi; Sakamoto, Kotaro; Sogabe, Satoshi; Kamada, Yusuke; Lane, Weston; Snell, Gyorgy; Iwata, Masashi; Goto, Masayuki; Inooka, Hiroshi; Sakamoto, Jun-Ichi; Nakada, Yoshihisa; Imaeda, Yasuhiro

    2017-09-01

    B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein-protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6-corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer. Starting from high-throughput screening hits 1a and 2a, we identified a novel BCL6-corepressor interaction inhibitor 8c (cell-free enzyme-linked immunosorbent assay [ELISA] IC 50 =0.10µM, cell-based mammalian two-hybrid [M2H] assay IC 50 =0.72µM) by utilizing structure-based drug design (SBDD) based on an X-ray crystal structure of 1a bound to BCL6. Compound 8c also showed a good pharmacokinetic profile, which was acceptable for both in vitro and in vivo studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Discovery, SAR, and Radiolabeling of Halogenated Benzimidazole Carboxamide Antagonists as Useful Tools for (alpha)4(beta)1 Integrin Expressed on T- and B-cell Lymphomas

    Energy Technology Data Exchange (ETDEWEB)

    Carpenter, R D; Natarajan, A; Lau, E Y; Andrei, M; Solano, D M; Lightstone, F C; DeNardo, S J; Lam, K S; Kurth, M J

    2010-02-08

    The cell surface receptor {alpha}{sub 4}{beta}{sub 1} integrin is an attractive yet poorly understood target for selective diagnosis and treatment of T- and B-cell lymphomas. This report focuses on the rapid microwave preparation of medicinally pertinent benzimidazole heterocycles, structure-activity relationships (SAR) of novel halobenzimidazole carboxamide antagonists 3-6, and preliminary biological evaluation of radioiodinated agents 7, 8, and 18. The I-125 derivative 18 had good tumor uptake (12 {+-} 1% ID/g at 24 h; 4.5 {+-} 1% ID/g at 48 h) and tumor:kidney ratio ({approx}4:1 at 24 h; 2.5:1 at 48 h) in xenograft murine models of B-cell lymphoma. Molecular homology models of {alpha}{sub 4}{beta}{sub 1} integrin have predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. These high affinity ({approx} pM binding) halogenated ligands are attractive tools for medicinal and biological use; the fluoro and iodo derivatives are potential radiodiagnostic ({sup 18}F) or radiotherapeutic ({sup 131}I) agents, whereas the chloro and bromo analogues could provide structural insight into integrin-ligand interactions through photoaffinity cross-linking/mass spectroscopy experiments, as well as co-crystallization X-ray studies.

  5. Advanced cell culture technology for essential oil production and micro array studies leading to discovery of genes for fragrance compounds in Michelia alba (Cempaka Putih)

    International Nuclear Information System (INIS)

    Rusli Ibrahim; Norazlina Nordin; Edrina Azlan

    2006-01-01

    Michelia spp. is known to produce high value essential oil for perfumery industry. The essence of world's most expensive perfumes, such as JOY and Jadore, is based on the oil of Michelia spp. One major problem anticipated in this approach, based on our early experiments, is limited amount of fragrance produced in cell cultures. The appropriate strategy is to superimpose DNA micro array studies on top of the cell culture project. The study covers natural flower development phases that led to the identification of genes or sets of genes that regulate the production of the fragrance. Seven developmental stages of Michelia alba flower namely Stage 5 to 11 were investigated for their volatile constituents. The essential oil was isolated by Simultaneous Distillation Extraction technique and the oil obtained was subjected to GC-MS analysis. In total, seventy-seven compounds representing 93-98% of the overall volatiles compounds were identified on the basis of mass spectra and retention indices. Thirty-three of these compounds belonged to isoprenoids group which comprised 30-50% of the total volatile compounds whereas the remaining belonged to fatty acid derivatives, benzenoid, phenylpropanoid and other hydrocarbon compounds. Studies were conducted to optimize culture parameters for scaling-up the production of callus, suspension cell cultures and somatic and product accumulation of essential oils using bioreactor technology. (Author)

  6. Representation Discovery using Harmonic Analysis

    CERN Document Server

    Mahadevan, Sridhar

    2008-01-01

    Representations are at the heart of artificial intelligence (AI). This book is devoted to the problem of representation discovery: how can an intelligent system construct representations from its experience? Representation discovery re-parameterizes the state space - prior to the application of information retrieval, machine learning, or optimization techniques - facilitating later inference processes by constructing new task-specific bases adapted to the state space geometry. This book presents a general approach to representation discovery using the framework of harmonic analysis, in particu

  7. Discovery of neptunium

    International Nuclear Information System (INIS)

    Abelson, P.H.

    1990-01-01

    A number of distinguished scientists irradiated uranium with neutrons during 1934-1938. All were knowledgeable about the periodic table. They observed a number of beta-emitting activities that seemed to be from transuranic elements. They assumed that elements 93 and 94 would have chemical properties similar to rhenium and osmium respectively. In consequence discovery of fission and neptunium was delayed. After fission was finally demonstrated, a new search for element 93 was initiated by McMillan. He showed that when thin films of uranium are exposed to neutrons, high energy fission products leave the film - 23 minute and 2.3 day activities. The 23 minute activity was known to be an isotope of uranium. Chemistry performed by Abelson in May 1940 produced conclusive evidence that the 2.3 day activity was from the transuranic element 93 later named neptunium

  8. Hippocampus discovery First steps

    Directory of Open Access Journals (Sweden)

    Eliasz Engelhardt

    Full Text Available The first steps of the discovery, and the main discoverers, of the hippocampus are outlined. Arantius was the first to describe a structure he named "hippocampus" or "white silkworm". Despite numerous controversies and alternate designations, the term hippocampus has prevailed until this day as the most widely used term. Duvernoy provided an illustration of the hippocampus and surrounding structures, considered the first by most authors, which appeared more than one and a half century after Arantius' description. Some authors have identified other drawings and texts which they claim predate Duvernoy's depiction, in studies by Vesalius, Varolio, Willis, and Eustachio, albeit unconvincingly. Considering the definition of the hippocampal formation as comprising the hippocampus proper, dentate gyrus and subiculum, Arantius and Duvernoy apparently described the gross anatomy of this complex. The pioneering studies of Arantius and Duvernoy revealed a relatively small hidden formation that would become one of the most valued brain structures.

  9. Discovery of 2',4'-dimethoxychalcone as a Hsp90 inhibitor and its effect on iressa-resistant non-small cell lung cancer (NSCLC).

    Science.gov (United States)

    Seo, Young Ho

    2015-10-01

    Heat shock protein 90 (Hsp90) is a ATP dependent molecular chaperone and has emerged as an attractive therapeutic target in the war on cancer due to its role in regulating maturation and stabilization of numerous oncogenic proteins. In this study, we discovered that 2',4'-dimethoxychalcone (1b) disrupted Hsp90 chaperoning function and inhibited the growth of iressa-resistant non-small cell lung cancer (NSCLC, H1975). The result suggested that 2',4'-dimethoxychalcone (1b) could serve as a potential therapeutic lead to circumvent the drug resistance acquired by EGFR mutation and Met amplification.

  10. Final report on LDRD project : elucidating performance of proton-exchange-membrane fuel cells via computational modeling with experimental discovery and validation.

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chao Yang (Pennsylvania State University, University Park, PA); Pasaogullari, Ugur (Pennsylvania State University, University Park, PA); Noble, David R.; Siegel, Nathan P.; Hickner, Michael A.; Chen, Ken Shuang

    2006-11-01

    In this report, we document the accomplishments in our Laboratory Directed Research and Development project in which we employed a technical approach of combining experiments with computational modeling and analyses to elucidate the performance of hydrogen-fed proton exchange membrane fuel cells (PEMFCs). In the first part of this report, we document our focused efforts on understanding water transport in and removal from a hydrogen-fed PEMFC. Using a transparent cell, we directly visualized the evolution and growth of liquid-water droplets at the gas diffusion layer (GDL)/gas flow channel (GFC) interface. We further carried out a detailed experimental study to observe, via direct visualization, the formation, growth, and instability of water droplets at the GDL/GFC interface using a specially-designed apparatus, which simulates the cathode operation of a PEMFC. We developed a simplified model, based on our experimental observation and data, for predicting the onset of water-droplet instability at the GDL/GFC interface. Using a state-of-the-art neutron imaging instrument available at NIST (National Institute of Standard and Technology), we probed liquid-water distribution inside an operating PEMFC under a variety of operating conditions and investigated effects of evaporation due to local heating by waste heat on water removal. Moreover, we developed computational models for analyzing the effects of micro-porous layer on net water transport across the membrane and GDL anisotropy on the temperature and water distributions in the cathode of a PEMFC. We further developed a two-phase model based on the multiphase mixture formulation for predicting the liquid saturation, pressure drop, and flow maldistribution across the PEMFC cathode channels. In the second part of this report, we document our efforts on modeling the electrochemical performance of PEMFCs. We developed a constitutive model for predicting proton conductivity in polymer electrolyte membranes and compared

  11. Towards 3rd generation organic tandem solar cells with 20% efficiency: Accelerated discovery and rational design of carbon-based photovoltaic materials through massive distributed volunteer computing

    Energy Technology Data Exchange (ETDEWEB)

    Aspuru-Guzik, Alan [Harvard Univ., Cambridge, MA (United States). Dept. of Chemistry and Chemical Biology

    2016-11-04

    Clean, affordable, and renewable energy sources are urgently needed to satisfy the 10s of terawatts (TW) energy need of human beings. Solar cells are one promising choice to replace traditional energy sources. Our broad efforts have expanded the knowledge of possible donor materials for organic photovoltaics, while increasing access of our results to the world through the Clean Energy Project database (www.molecularspace.org). Machine learning techniques, including Gaussian Processes have been used to calibrate frontier molecular orbital energies, and OPV bulk properties (open-circuit voltage, percent conversion efficiencies, and short-circuit current). This grant allowed us to delve into the solid-state properties of OPVs (charge-carrier dynamics). One particular example allowed us to predict charge-carrier dynamics and make predictions about future hydrogen-bonded materials.

  12. Discoveries of isotopes by fission

    Indian Academy of Sciences (India)

    2015-08-28

    Aug 28, 2015 ... Of the about 3000 isotopes presently known, about 20% have been discovered in fission. The history of fission as it relates to the discovery of isotopes as well as the various reaction mechanisms leading to isotope discoveries involving fission are presented.

  13. Materials discovery through crystal growth

    Science.gov (United States)

    zur Loye, Hans-Conrad

    2016-04-01

    The discovery of new materials and associated desirable properties has been a driving force behind chemical innovation for centuries. When we look at some of the many recent technological advances, and how widespread and significant their impact has been, we appreciate how much they have relied on new materials. The increase in hard drive storage capacity due to new giant magneto-resistive materials, the ever-shrinking cell phone due to improved microwave dielectric materials, the enhancement in lithium battery storage capacity due to new intercalation materials, or the improved capacitor due to new ferroelectric materials are all excellent examples. How were these materials discovered? While there is no single answer, in all cases there was a First-Material, the archetype in which the phenomenon was first observed, the one that led to further investigations and the subsequent preparation of improved 2nd or 3rd generation materials. It is this First-Material, the archetype, that was discovered - often via crystal growth.

  14. Lysophospholipid receptors in drug discovery.

    Science.gov (United States)

    Kihara, Yasuyuki; Mizuno, Hirotaka; Chun, Jerold

    2015-05-01

    Lysophospholipids (LPs), including lysophosphatidic acid (LPA), sphingosine 1-phospate (S1P), lysophosphatidylinositol (LPI), and lysophosphatidylserine (LysoPS), are bioactive lipids that transduce signals through their specific cell-surface G protein-coupled receptors, LPA1-6, S1P1-5, LPI1, and LysoPS1-3, respectively. These LPs and their receptors have been implicated in both physiological and pathophysiological processes such as autoimmune diseases, neurodegenerative diseases, fibrosis, pain, cancer, inflammation, metabolic syndrome, bone formation, fertility, organismal development, and other effects on most organ systems. Advances in the LP receptor field have enabled the development of novel small molecules targeting LP receptors for several diseases. Most notably, fingolimod (FTY720, Gilenya, Novartis), an S1P receptor modulator, became the first FDA-approved medicine as an orally bioavailable drug for treating relapsing forms of multiple sclerosis. This success is currently being followed by multiple, mechanistically related compounds targeting S1P receptor subtypes, which are in various stages of clinical development. In addition, an LPA1 antagonist, BMS-986020 (Bristol-Myers Squibb), is in Phase 2 clinical development for treating idiopathic pulmonary fibrosis, as a distinct compound, SAR100842 (Sanofi) for the treatment of systemic sclerosis and related fibrotic diseases. This review summarizes the current state of drug discovery in the LP receptor field. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Application of genefishing discovery system on differential gene ...

    African Journals Online (AJOL)

    GREGORY

    2010-08-30

    Aug 30, 2010 ... this discovery system for a prokaryotic system by modifying the eukaryotic protocol using the poly (A)- ... eukaryotic system mainly in humans, screening of ... RNA isolation. Total RNA extraction from the bacterial cells was performed at room temperature using RNeasy® Mini Kit (Qiagen). Initially, the cells.

  16. Discovery Mondays: Surveyors' Tools

    CERN Multimedia

    2003-01-01

    Surveyors of all ages, have your rulers and compasses at the ready! This sixth edition of Discovery Monday is your chance to learn about the surveyor's tools - the state of the art in measuring instruments - and see for yourself how they work. With their usual daunting precision, the members of CERN's Surveying Group have prepared some demonstrations and exercises for you to try. Find out the techniques for ensuring accelerator alignment and learn about high-tech metrology systems such as deviation indicators, tracking lasers and total stations. The surveyors will show you how they precisely measure magnet positioning, with accuracy of a few thousandths of a millimetre. You can try your hand at precision measurement using different types of sensor and a modern-day version of the Romans' bubble level, accurate to within a thousandth of a millimetre. You will learn that photogrammetry techniques can transform even a simple digital camera into a remarkable measuring instrument. Finally, you will have a chance t...

  17. A dual platform approach to transcript discovery for the planarian Schmidtea mediterranea to establish RNAseq for stem cell and regeneration biology.

    Directory of Open Access Journals (Sweden)

    Martin J Blythe

    2010-12-01

    Full Text Available The use of planarians as a model system is expanding and the mechanisms that control planarian regeneration are being elucidated. The planarian Schmidtea mediterranea in particular has become a species of choice. Currently the planarian research community has access to this whole genome sequencing project and over 70,000 expressed sequence tags. However, the establishment of massively parallel sequencing technologies has provided the opportunity to define genetic content, and in particular transcriptomes, in unprecedented detail. Here we apply this approach to the planarian model system. We have sequenced, mapped and assembled 581,365 long and 507,719,814 short reads from RNA of intact and mixed stages of the first 7 days of planarian regeneration. We used an iterative mapping approach to identify and define de novo splice sites with short reads and increase confidence in our transcript predictions. We more than double the number of transcripts currently defined by publicly available ESTs, resulting in a collection of 25,053 transcripts described by combining platforms. We also demonstrate the utility of this collection for an RNAseq approach to identify potential transcripts that are enriched in neoblast stem cells and their progeny by comparing transcriptome wide expression levels between irradiated and intact planarians. Our experiments have defined an extensive planarian transcriptome that can be used as a template for RNAseq and can also help to annotate the S. mediterranea genome. We anticipate that suites of other 'omic approaches will also be facilitated by building on this comprehensive data set including RNAseq across many planarian regenerative stages, scenarios, tissues and phenotypes generated by RNAi.

  18. Synthetic biology for pharmaceutical drug discovery

    Science.gov (United States)

    Trosset, Jean-Yves; Carbonell, Pablo

    2015-01-01

    Synthetic biology (SB) is an emerging discipline, which is slowly reorienting the field of drug discovery. For thousands of years, living organisms such as plants were the major source of human medicines. The difficulty in resynthesizing natural products, however, often turned pharmaceutical industries away from this rich source for human medicine. More recently, progress on transformation through genetic manipulation of biosynthetic units in microorganisms has opened the possibility of in-depth exploration of the large chemical space of natural products derivatives. Success of SB in drug synthesis culminated with the bioproduction of artemisinin by microorganisms, a tour de force in protein and metabolic engineering. Today, synthetic cells are not only used as biofactories but also used as cell-based screening platforms for both target-based and phenotypic-based approaches. Engineered genetic circuits in synthetic cells are also used to decipher disease mechanisms or drug mechanism of actions and to study cell–cell communication within bacteria consortia. This review presents latest developments of SB in the field of drug discovery, including some challenging issues such as drug resistance and drug toxicity. PMID:26673570

  19. Supernovae Discovery Efficiency

    Science.gov (United States)

    John, Colin

    2018-01-01

    Abstract:We present supernovae (SN) search efficiency measurements for recent Hubble Space Telescope (HST) surveys. Efficiency is a key component to any search, and is important parameter as a correction factor for SN rates. To achieve an accurate value for efficiency, many supernovae need to be discoverable in surveys. This cannot be achieved from real SN only, due to their scarcity, so fake SN are planted. These fake supernovae—with a goal of realism in mind—yield an understanding of efficiency based on position related to other celestial objects, and brightness. To improve realism, we built a more accurate model of supernovae using a point-spread function. The next improvement to realism is planting these objects close to galaxies and of various parameters of brightness, magnitude, local galactic brightness and redshift. Once these are planted, a very accurate SN is visible and discoverable by the searcher. It is very important to find factors that affect this discovery efficiency. Exploring the factors that effect detection yields a more accurate correction factor. Further inquires into efficiency give us a better understanding of image processing, searching techniques and survey strategies, and result in an overall higher likelihood to find these events in future surveys with Hubble, James Webb, and WFIRST telescopes. After efficiency is discovered and refined with many unique surveys, it factors into measurements of SN rates versus redshift. By comparing SN rates vs redshift against the star formation rate we can test models to determine how long star systems take from the point of inception to explosion (delay time distribution). This delay time distribution is compared to SN progenitors models to get an accurate idea of what these stars were like before their deaths.

  20. Antibody informatics for drug discovery

    DEFF Research Database (Denmark)

    Shirai, Hiroki; Prades, Catherine; Vita, Randi

    2014-01-01

    to the antibody science in every project in antibody drug discovery. Recent experimental technologies allow for the rapid generation of large-scale data on antibody sequences, affinity, potency, structures, and biological functions; this should accelerate drug discovery research. Therefore, a robust bioinformatic...... infrastructure for these large data sets has become necessary. In this article, we first identify and discuss the typical obstacles faced during the antibody drug discovery process. We then summarize the current status of three sub-fields of antibody informatics as follows: (i) recent progress in technologies...... for antibody rational design using computational approaches to affinity and stability improvement, as well as ab-initio and homology-based antibody modeling; (ii) resources for antibody sequences, structures, and immune epitopes and open drug discovery resources for development of antibody drugs; and (iii...

  1. Discovery of the cadmium isotopes

    International Nuclear Information System (INIS)

    Amos, S.; Thoennessen, M.

    2010-01-01

    Thirty-seven cadmium isotopes have been observed so far and the discovery of these isotopes is discussed here. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.

  2. Synthetic biology of antimicrobial discovery

    Science.gov (United States)

    Zakeri, Bijan; Lu, Timothy K.

    2012-01-01

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

  3. Scientific discovery through weighted sampling

    NARCIS (Netherlands)

    E. Sidirourgos (Eleftherios); M.L. Kersten (Martin); P.A. Boncz (Peter)

    2013-01-01

    textabstractScientific discovery has shifted from being an exercise of theory and computation, to become the exploration of an ocean of observational data. Scientists explore data originated from modern scientific instruments in order to discover

  4. Radioactivity. Centenary of radioactivity discovery

    International Nuclear Information System (INIS)

    Charpak, G.; Tubiana, M.; Bimbot, R.

    1997-01-01

    This small booklet was edited for the occasion of the exhibitions of the celebration of the centenary of radioactivity discovery which took place in various locations in France from 1996 to 1998. It recalls some basic knowledge concerning radioactivity and its applications: history of discovery, atoms and isotopes, radiations, measurement of ionizing radiations, natural and artificial radioactivity, isotope dating and labelling, radiotherapy, nuclear power and reactors, fission and fusion, nuclear wastes, dosimetry, effects and radioprotection. (J.S.)

  5. Computational methods in drug discovery

    Directory of Open Access Journals (Sweden)

    Sumudu P. Leelananda

    2016-12-01

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

  6. Universal Knowledge Discovery from Big Data: Towards a Paradigm Shift from 'Knowledge Discovery' to 'Wisdom Discovery'

    OpenAIRE

    Shen, Bin

    2014-01-01

    Many people hold a vision that big data will provide big insights and have a big impact in the future, and big-data-assisted scientific discovery is seen as an emerging and promising scientific paradigm. However, how to turn big data into deep insights with tremendous value still remains obscure. To meet the challenge, universal knowledge discovery from big data (UKD) is proposed. The new concept focuses on discovering universal knowledge, which exists in the statistical analyses of big data ...

  7. The Europa Ocean Discovery mission

    Energy Technology Data Exchange (ETDEWEB)

    Edwards, B.C. [Los Alamos National Lab., NM (United States); Chyba, C.F. [Univ. of Arizona, Tucson, AZ (United States); Abshire, J.B. [National Aeronautics and Space Administration, Greenbelt, MD (United States). Goddard Space Flight Center] [and others

    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`s 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.

  8. Deep Learning in Drug Discovery.

    Science.gov (United States)

    Gawehn, Erik; Hiss, Jan A; Schneider, Gisbert

    2016-01-01

    Artificial neural networks had their first heyday in molecular informatics and drug discovery approximately two decades ago. Currently, we are witnessing renewed interest in adapting advanced neural network architectures for pharmaceutical research by borrowing from the field of "deep learning". Compared with some of the other life sciences, their application in drug discovery is still limited. Here, we provide an overview of this emerging field of molecular informatics, present the basic concepts of prominent deep learning methods and offer motivation to explore these techniques for their usefulness in computer-assisted drug discovery and design. We specifically emphasize deep neural networks, restricted Boltzmann machine networks and convolutional networks. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Bioinformatics in translational drug discovery.

    Science.gov (United States)

    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).

  10. In defence of discovery learning.

    Science.gov (United States)

    Vereijken, B; Whiting, H T

    1990-06-01

    The present paper discusses the influence of different training methods--i.e., knowledge of results, preferred frequency, and the availability of a model--on the learning of a complex motor skill, in this case the learning of slalom ski-type movements on a ski-simulator. Results of three experiments performed on this apparatus showed that, although the training methods used influence the course of learning, none of the methods used was actually superior to discovery learning. It is suggested that discovery learning forces the learner to explore the dynamics of the system in which he or she operates, in an iterative way. Possibilities for cooperative working between prescription and discovery learning are discussed.

  11. Functional genomics and cancer drug target discovery.

    Science.gov (United States)

    Moody, Susan E; Boehm, Jesse S; Barbie, David A; Hahn, William C

    2010-06-01

    The recent development of technologies for whole-genome sequencing, copy number analysis and expression profiling enables the generation of comprehensive descriptions of cancer genomes. However, although the structural analysis and expression profiling of tumors and cancer cell lines can allow the identification of candidate molecules that are altered in the malignant state, functional analyses are necessary to confirm such genes as oncogenes or tumor suppressors. Moreover, recent research suggests that tumor cells also depend on synthetic lethal targets, which are not mutated or amplified in cancer genomes; functional genomics screening can facilitate the discovery of such targets. This review provides an overview of the tools available for the study of functional genomics, and discusses recent research involving the use of these tools to identify potential novel drug targets in cancer.

  12. Using Aptamers for Cancer Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    Yun Min Chang

    2013-01-01

    Full Text Available Aptamers are single-stranded synthetic DNA- or RNA-based oligonucleotides that fold into various shapes to bind to a specific target, which includes proteins, metals, and molecules. Aptamers have high affinity and high specificity that are comparable to that of antibodies. They are obtained using iterative method, called (Systematic Evolution of Ligands by Exponential Enrichment SELEX and cell-based SELEX (cell-SELEX. Aptamers can be paired with recent advances in nanotechnology, microarray, microfluidics, and other technologies for applications in clinical medicine. One particular area that aptamers can shed a light on is biomarker discovery. Biomarkers are important in diagnosis and treatment of cancer. In this paper, we will describe ways in which aptamers can be used to discover biomarkers for cancer diagnosis and therapeutics.

  13. A new approach to the rationale discovery of polymeric biomaterials

    Science.gov (United States)

    Kohn, Joachim; Welsh, William J.; Knight, Doyle

    2007-01-01

    This paper attempts to illustrate both the need for new approaches to biomaterials discovery as well as the significant promise inherent in the use of combinatorial and computational design strategies. The key observation of this Leading Opinion Paper is that the biomaterials community has been slow to embrace advanced biomaterials discovery tools such as combinatorial methods, high throughput experimentation, and computational modeling in spite of the significant promise shown by these discovery tools in materials science, medicinal chemistry and the pharmaceutical industry. It seems that the complexity of living cells and their interactions with biomaterials has been a conceptual as well as a practical barrier to the use of advanced discovery tools in biomaterials science. However, with the continued increase in computer power, the goal of predicting the biological response of cells in contact with biomaterials surfaces is within reach. Once combinatorial synthesis, high throughput experimentation, and computational modeling are integrated into the biomaterials discovery process, a significant acceleration is possible in the pace of development of improved medical implants, tissue regeneration scaffolds, and gene/drug delivery systems. PMID:17644176

  14. Drug discovery for alopecia: gone today, hair tomorrow.

    Science.gov (United States)

    Santos, Zenildo; Avci, Pinar; Hamblin, Michael R

    2015-03-01

    Hair loss or alopecia affects the majority of the population at some time in their life, and increasingly, sufferers are demanding treatment. Three main types of alopecia (androgenic [AGA], areata [AA] and chemotherapy-induced [CIA]) are very different, and have their own laboratory models and separate drug-discovery efforts. In this article, the authors review the biology of hair, hair follicle (HF) cycling, stem cells and signaling pathways. AGA, due to dihydrotesterone, is treated by 5-α reductase inhibitors, androgen receptor blockers and ATP-sensitive potassium channel-openers. AA, which involves attack by CD8(+)NK group 2D-positive (NKG2D(+)) T cells, is treated with immunosuppressives, biologics and JAK inhibitors. Meanwhile, CIA is treated by apoptosis inhibitors, cytokines and topical immunotherapy. The desire to treat alopecia with an easy topical preparation is expected to grow with time, particularly with an increasing aging population. The discovery of epidermal stem cells in the HF has given new life to the search for a cure for baldness. Drug discovery efforts are being increasingly centered on these stem cells, boosting the hair cycle and reversing miniaturization of HF. Better understanding of the molecular mechanisms underlying the immune attack in AA will yield new drugs. New discoveries in HF neogenesis and low-level light therapy will undoubtedly have a role to play.

  15. Computational Discovery of Niclosamide Ethanolamine, a Repurposed Drug Candidate That Reduces Growth of Hepatocellular Carcinoma Cells In Vitro and in Mice by Inhibiting Cell Division Cycle 37 Signaling.

    Science.gov (United States)

    Chen, Bin; Wei, Wei; Ma, Li; Yang, Bin; Gill, Ryan M; Chua, Mei-Sze; Butte, Atul J; So, Samuel

    2017-06-01

    Drug repositioning offers a shorter approval process than new drug development. We therefore searched large public datasets of drug-induced gene expression signatures to identify agents that might be effective against hepatocellular carcinoma (HCC). We searched public databases of messenger RNA expression patterns reported from HCC specimens from patients, HCC cell lines, and cells exposed to various drugs. We identified drugs that might specifically increase expression of genes that are down-regulated in HCCs and reduce expression of genes up-regulated in HCCs using a nonparametric, rank-based pattern-matching strategy based on the Kolmogorov-Smirnov statistic. We evaluated the anti-tumor activity of niclosamide and its ethanolamine salt (NEN) in HCC cell lines (HepG2, Huh7, Hep3B, Hep40, and PLC/PRF/5), primary human hepatocytes, and 2 mouse models of HCC. In one model of HCC, liver tumor development was induced by hydrodynamic delivery of a sleeping beauty transposon expressing an activated form of Ras (v12) and truncated β-catenin (N90). In another mouse model, patient-derived xenografts were established by implanting HCC cells from patients into livers of immunocompromised mice. Tumor growth was monitored by bioluminescence imaging. Tumor-bearing mice were fed a regular chow diet or a chow diet containing niclosamide or NEN. In a separate experiment using patient-derived xenografts, tumor-bearing mice were given sorafenib (the standard of care for patients with advanced HCC), NEN, or niclosamide alone; a combination of sorafenib and NEN; or a combination sorafenib and niclosamide in their drinking water, or regular water (control), and tumor growth was monitored. Based on gene expression signatures, we identified 3 anthelmintics that significantly altered the expression of genes that are up- or down-regulated in HCCs. Niclosamide and NEN specifically reduced the viability of HCC cells: the agents were at least 7-fold more cytotoxic to HCCs than primary

  16. OPEN DATA FOR DISCOVERY SCIENCE.

    Science.gov (United States)

    Payne, Philip R O; Huang, Kun; Shah, Nigam H; Tenenbaum, Jessica

    2017-01-01

    The modern healthcare and life sciences ecosystem is moving towards an increasingly open and data-centric approach to discovery science. This evolving paradigm is predicated on a complex set of information needs related to our collective ability to share, discover, reuse, integrate, and analyze open biological, clinical, and population level data resources of varying composition, granularity, and syntactic or semantic consistency. Such an evolution is further impacted by a concomitant growth in the size of data sets that can and should be employed for both hypothesis discovery and testing. When such open data can be accessed and employed for discovery purposes, a broad spectrum of high impact end-points is made possible. These span the spectrum from identification of de novo biomarker complexes that can inform precision medicine, to the repositioning or repurposing of extant agents for new and cost-effective therapies, to the assessment of population level influences on disease and wellness. Of note, these types of uses of open data can be either primary, wherein open data is the substantive basis for inquiry, or secondary, wherein open data is used to augment or enrich project-specific or proprietary data that is not open in and of itself. This workshop is concerned with the key challenges, opportunities, and methodological best practices whereby open data can be used to drive the advancement of discovery science in all of the aforementioned capacities.

  17. Hubble 15 years of discovery

    CERN Document Server

    Lindberg Christensen, Lars; Kornmesser, M

    2006-01-01

    Hubble: 15 Years of Discovery was a key element of the European Space Agency's 15th anniversary celebration activities for the 1990 launch of the NASA/ESA Hubble Space Telescope. As an observatory in space, Hubble is one of the most successful scientific projects of all time, both in terms of scientific output and its immediate public appeal.

  18. Smartphones: A Potential Discovery Tool

    Directory of Open Access Journals (Sweden)

    Wendy Starkweather

    2009-09-01

    Full Text Available The anticipated wide adoption of smartphones by researchers is viewed by the authors as a basis for developing mobile-based services. In response to the UNLV Libraries’ strategic plan’s focus on experimentation and outreach, the authors investigate the current and potential role of smartphones as a valuable discovery tool for library users.

  19. Translational medicine and drug discovery

    National Research Council Canada - National Science Library

    Littman, Bruce H; Krishna, Rajesh

    2011-01-01

    ..., and examples of their application to real-life drug discovery and development. The latest thinking is presented by researchers from many of the world's leading pharmaceutical companies, including Pfizer, Merck, Eli Lilly, Abbott, and Novartis, as well as from academic institutions and public- private partnerships that support translational research...

  20. Structural Biology Guides Antibiotic Discovery

    Science.gov (United States)

    Polyak, Steven

    2014-01-01

    Modern drug discovery programs require the contribution of researchers in a number of specialist areas. One of these areas is structural biology. Using X-ray crystallography, the molecular basis of how a drug binds to its biological target and exerts its mode of action can be defined. For example, a drug that binds into the active site of an…

  1. A Discovery Approach to Movement.

    Science.gov (United States)

    O'Hagin, Isabel B.

    1998-01-01

    Investigates the effects of the discovery approach to movement-based instruction on children's level of musicality. Finds that the students with the highest musicality were girls, demonstrated reflective movements and a personal sense of style while moving, and made sense of the music by organizing, categorizing, and developing movement ideas.…

  2. Discoveries of isotopes by fission

    Indian Academy of Sciences (India)

    activities as the potential discovery of elements heavier than uranium [5]. He drew this conclusion ... alkaline earth metals in the irradiation of uranium by neutrons) Hahn and Strassmann did. 458. Pramana – J. ... the production of active barium isotopes from uranium and thorium by neutron irradiation;. Proof of further active ...

  3. New paradigms in GPCR drug discovery.

    Science.gov (United States)

    Jacobson, Kenneth A

    2015-12-15

    G protein-coupled receptors (GPCRs) remain a major domain of pharmaceutical discovery. The identification of GPCR lead compounds and their optimization are now structure-based, thanks to advances in X-ray crystallography, molecular modeling, protein engineering and biophysical techniques. In silico screening provides useful hit molecules. New pharmacological approaches to tuning the pleotropic action of GPCRs include: allosteric modulators, biased ligands, GPCR heterodimer-targeted compounds, manipulation of polypharmacology, receptor antibodies and tailoring of drug molecules to fit GPCR pharmacogenomics. Measurements of kinetics and drug efficacy are factors influencing clinical success. With the exception of inhibitors of GPCR kinases, targeting of intracellular GPCR signaling or receptor cycling for therapeutic purposes remains a futuristic concept. New assay approaches are more efficient and multidimensional: cell-based, label-free, fluorescence-based assays, and biosensors. Tailoring GPCR drugs to a patient's genetic background is now being considered. Chemoinformatic tools can predict ADME-tox properties. New imaging technology visualizes drug action in vivo. Thus, there is reason to be optimistic that new technology for GPCR ligand discovery will help reverse the current narrowing of the pharmaceutical pipeline. Published by Elsevier Inc.

  4. Novel drug discovery for Chagas disease.

    Science.gov (United States)

    Moraes, Carolina B; Franco, Caio H

    2016-01-01

    Chagas disease is a chronic infection associated with long-term morbidity. Increased funding and advocacy for drug discovery for neglected diseases have prompted the introduction of several important technological advances, and Chagas disease is among the neglected conditions that has mostly benefited from technological developments. A number of screening campaigns, and the development of new and improved in vitro and in vivo assays, has led to advances in the field of drug discovery. This review highlights the major advances in Chagas disease drug screening, and how these are being used not only to discover novel chemical entities and drug candidates, but also increase our knowledge about the disease and the parasite. Different methodologies used for compound screening and prioritization are discussed, as well as novel techniques for the investigation of these targets. The molecular mechanism of action is also discussed. Technological advances have been executed with scientific rigour for the development of new in vitro cell-based assays and in vivo animal models, to bring about novel and better drugs for Chagas disease, as well as to increase our understanding of what are the necessary properties for a compound to be successful in the clinic. The gained knowledge, combined with new exciting approaches toward target deconvolution, will help identifying new targets for Chagas disease chemotherapy in the future.

  5. Mass spectrometry for protein quantification in biomarker discovery.

    Science.gov (United States)

    Wang, Mu; You, Jinsam

    2012-01-01

    Major technological advances have made proteomics an extremely active field for biomarker discovery in recent years due primarily to the development of newer mass spectrometric technologies and the explosion in genomic and protein bioinformatics. This leads to an increased emphasis on larger scale, faster, and more efficient methods for detecting protein biomarkers in human tissues, cells, and biofluids. Most current proteomic methodologies for biomarker discovery, however, are not highly automated and are generally labor-intensive and expensive. More automation and improved software programs capable of handling a large amount of data are essential to reduce the cost of discovery and to increase throughput. In this chapter, we discuss and describe mass spectrometry-based proteomic methods for quantitative protein analysis.

  6. Using directed information for influence discovery in interconnected dynamical systems

    Science.gov (United States)

    Rao, Arvind; Hero, Alfred O.; States, David J.; Engel, James Douglas

    2008-08-01

    Structure discovery in non-linear dynamical systems is an important and challenging problem that arises in various applications such as computational neuroscience, econometrics, and biological network discovery. Each of these systems have multiple interacting variables and the key problem is the inference of the underlying structure of the systems (which variables are connected to which others) based on the output observations (such as multiple time trajectories of the variables). Since such applications demand the inference of directed relationships among variables in these non-linear systems, current methods that have a linear assumption on structure or yield undirected variable dependencies are insufficient. Hence, in this work, we present a methodology for structure discovery using an information-theoretic metric called directed time information (DTI). Using both synthetic dynamical systems as well as true biological datasets (kidney development and T-cell data), we demonstrate the utility of DTI in such problems.

  7. Arthritis Genetics Analysis Aids Drug Discovery

    Science.gov (United States)

    ... NIH Research Matters January 13, 2014 Arthritis Genetics Analysis Aids Drug Discovery An international research team identified 42 new ... Edition Distracted Driving Raises Crash Risk Arthritis Genetics Analysis Aids Drug Discovery Oxytocin Affects Facial Recognition Connect with Us ...

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

    Science.gov (United States)

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

    2012-09-01

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

  9. [Artificial Intelligence in Drug Discovery].

    Science.gov (United States)

    Fujiwara, Takeshi; Kamada, Mayumi; Okuno, Yasushi

    2018-04-01

    According to the increase of data generated from analytical instruments, application of artificial intelligence(AI)technology in medical field is indispensable. In particular, practical application of AI technology is strongly required in "genomic medicine" and "genomic drug discovery" that conduct medical practice and novel drug development based on individual genomic information. In our laboratory, we have been developing a database to integrate genome data and clinical information obtained by clinical genome analysis and a computational support system for clinical interpretation of variants using AI. In addition, with the aim of creating new therapeutic targets in genomic drug discovery, we have been also working on the development of a binding affinity prediction system for mutated proteins and drugs by molecular dynamics simulation using supercomputer "Kei". We also have tackled for problems in a drug virtual screening. Our developed AI technology has successfully generated virtual compound library, and deep learning method has enabled us to predict interaction between compound and target protein.

  10. Glycoscience aids in biomarker discovery

    Directory of Open Access Journals (Sweden)

    Serenus Hua1,2 & Hyun Joo An1,2,*

    2012-06-01

    Full Text Available The glycome consists of all glycans (or carbohydrates within abiological system, and modulates a wide range of important biologicalactivities, from protein folding to cellular communications.The mining of the glycome for disease markers representsa new paradigm for biomarker discovery; however, this effortis severely complicated by the vast complexity and structuraldiversity of glycans. This review summarizes recent developmentsin analytical technology and methodology as applied tothe fields of glycomics and glycoproteomics. Mass spectrometricstrategies for glycan compositional profiling are described, as arepotential refinements which allow structure-specific profiling.Analytical methods that can discern protein glycosylation at aspecific site of modification are also discussed in detail.Biomarker discovery applications are shown at each level ofanalysis, highlighting the key role that glycoscience can play inhelping scientists understand disease biology.

  11. Enteric Neurobiology: Discoveries and Directions.

    Science.gov (United States)

    Wood, Jackie D

    Discovery and documentation of noncholinergic-nonadrenergic neurotransmission in the enteric nervous system started a revolution in mechanisms of neural control of the digestive tract that continues into a twenty-first century era of translational gastroenterology, which is now firmly embedded in the term, neurogastroenterology. This chapter, on Enteric Neurobiology: Discoveries and Directions, tracks the step-by-step advances in enteric neuronal electrophysiology and synaptic behavior and progresses to the higher order functions of central pattern generators, hard wired synaptic circuits and libraries of neural programs in the brain-in-the-gut that underlie the several different patterns of motility and secretory behaviors that occur in the specialized, serially-connected compartments extending from the esophagus to the anus.

  12. A quantum causal discovery algorithm

    Science.gov (United States)

    Giarmatzi, Christina; Costa, Fabio

    2018-03-01

    Finding a causal model for a set of classical variables is now a well-established task—but what about the quantum equivalent? Even the notion of a quantum causal model is controversial. Here, we present a causal discovery algorithm for quantum systems. The input to the algorithm is a process matrix describing correlations between quantum events. Its output consists of different levels of information about the underlying causal model. Our algorithm determines whether the process is causally ordered by grouping the events into causally ordered non-signaling sets. It detects if all relevant common causes are included in the process, which we label Markovian, or alternatively if some causal relations are mediated through some external memory. For a Markovian process, it outputs a causal model, namely the causal relations and the corresponding mechanisms, represented as quantum states and channels. Our algorithm opens the route to more general quantum causal discovery methods.

  13. The discovery of immunoglobulin E.

    Science.gov (United States)

    Ribatti, Domenico

    2016-03-01

    The discovery of immunoglobulin E (IgE) was a breakthrough in the field of allergy and immunology. Our understanding of mechanisms of allergic reactions and the role of IgE in these disorders has paralleled to the discovery of treatment modalities for patients with allergy. The first clue to the existence of a substance responsible for hypersensitivity reactions was demonstrated in 1921 by Prausnitz and Kustner, and after four decades it was identified as an immunoglobulin subclass by Ishizakas and co-workers. In 1968, the WHO International Reference Centre for Immunoglobulins announced the presence of a fifth immunoglobulin isotype, IgE. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Androgenetic alopecia: stress of discovery.

    Science.gov (United States)

    Passchier, Jan; Erdman, Jeroen; Hammiche, Fatima; Erdman, Ruud A M

    2006-02-01

    The psychological problems of men in the initial stages of alopecia androgenetica (hereditary male hair loss) have seldom been studied. We evaluated two groups of 80 men with alopecia androgenetica in Stages II to IV, indicating the amount of hair loss (overall N=160; for Group I: M=48 yr., SD=18.2; for Group II: M=50 yr., SD=18.0) who visited a dermatology clinic for benign dermatological complaints but not for hair loss, by questionnaires and interview, retrospectively. As predicted, hair problems were reported to be significantly greater overall at the moment of discovery of hair loss than later. About half of the men reported feeling annoyed to very annoyed about the discovery of hair loss. For those patients, provision of information by internet might facilitate a visit to the dermatologist.

  15. Cyber-Enabled Scientific Discovery

    International Nuclear Information System (INIS)

    Chan, Tony; Jameson, Leland

    2007-01-01

    It is often said that numerical simulation is third in the group of three ways to explore modern science: theory, experiment and simulation. Carefully executed modern numerical simulations can, however, be considered at least as relevant as experiment and theory. In comparison to physical experimentation, with numerical simulation one has the numerically simulated values of every field variable at every grid point in space and time. In comparison to theory, with numerical simulation one can explore sets of very complex non-linear equations such as the Einstein equations that are very difficult to investigate theoretically. Cyber-enabled scientific discovery is not just about numerical simulation but about every possible issue related to scientific discovery by utilizing cyberinfrastructure such as the analysis and storage of large data sets, the creation of tools that can be used by broad classes of researchers and, above all, the education and training of a cyber-literate workforce

  16. 12 CFR 308.107 - Document discovery.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Document discovery. 308.107 Section 308.107... PRACTICE AND PROCEDURE General Rules of Procedure § 308.107 Document discovery. (a) Parties to proceedings... only through the production of documents. No other form of discovery shall be allowed. (b) Any...

  17. 34 CFR 81.16 - Discovery.

    Science.gov (United States)

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false Discovery. 81.16 Section 81.16 Education Office of the... voluntarily. (b) The ALJ, at a party's request, may order compulsory discovery described in paragraph (c) of... respect to an issue in the case; (3) The discovery request was not made primarily for the purposes of...

  18. 42 CFR 426.532 - Discovery.

    Science.gov (United States)

    2010-10-01

    ... purpose of this section, the term documents includes relevant information, reports, answers, records... § 426.532 Discovery. (a) General rule. If the Board orders discovery, the Board must establish a... or burdensome; or (iii) Will unduly delay the proceeding. (c) Types of discovery available. A party...

  19. The discovery of the antiproton

    International Nuclear Information System (INIS)

    Chamberlain, Owen

    1989-01-01

    A number of groups of particle physicists competed to provide track evidence of the existence of Dirac's postulated antiproton in the mid-1950s. The work of the several teams is described briefly. The author describes the work of his own group on the Bevatron in more detail, and how they finally observed the antiproton. The article finishes with an assessment of the importance of this discovery. (UK)

  20. Model organisms and target discovery.

    Science.gov (United States)

    Muda, Marco; McKenna, Sean

    2004-09-01

    The wealth of information harvested from full genomic sequencing projects has not generated a parallel increase in the number of novel targets for therapeutic intervention. Several pharmaceutical companies have realized that novel drug targets can be identified and validated using simple model organisms. After decades of service in basic research laboratories, yeasts, worms, flies, fishes, and mice are now the cornerstones of modern drug discovery programs.: © 2004 Elsevier Ltd . All rights reserved.

  1. Gas reserves, discoveries and production

    International Nuclear Information System (INIS)

    Saniere, A.

    2006-01-01

    Between 2000 and 2004, new discoveries, located mostly in the Asia/Pacific region, permitted a 71% produced reserve replacement rate. The Middle East and the offshore sector represent a growing proportion of world gas production Non-conventional gas resources are substantial but are not exploited to any significant extent, except in the United States, where they account for 30% of U.S. gas production. (author)

  2. Sea Level Rise Data Discovery

    Science.gov (United States)

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

    2016-12-01

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

  3. Discovery of a Makemakean Moon

    Science.gov (United States)

    Parker, Alex H.; Buie, Marc W.; Grundy, Will M.; Noll, Keith S.

    2016-01-01

    We describe the discovery of a satellite in orbit about the dwarf planet (136472) Makemake. This satellite, provisionally designated S/2015 (136472) 1, was detected in imaging data collected with the Hubble Space Telescope's Wide Field Camera 3 on UTC 2015 April 27 at 7.80 +/- 0.04 mag fainter than Makemake and at a separation of 0farcs57. It likely evaded detection in previous satellite searches due to a nearly edge-on orbital configuration, placing it deep within the glare of Makemake during a substantial fraction of its orbital period. This configuration would place Makemake and its satellite near a mutual event season. Insufficient orbital motion was detected to make a detailed characterization of its orbital properties, prohibiting a measurement of the system mass with the discovery data alone. Preliminary analysis indicates that if the orbit is circular, its orbital period must be longer than 12.4 days and must have a semimajor axis > or approx. = 21,000 km. We find that the properties of Makemake's moon suggest that the majority of the dark material detected in the system by thermal observations may not reside on the surface of Makemake, but may instead be attributable to S/2015 (136472) 1 having a uniform dark surface. This dark moon hypothesis can be directly tested with future James Webb Space Telescope observations. We discuss the implications of this discovery for the spin state, figure, and thermal properties of Makemake and the apparent ubiquity of trans-Neptunian dwarf planet satellites.

  4. A New Universe of Discoveries

    Science.gov (United States)

    Córdova, France A.

    2016-01-01

    The convergence of emerging advances in astronomical instruments, computational capabilities and talented practitioners (both professional and civilian) is creating an extraordinary new environment for making numerous fundamental discoveries in astronomy, ranging from the nature of exoplanets to understanding the evolution of solar systems and galaxies. The National Science Foundation is playing a critical role in supporting, stimulating, and shaping these advances. NSF is more than an agency of government or a funding mechanism for the infrastructure of science. The work of NSF is a sacred trust that every generation of Americans makes to those of the next generation, that we will build on the body of knowledge we inherit and continue to push forward the frontiers of science. We never lose sight of NSF's obligation to "explore the unexplored" and inspire all of humanity with the wonders of discovery. As the only Federal agency dedicated to the support of basic research and education in all fields of science and engineering, NSF has empowered discoveries across a broad spectrum of scientific inquiry for more than six decades. The result is fundamental scientific research that has had a profound impact on our nation's innovation ecosystem and kept our nation at the very forefront of the world's science-and-engineering enterprise.

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

    Science.gov (United States)

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

    2017-02-01

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

  6. Historical review of the discovery of cadherin, in memory of Tokindo Okada.

    Science.gov (United States)

    Takeichi, Masatoshi

    2018-01-01

    The cadherin family of cell-cell adhesion molecules plays a pivotal role in animal tissue formation. Discovery of this molecular family can be traced back to some unexpected observations of strange cell behavior that were made around 1970 in the Kyoto University laboratory of Tokindo Okada, and then in the Department of Embryology at the Carnegie Institution of Washington (currently the Carnegie Institution for Science). This article looks back on these discoveries, and recalls how these observations led to the identification of important cell-cell adhesion molecules known as cadherins. © 2017 Japanese Society of Developmental Biologists.

  7. Polar Domain Discovery with Sparkler

    Science.gov (United States)

    Duerr, R.; Khalsa, S. J. S.; Mattmann, C. A.; Ottilingam, N. K.; Singh, K.; Lopez, L. A.

    2017-12-01

    The scientific web is vast and ever growing. It encompasses millions of textual, scientific and multimedia documents describing research in a multitude of scientific streams. Most of these documents are hidden behind forms which require user action to retrieve and thus can't be directly accessed by content crawlers. These documents are hosted on web servers across the world, most often on outdated hardware and network infrastructure. Hence it is difficult and time-consuming to aggregate documents from the scientific web, especially those relevant to a specific domain. Thus generating meaningful domain-specific insights is currently difficult. We present an automated discovery system (Figure 1) using Sparkler, an open-source, extensible, horizontally scalable crawler which facilitates high throughput and focused crawling of documents pertinent to a particular domain such as information about polar regions. With this set of highly domain relevant documents, we show that it is possible to answer analytical questions about that domain. Our domain discovery algorithm leverages prior domain knowledge to reach out to commercial/scientific search engines to generate seed URLs. Subject matter experts then annotate these seed URLs manually on a scale from highly relevant to irrelevant. We leverage this annotated dataset to train a machine learning model which predicts the `domain relevance' of a given document. We extend Sparkler with this model to focus crawling on documents relevant to that domain. Sparkler avoids disruption of service by 1) partitioning URLs by hostname such that every node gets a different host to crawl and by 2) inserting delays between subsequent requests. With an NSF-funded supercomputer Wrangler, we scaled our domain discovery pipeline to crawl about 200k polar specific documents from the scientific web, within a day.

  8. DISCOVERY OF A MAKEMAKEAN MOON

    Energy Technology Data Exchange (ETDEWEB)

    Parker, Alex H.; Buie, Marc W. [Southwest Research Institute, 1050 Walnut Street, Suite 300, Boulder, CO 80302 (United States); Grundy, Will M. [Lowell Observatory, Flagstaff, AZ (United States); Noll, Keith S., E-mail: aparker@boulder.swri.edu [NASA Goddard Space Flight Center, Greenbelt, MD (United States)

    2016-07-01

    We describe the discovery of a satellite in orbit about the dwarf planet (136472) Makemake. This satellite, provisionally designated S/2015 (136472) 1, was detected in imaging data collected with the Hubble Space Telescope ’s Wide Field Camera 3 on UTC 2015 April 27 at 7.80 ± 0.04 mag fainter than Makemake and at a separation of 0.″57. It likely evaded detection in previous satellite searches due to a nearly edge-on orbital configuration, placing it deep within the glare of Makemake during a substantial fraction of its orbital period. This configuration would place Makemake and its satellite near a mutual event season. Insufficient orbital motion was detected to make a detailed characterization of its orbital properties, prohibiting a measurement of the system mass with the discovery data alone. Preliminary analysis indicates that if the orbit is circular, its orbital period must be longer than 12.4 days and must have a semimajor axis ≳21,000 km. We find that the properties of Makemake’s moon suggest that the majority of the dark material detected in the system by thermal observations may not reside on the surface of Makemake, but may instead be attributable to S/2015 (136472) 1 having a uniform dark surface. This “dark moon hypothesis” can be directly tested with future James Webb Space Telescope observations. We discuss the implications of this discovery for the spin state, figure, and thermal properties of Makemake and the apparent ubiquity of trans-Neptunian dwarf planet satellites.

  9. New vaccines: challenges of discovery.

    Science.gov (United States)

    Mahmoud, Adel

    2016-09-01

    Vaccines have been a major component of preventing and controlling infectious diseases. The basis for discovery of what protects is reviewed as well as new attempts in utilizing Reverse Vaccinology, RNA-RNA methods and proteome analysis are adding significantly to our knowledge. The challenge of how to define protective and defined components of microbes is still hampering efforts to discover new vaccines. Recent excitement about immunotherapy of cancer opens the way to develop vaccines against multiple malignancies. © 2016 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.

  10. Scientific discovery using genetic programming

    DEFF Research Database (Denmark)

    Keijzer, Maarten

    2001-01-01

    in this work can be summarized as: The symbolic expressions produced by genetic programming can be made suitable for analysis and interpretation by using units of measurements to guide or restrict the search. To achieve this, the following has been accomplished: A standard genetic programming system...... that are numerically stable and correct. A case study using four real-world problems in the induction of dimensionally correct empirical equations on data using the two different methods is presented to illustrate to use and limitations of these methods in a framework of scientific discovery....

  11. The Discovery of Artificial Radioactivity

    Science.gov (United States)

    Guerra, Francesco; Leone, Matteo; Robotti, Nadia

    2012-03-01

    We reconstruct Frédéric Joliot and Irène Curie's discovery of artificial radioactivity in January 1934 based in part on documents preserved in the Joliot-Curie Archives in Paris, France. We argue that their discovery followed from the convergence of two parallel lines of research, on the neutron and on the positron, that were focused on a well-defined experimental problem, the nuclear transmutation of aluminum and other light elements. We suggest that a key role was played by a suggestion that Francis Perrin made at the seventh Solvay Conference at the end of October 1933, that the alpha-particle bombardment of aluminum produces an intermediate unstable isotope of phosphorus, which then decays by positron emission. We also suggest that a further idea that Perrin published in December 1933, and the pioneering theory of beta decay that Enrico Fermi also first published in December 1933, established a new theoretical framework that stimulated Joliot to resume the researches that he and Curie had interrupted after the Solvay Conference, now for the first time using a Geiger-Müller counter to detect the positrons emitted when he bombarded aluminum with polonium alpha particles.

  12. Discovery of Allostery in PKA Signaling.

    Science.gov (United States)

    Zhang, Ping; Kornev, Alexandr P; Wu, Jian; Taylor, Susan S

    2015-06-01

    cAMP-dependent protein kinase (PKA) was the second protein kinase to be discovered and the PKA catalytic (C) subunit serves as a prototype for the large protein kinase superfamily that contains over 500 gene products. The protein kinases regulate much of biology in eukaryotic cells and they are now also a major therapeutic target. Although PKA was discovered nearly 50 years ago and the subsequent discovery of the regulatory subunits that bind cAMP and release the catalytic activity from the holoenzyme followed quickly. Thus in PKA we see the convergence of two major signaling mechanisms - protein phosphorylation and second messenger signaling through cAMP. Crystallography provides a foundation for understanding function, and the structure of the isolated regulatory (R) and C-subunits have been extremely informative. Yet it is the R 2 C 2 holoenzyme that predominates in cells, and one can only appreciate the allosteric features of PKA signaling by seeing the full length protein. The symmetry and the quaternary constraints that one R:C hetero-dimer exerts on the other in the holoenzyme simply are not present in the isolated subunits or even in the R:C hetero-dimer.

  13. Integration of Antibody Array Technology into Drug Discovery and Development.

    Science.gov (United States)

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

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

  14. mHealth Visual Discovery Dashboard.

    Science.gov (United States)

    Fang, Dezhi; Hohman, Fred; Polack, Peter; Sarker, Hillol; Kahng, Minsuk; Sharmin, Moushumi; al'Absi, Mustafa; Chau, Duen Horng

    2017-09-01

    We present Discovery Dashboard, a visual analytics system for exploring large volumes of time series data from mobile medical field studies. Discovery Dashboard offers interactive exploration tools and a data mining motif discovery algorithm to help researchers formulate hypotheses, discover trends and patterns, and ultimately gain a deeper understanding of their data. Discovery Dashboard emphasizes user freedom and flexibility during the data exploration process and enables researchers to do things previously challenging or impossible to do - in the web-browser and in real time. We demonstrate our system visualizing data from a mobile sensor study conducted at the University of Minnesota that included 52 participants who were trying to quit smoking.

  15. Recent discoveries of anticancer flavonoids.

    Science.gov (United States)

    Raffa, Demetrio; Maggio, Benedetta; Raimondi, Maria Valeria; Plescia, Fabiana; Daidone, Giuseppe

    2017-12-15

    In this review we report the recent advances in anticancer activity of the family of natural occurring flavonoids, covering the time span of the last five years. The bibliographic data will be grouped, on the basis of biological information, in two great categories: reports in which the extract plants bioactivity is reported and the identification of each flavonoid is present or not, and reports in which the anticancer activity is attributable to purified and identified flavonoids from plants. Wherever possible, the targets and mechanisms of action as well as the structure-activity relationships of the molecules will be reported. Also, in the review it was thoroughly investigated the recent discovery on flavonoids containing the 2-phenyl-4H-chromen-4-one system even if some examples of unusual flavonoids, bearing a non-aromatic B-ring or other ring condensed to the base structure are reported. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. Transgenic parasites accelerate drug discovery

    Science.gov (United States)

    Rodriguez, Ana; Tarleton, Rick L.

    2013-01-01

    Parasitic neglected diseases are in dire need of new drugs either to replace old drugs rendered ineffective because of resistance development, to cover clinical needs that had never been addressed or to tackle other associated problems of existing drugs such as high cost, difficult administration, restricted coverage or toxicity. The availability of transgenic parasites expressing reporter genes facilitates the discovery of new drugs through high throughput screenings, but also by allowing rapid screening in animal models of disease. Taking advantage of these, we propose an alternative pathway of drug development for neglected diseases, going from high throughput screening directly into in vivo testing of the top ranked compounds selected by medicinal chemistry. Rapid assessment animal models allow for identification of compounds with bona fide activity in vivo early in the development chain, constituting a solid basis for further development and saving valuable time and resources. PMID:22277131

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

    Science.gov (United States)

    Foster, Anita K.; MacDonald, Jean B.

    2013-01-01

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

  18. Zebrafish xenograft models of cancer and metastasis for drug discovery.

    Science.gov (United States)

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

    2017-04-01

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

  19. In silico discoveries for biomedical sciences

    NARCIS (Netherlands)

    Haagen, Herman van

    2011-01-01

    Text-mining is a challenging field of research initially meant for reading large text collections with a computer. Text-mining is useful in summarizing text, searching for the informative documents, and most important to do knowledge discovery. Knowledge discovery is the main subject of this thesis.

  20. Discovery and Innovation: About this journal

    African Journals Online (AJOL)

    Discovery and Innovation: About this journal. Journal Home > Discovery and Innovation: About this journal. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register · Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives. People. » Contact ...

  1. 15 CFR 785.8 - Discovery.

    Science.gov (United States)

    2010-01-01

    ... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Discovery. 785.8 Section 785.8 Commerce and Foreign Trade Regulations Relating to Commerce and Foreign Trade (Continued) BUREAU OF INDUSTRY AND SECURITY, DEPARTMENT OF COMMERCE ADDITIONAL PROTOCOL REGULATIONS ENFORCEMENT § 785.8 Discovery...

  2. Accounting for discovery bias in genomic prediction

    Science.gov (United States)

    Our objective was to evaluate an approach to mitigating discovery bias in genomic prediction. Accuracy may be improved by placing greater emphasis on regions of the genome expected to be more influential on a trait. Methods emphasizing regions result in a phenomenon known as “discovery bias” if info...

  3. 31 CFR 10.71 - Discovery.

    Science.gov (United States)

    2010-07-01

    ... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Discovery. 10.71 Section 10.71 Money and Finance: Treasury Office of the Secretary of the Treasury PRACTICE BEFORE THE INTERNAL REVENUE... seeking the discovery through another source. (e) Failure to comply. Where a party fails to comply with an...

  4. False Discovery Rates and Multiple Testing

    Indian Academy of Sciences (India)

    IAS Admin

    RESONANCE | December 2013. GENERAL | ARTICLE. False Discovery Rates and Multiple Testing. Soumen Dey and Mohan Delampady. Keywords. False discovery rate, FDR,. pFDR, multiple testing, empiri- cal Bayes, hierarchical Bayes, high-dimensional problems. Soumen Dey is a research scholar at ISI, Bangalore.

  5. On Consistency Maintenance In Service Discovery

    NARCIS (Netherlands)

    Sundramoorthy, V.; Hartel, Pieter H.; Scholten, Johan

    2005-01-01

    Communication and node failures degrade the ability of a service discovery protocol to ensure Users receive the correct service information when the service changes. We propose that service discovery protocols employ a set of recovery techniques to recover from failures and regain consistency. We

  6. 42 CFR 3.516 - Discovery.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Discovery. 3.516 Section 3.516 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PATIENT SAFETY ORGANIZATIONS AND PATIENT SAFETY WORK PRODUCT Enforcement Program § 3.516 Discovery. (a) A party may make a request...

  7. 31 CFR 16.21 - Discovery.

    Science.gov (United States)

    2010-07-01

    ... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Discovery. 16.21 Section 16.21 Money and Finance: Treasury Office of the Secretary of the Treasury REGULATIONS IMPLEMENTING THE PROGRAM... to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

  8. Service discovery in heterogeneous wireless networks

    NARCIS (Netherlands)

    Blangé, M.J.; Karkowski, I.P.; Vermeulen, B.C.B.

    2005-01-01

    In this paper we describe a possible solution to the problem of service discovery in heterogeneous wireless networks. This solution involves introduction of a network independent service discovery layer, with as main goal the improved robustness of applications running on top of it. A possible

  9. 12 CFR 908.46 - Discovery.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Discovery. 908.46 Section 908.46 Banks and Banking FEDERAL HOUSING FINANCE BOARD FEDERAL HOUSING FINANCE BOARD ORGANIZATION AND OPERATIONS RULES OF... Congress, or the principles of common law. (e) Time limits. All discovery, including all responses to...

  10. Can biochemistry drive drug discovery beyond simple potency measurements?

    Science.gov (United States)

    Chène, Patrick

    2012-04-01

    Among the fields of expertise required to develop drugs successfully, biochemistry holds a key position in drug discovery at the interface between chemistry, structural biology and cell biology. However, taking the example of protein kinases, it appears that biochemical assays are mostly used in the pharmaceutical industry to measure compound potency and/or selectivity. This limited use of biochemistry is surprising, given that detailed biochemical analyses are commonly used in academia to unravel molecular recognition processes. In this article, I show that biochemistry can provide invaluable information on the dynamics and energetics of compound-target interactions that cannot be obtained on the basis of potency measurements and structural data. Therefore, an extensive use of biochemistry in drug discovery could facilitate the identification and/or development of new drugs. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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.

  12. Knowledge Discovery from Vibration Measurements

    Directory of Open Access Journals (Sweden)

    Jun Deng

    2014-01-01

    Full Text Available The framework as well as the particular algorithms of pattern recognition process is widely adopted in structural health monitoring (SHM. However, as a part of the overall process of knowledge discovery from data bases (KDD, the results of pattern recognition are only changes and patterns of changes of data features. In this paper, based on the similarity between KDD and SHM and considering the particularity of SHM problems, a four-step framework of SHM is proposed which extends the final goal of SHM from detecting damages to extracting knowledge to facilitate decision making. The purposes and proper methods of each step of this framework are discussed. To demonstrate the proposed SHM framework, a specific SHM method which is composed by the second order structural parameter identification, statistical control chart analysis, and system reliability analysis is then presented. To examine the performance of this SHM method, real sensor data measured from a lab size steel bridge model structure are used. The developed four-step framework of SHM has the potential to clarify the process of SHM to facilitate the further development of SHM techniques.

  13. Shotgun Proteomics and Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    W. Hayes McDonald

    2002-01-01

    Full Text Available Coupling large-scale sequencing projects with the amino acid sequence information that can be gleaned from tandem mass spectrometry (MS/MS has made it much easier to analyze complex mixtures of proteins. The limits of this “shotgun” approach, in which the protein mixture is proteolytically digested before separation, can be further expanded by separating the resulting mixture of peptides prior to MS/MS analysis. Both single dimensional high pressure liquid chromatography (LC and multidimensional LC (LC/LC can be directly interfaced with the mass spectrometer to allow for automated collection of tremendous quantities of data. While there is no single technique that addresses all proteomic challenges, the shotgun approaches, especially LC/LC-MS/MS-based techniques such as MudPIT (multidimensional protein identification technology, show advantages over gel-based techniques in speed, sensitivity, scope of analysis, and dynamic range. Advances in the ability to quantitate differences between samples and to detect for an array of post-translational modifications allow for the discovery of classes of protein biomarkers that were previously unassailable.

  14. Mathematical models in biological discovery

    CERN Document Server

    Walter, Charles

    1977-01-01

    When I was asked to help organize an American Association for the Advancement of Science symposium about how mathematical models have con­ tributed to biology, I agreed immediately. The subject is of immense importance and wide-spread interest. However, too often it is discussed in biologically sterile environments by "mutual admiration society" groups of "theoreticians", many of whom have never seen, and most of whom have never done, an original scientific experiment with the biolog­ ical materials they attempt to describe in abstract (and often prejudiced) terms. The opportunity to address the topic during an annual meeting of the AAAS was irresistable. In order to try to maintain the integrity ;,f the original intent of the symposium, it was entitled, "Contributions of Mathematical Models to Biological Discovery". This symposium was organized by Daniel Solomon and myself, held during the 141st annual meeting of the AAAS in New York during January, 1975, sponsored by sections G and N (Biological and Medic...

  15. NIF Discovery Science Eagle Nebula

    Science.gov (United States)

    Kane, Jave; Martinez, David; Pound, Marc; Heeter, Robert; Casner, Alexis; Villette, Bruno; Mancini, Roberto

    2017-10-01

    The University of Maryland and and LLNL are investigating the origin and dynamics of the famous Pillars of the Eagle Nebula and similar parsec-scale structures at the boundaries of HII regions in molecular hydrogen clouds. The National Ignition Facility (NIF) Discovery Science program Eagle Nebula has performed NIF shots to study models of pillar formation. The shots feature a new long-duration x-ray source, in which multiple hohlraums mimicking a cluster of stars are driven with UV light in series for 10 to 15 ns each to create a 30 to 60 ns output x-ray pulse. The source generates deeply nonlinear hydrodynamics in the Eagle science package, a structure of dense plastic and foam mocking up a molecular cloud containing a dense core. Omega EP and NIF shots have validated the source concept, showing that earlier hohlraums do not compromise later ones by preheat or by ejecting ablated plumes that deflect later beams. The NIF shots generated radiographs of shadowing-model pillars, and also showed evidence that cometary structures can be generated. The velocity and column density profiles of the NIF shadowing and cometary pillars have been compared with observations of the Eagle Pillars made at the millimeter-wave BIMA and CARMA observatories. Prepared by LLNL under Contract DE-AC52-07NA27344.

  16. Discovery Mondays: Zoom on materials

    CERN Multimedia

    2003-01-01

    Following the success of the first Discovery Monday, which had over 100 visitors, the series of evening events in Microcosm continues. On Monday 2nd June, discover the world of materials. Find out how CERN scientists examine, manufacture and study different materials, at different scales. Did you know for example that using electrons you can observe a hair at a scale equivalent to looking at a boat with the naked eye? Also, that using ultrasound, you can measure the thickness of an object that is completely inaccessible? Find out more about these techniques, and also the high-tech machining and soldering that is carried out in CERN's central workshop. Plus, see how engineers can detect tiny leaks through solder points - essential for maintaining the vacuum in the LHC. The evening is open to all, without reservation, suggested age 12 and above. Rendez-vous in Microcosm on Monday 2nd June From 19.30 - 21.00 Free entry For more information : http://www.cern.ch/microcosm Using a scanning microscope, the head o...

  17. The Discovery of Dabigatran Etexilate

    Directory of Open Access Journals (Sweden)

    Joanne evan Ryn

    2013-02-01

    Full Text Available Thromboembolic disease is a major cause of mortality and morbidity in the developed world and is caused by an excessive stimulation of coagulation. Thrombin is a key serine protease in the coagulation cascade and numerous efforts have been made to develop safe and effective orally active direct thrombin inhibitors (DTIs. Current anticoagulant therapy includes the use of indirect thrombin inhibitors (e.g. heparins, low-molecular-weight-heparins [LMWHs] and vitamin K antagonists (VKA such as warfarin. However there are several caveats in the clinical use of these agents including narrow therapeutic window, parenteral delivery, and food- and drug-drug interactions. Dabigatran is a synthetic, reversible DTI with high affinity and specificity for its target binding both free and clot-bound thrombin, and offers a favorable pharmacokinetic profile. Large randomized clinical trials have demonstrated that dabigatran provides comparable or superior thromboprophylaxis in multiple thromboembolic disease indications compared to standard of care. This minireview will highlight the discovery and development of dabigatran, the first in a class of new oral anticoagulant (NOAC agents to be licensed worldwide for the prevention of thromboembolism in the setting of orthopedic surgery and stroke prevent in atrial fibrillation.

  18. Respiratory knowledge discovery utilising expertise

    Directory of Open Access Journals (Sweden)

    Tristan Ling

    2012-12-01

    Full Text Available BackgroundSignificant amounts of medical data are being archived, in the hope that they can be analysed and provide insight. A critical problem with analysing such data is the amount of existing knowledge required to produce effective results.AimsThis study tests a method that seeks to overcome these problems with analysis, by testing it over a large set of archived lung function test results. A knowledge base of lung function interpretation expertise has been compiled and serves as a base for analysis.MethodA user examines the dataset with the assistance of the knowledge discovery tool. Two pertinent respiratory research questions are analysed (the relative correlation between diffusing capacity and FEV1 or FVC bronchodilator response, and the effects of BMI on various parameters of lung function, and the results compared and contrasted with relevant literature.ResultsThe method finds interesting results from the lung function data supporting and questioning other published studies, while also finding correlations that suggest further areas of research.ConclusionWhile the analysis does not necessarily reveal groundbreaking information, it shows that the method can successfully discover new knowledge and is useful in a research context.

  19. West Nile Virus Drug Discovery

    Directory of Open Access Journals (Sweden)

    Siew Pheng Lim

    2013-12-01

    Full Text Available The outbreak of West Nile virus (WNV in 1999 in the USA, and its continued spread throughout the Americas, parts of Europe, the Middle East and Africa, underscored the need for WNV antiviral development. Here, we review the current status of WNV drug discovery. A number of approaches have been used to search for inhibitors of WNV, including viral infection-based screening, enzyme-based screening, structure-based virtual screening, structure-based rationale design, and antibody-based therapy. These efforts have yielded inhibitors of viral or cellular factors that are critical for viral replication. For small molecule inhibitors, no promising preclinical candidate has been developed; most of the inhibitors could not even be advanced to the stage of hit-to-lead optimization due to their poor drug-like properties. However, several inhibitors developed for related members of the family Flaviviridae, such as dengue virus and hepatitis C virus, exhibited cross-inhibition of WNV, suggesting the possibility to re-purpose these antivirals for WNV treatment. Most promisingly, therapeutic antibodies have shown excellent efficacy in mouse model; one of such antibodies has been advanced into clinical trial. The knowledge accumulated during the past fifteen years has provided better rationale for the ongoing WNV and other flavivirus antiviral development.

  20. Students Excited by Stellar Discovery

    Science.gov (United States)

    2011-02-01

    In the constellation of Ophiuchus, above the disk of our Milky Way Galaxy, there lurks a stellar corpse spinning 30 times per second -- an exotic star known as a radio pulsar. This object was unknown until it was discovered last week by three high school students. These students are part of the Pulsar Search Collaboratory (PSC) project, run by the National Radio Astronomy Observatory (NRAO) in Green Bank, WV, and West Virginia University (WVU). The pulsar, which may be a rare kind of neutron star called a recycled pulsar, was discovered independently by Virginia students Alexander Snider and Casey Thompson, on January 20, and a day later by Kentucky student Hannah Mabry. "Every day, I told myself, 'I have to find a pulsar. I better find a pulsar before this class ends,'" said Mabry. When she actually made the discovery, she could barely contain her excitement. "I started screaming and jumping up and down." Thompson was similarly expressive. "After three years of searching, I hadn't found a single thing," he said, "but when I did, I threw my hands up in the air and said, 'Yes!'." Snider said, "It actually feels really neat to be the first person to ever see something like that. It's an uplifting feeling." As part of the PSC, the students analyze real data from NRAO's Robert C. Byrd Green Bank Telescope (GBT) to find pulsars. The students' teachers -- Debra Edwards of Sherando High School, Leah Lorton of James River High School, and Jennifer Carter of Rowan County Senior High School -- all introduced the PSC in their classes, and interested students formed teams to continue the work. Even before the discovery, Mabry simply enjoyed the search. "It just feels like you're actually doing something," she said. "It's a good feeling." Once the pulsar candidate was reported to NRAO, Project Director Rachel Rosen took a look and agreed with the young scientists. A followup observing session was scheduled on the GBT. Snider and Mabry traveled to West Virginia to assist in the

  1. Discoveries on the Norwegian continental shelf

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-02-01

    As discussed in this document, there are 108 discoveries on the Norwegian continental shelf which so far have not been approved for development. The oil and gas resources of the Norwegian Sea and the Barents Sea are mostly found in discoveries containing large volumes of gas. Eighty-one of the discoveries which are not approved for development are located in the North Sea and more than 60% of the discoveries in this province contain less than 5 mill Sm{sup 3} oil equivalents. In the Norwegian Sea and the Barents Sea there are 27 discoveries which are not approved for development and whose total resources are estimated at 500 mill Sm{sup 3} oil equivalents. About 60% of the oil resources is expected to be comprised by development plans in 1997 or 1998. Another 20% is in new discoveries currently being evaluated or in discoveries containing large volumes of gas. Production forecasts indicate substantial vacant oil processing capacity after 2000. Vacant gas processing capacity will mainly arise after 2005. 23 figs., 3 tabs.

  2. Functional Principles of Registry-based Service Discovery

    NARCIS (Netherlands)

    Sundramoorthy, V.; Tan, C.; Hartel, Pieter H.; den Hartog, Jeremy; Scholten, Johan

    As Service Discovery Protocols (SDP) are becoming increasingly important for ubiquitous computing, they must behave according to predefined principles. We present the functional Principles of Service Discovery for robust, registry-based service discovery. A methodology to guarantee adherence to

  3. Systems biology and biomarker discovery

    Energy Technology Data Exchange (ETDEWEB)

    Rodland, Karin D.

    2010-12-01

    Medical practitioners have always relied on surrogate markers of inaccessible biological processes to make their diagnosis, whether it was the pallor of shock, the flush of inflammation, or the jaundice of liver failure. Obviously, the current implementation of biomarkers for disease is far more sophisticated, relying on highly reproducible, quantitative measurements of molecules that are often mechanistically associated with the disease in question, as in glycated hemoglobin for the diagnosis of diabetes [1] or the presence of cardiac troponins in the blood for confirmation of myocardial infarcts [2]. In cancer, where the initial symptoms are often subtle and the consequences of delayed diagnosis often drastic for disease management, the impetus to discover readily accessible, reliable, and accurate biomarkers for early detection is compelling. Yet despite years of intense activity, the stable of clinically validated, cost-effective biomarkers for early detection of cancer is pathetically small and still dominated by a handful of markers (CA-125, CEA, PSA) first discovered decades ago. It is time, one could argue, for a fresh approach to the discovery and validation of disease biomarkers, one that takes full advantage of the revolution in genomic technologies and in the development of computational tools for the analysis of large complex datasets. This issue of Disease Markers is dedicated to one such new approach, loosely termed the 'Systems Biology of Biomarkers'. What sets the Systems Biology approach apart from other, more traditional approaches, is both the types of data used, and the tools used for data analysis - and both reflect the revolution in high throughput analytical methods and high throughput computing that has characterized the start of the twenty first century.

  4. Biomarkers: in medicine, drug discovery, and environmental health

    National Research Council Canada - National Science Library

    Vaidya, Vishal S; Bonventre, Joseph V

    2010-01-01

    ... Identification Using Mass Spectrometry Sample Preparation Protein Quantitation Examples of Biomarker Discovery and Evaluation Challenges in Proteomic Biomarker Discovery The Road Forward: Targeted ...

  5. Orphan nuclear receptors, excellent targets of drug discovery.

    Science.gov (United States)

    Shi, Yanhong

    2006-11-01

    To date, the pharmaceutical industry has placed a considerable amount of interest in the discovery of drug targets and diagnostics. One of the most challenging areas of drug discovery today is the search for novel receptor-ligand pairs. Nuclear receptors comprise a large superfamily of ligand-dependent transcription factors that regulate the expression of genes critical for a variety of biological processes, including development, growth, differentiation, and homeostasis. Orphan nuclear receptors, for which the ligands are not yet identified, represent the most ancient component of the nuclear receptor superfamily. Orphan nuclear receptors not only offer a unique system to uncover novel signaling pathways that impact human health, but also provide excellent targets of drug discoveries for a variety of human diseases. This review highlights advances made on ligand identification for orphan nuclear receptors using transgenic mouse models, cell-based screening, direct binding, structure-based assays, and computer-aided virtual screening. With rapid advances in combinatorial chemistry and high throughput screening, along with other modern technologies, this field promises a bountiful harvest.

  6. History of the discovery of neuronal death in embryos.

    Science.gov (United States)

    Hamburger, V

    1992-11-01

    The German anatomists, M. Ernst and A. Glücksmann, deserve credit for the discovery of widespread cell death in embryonic tissues, including the nervous tissue. In 1934, V. Hamburger described a significant hypoplasia in dorsal root ganglia (DGR) and lateral motor columns, following the extirpation of limb buds in chick embryos. In the early 1940s, Dr. Rita Levi-Montalcini in Turin (Italy) repeated the experiment and suggested that the hypoplasia might result from the death of young differentiated neurons. In a joint reinvestigation, published in 1949, large numbers of degenerating neurons were described in brachial DRG, following wing bud extirpations. In the same embryos, Dr. Levi-Montalcini observed massive neuronal death in cervical and thoracic DRG which had not been affected by the operation. This was the discovery of naturally occurring neuronal death. Long after the discovery of Nerve Growth Factor (NGF) it was recognized that NGF and natural neuronal death are two sides of the same coin: the latter results from an insufficient supply of the former by the target tissues.

  7. Anatomy of the Crowd4Discovery crowdfunding campaign.

    Science.gov (United States)

    Perlstein, Ethan O

    2013-01-01

    Crowdfunding allows the public to fund creative projects, including curiosity-driven scientific research. Last Fall, I was part of a team that raised $25,460 from an international coalition of "micropatrons" for an open, pharmacological research project called Crowd4Discovery. The goal of Crowd4Discovery is to determine the precise location of amphetamines inside mouse brain cells, and we are sharing the results of this project on the Internet as they trickle in. In this commentary, I will describe the genesis of Crowd4Discovery, our motivations for crowdfunding, an analysis of our fundraising data, and the nuts and bolts of running a crowdfunding campaign. Science crowdfunding is in its infancy but has already been successfully used by an array of scientists in academia and in the private sector as both a supplement and a substitute to grants. With traditional government sources of funding for basic scientific research contracting, an alternative model that couples fundraising and outreach - and in the process encourages more openness and accountability - may be increasingly attractive to researchers seeking to diversify their funding streams.

  8. Discovery and validation of the tumor-suppressive function of long noncoding RNA PANDA in human diffuse large B-cell lymphoma through the inactivation of MAPK/ERK signaling pathway.

    Science.gov (United States)

    Wang, Yingjun; Zhang, Mingzhi; Xu, Huanan; Wang, Yifei; Li, Zhaoming; Chang, Yu; Wang, Xinhuan; Fu, Xiaorui; Zhou, Zhiyuan; Yang, Siyuan; Wang, Bei; Shang, Yufeng

    2017-09-22

    Diffuse large B-cell lymphoma (DLBCL) is one of the leading causes of cancer-related mortality, and responds badly to existing treatment. Thus, it is of urgent need to identify novel prognostic markers and therapeutic targets of DLBCL. Recent studies have shown that long non-coding RNAs (lncRNAs) play an important role in the development of cancer. By using the next generation HiSeq sequencing assay, we determined lncRNAs exhibiting differential expression between DLBCL patients and healthy controls. Then, RT-qPCR was performed for identification in clinical samples and cell materials, and lncRNA PANDA was verified to be down-regulated in DLBCL patients and have considerable diagnostic potential. In addition, decreased serum PANDA level was correlated to poorer clinical outcome and lower overall survival in DLBCL patients. Subsequently, we determined the experimental role of lncRNA PANDA in DLBCL progression. Luciferase reporter assay and chromatin immunoprecipitation assay suggested that lncRNA PANDA was induced by p53 and p53 interacts with the promoter region of PANDA. Cell functional assay further indicated that PANDA functioned as a tumor suppressor gene through the suppression of cell growth by a G0/G1 cell cycle arrest in DLBCL. More importantly, Cignal Signal Transduction Reporter Array and western blot assay showed that lncRNA PANDA inactivated the MAPK/ERK signaling pathway. In conclusion, our integrated approach demonstrates that PANDA in DLBCL confers a tumor suppressive function through inhibiting cell proliferation and silencing MAPK/ERK signaling pathway. Thus, PANDA may be a promising therapeutic target for patients with DLBCL.

  9. Queen's discovery lauded by top scientific journal

    CERN Multimedia

    McGrady, S

    2002-01-01

    A scientific breakthrough at Queen's University's Sudbury Neutrino Observatory has received major international recognition. The journal Science ranked the discovery that cracked the "neutrino problem" second, in the journal's top 10 scientific achievements of 2002 (1/2 page).

  10. Literature-Related Discovery: A Review

    National Research Council Canada - National Science Library

    Kostoff, Ronald N; Block, Joel A; Solka, Jeffrey L; Briggs, Michael B; Rushenberg, Robert L; Stump, Jesse A; Johnson, Dustin; Lyons, Terence J; Wyatt, Jeffrey R

    2007-01-01

    .... Literature-related discovery (LRD) is the linking of two or more literature concepts that have heretofore not been linked to produce novel interesting, plausible, and intelligible knowledge (i.e...

  11. Specification Editing and Discovery Assistant Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The project will prototype a specification editing and discovery tool (SPEEDY) for C/C++ that will assist software developers with modular formal verification tasks...

  12. An introduction to web scale discovery systems.

    Science.gov (United States)

    Hoy, Matthew B

    2012-01-01

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

  13. Advances in synthetic peptides reagent discovery

    Science.gov (United States)

    Adams, Bryn L.; Sarkes, Deborah A.; Finch, Amethist S.; Stratis-Cullum, Dimitra N.

    2013-05-01

    Bacterial display technology offers a number of advantages over competing display technologies (e.g, phage) for the rapid discovery and development of peptides with interaction targeted to materials ranging from biological hazards through inorganic metals. We have previously shown that discovery of synthetic peptide reagents utilizing bacterial display technology is relatively simple and rapid to make laboratory automation possible. This included extensive study of the protective antigen system of Bacillus anthracis, including development of discovery, characterization, and computational biology capabilities for in-silico optimization. Although the benefits towards CBD goals are evident, the impact is far-reaching due to our ability to understand and harness peptide interactions that are ultimately extendable to the hybrid biomaterials of the future. In this paper, we describe advances in peptide discovery including, new target systems (e.g. non-biological materials), advanced library development and clone analysis including integrated reporting.

  14. Discovery of Cyclic Peptide Estrogens and Antiestrogens

    National Research Council Canada - National Science Library

    Clark, Daniel

    2004-01-01

    The identification of proteins involved in the initiation of disease and the identification of small molecules that modulate these proteins are of great importance for the discovery of improved therapeutics...

  15. Discovery of Cyclic Peptide Estrogens and Antiestrogens

    National Research Council Canada - National Science Library

    Clark, Daniel

    2003-01-01

    Identification of proteins involved in the initiation of disease and the identification of small molecules that can modulate these proteins are of great importance towards the discovery of treatments...

  16. 42 CFR 1005.7 - Discovery.

    Science.gov (United States)

    2010-10-01

    ... OF EXCLUSIONS, CIVIL MONEY PENALTIES AND ASSESSMENTS § 1005.7 Discovery. (a) A party may make a... contained in this section will be interpreted to require the creation of a document, except that requested...

  17. Taxonomy Enabled Discovery (TED), Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — The proposal addresses the NASA's need to enable scientific discovery and the topic's requirements for: processing large volumes of data, commonly available on the...

  18. Feature Discovery by Competitive Learning.

    Science.gov (United States)

    1984-06-01

    in a high-dimensional hyperspace , our competitive learning mechanism will form essentially spherical regions that partition the space into one such...Malsburg, C. (1973). Self-Organizing of orientation sensitive cells in the striate cortex. Kybernetlk. 14, 85.100. .DflNG pAGE BLANK-14OT F L D Capltive

  19. Applying genetics in inflammatory disease drug discovery

    DEFF Research Database (Denmark)

    Folkersen, Lasse; Biswas, Shameek; Frederiksen, Klaus Stensgaard

    2015-01-01

    , with several notable exceptions, the journey from a small-effect genetic variant to a functional drug has proven arduous, and few examples of actual contributions to drug discovery exist. Here, we discuss novel approaches of overcoming this hurdle by using instead public genetics resources as a pragmatic guide...... alongside existing drug discovery methods. Our aim is to evaluate human genetic confidence as a rationale for drug target selection....

  20. The discovery of the structure of DNA

    Science.gov (United States)

    Squires, G. L.

    2003-04-01

    On 25 April 1953, Nature published a letter by Francis Crick and James Watson, at the Cavendish Laboratory, Cambridge, proposing a structure for DNA. This letter marked the beginning of a revolution in biology. Besides Crick and Watson, two other scientists, Rosalind Franklin and Maurice Wilkins, played key roles in the discovery. After sketching the early careers of the four scientists, the present article gives an account of the physics and chemistry involved in the discovery, and the events leading up to it.

  1. The Gozo discovery bus : a successful experiment

    OpenAIRE

    Vella, Maryrose

    2008-01-01

    The introduction of a tourist discovery bus in Gozo came about as a result of an EU Project which is part of the Interreg III B Archimed programmes in which the Islands and Small States Institute of the University of Malta participated. Other countries participating in this programme besides Malta, represented by the Islands and Small States Institute, are Italy, Cyprus and Greece. The discovery bus service was aimed at encouraging more tourists to come to Gozo and enabling them to visit stra...

  2. Compound Data Mining for Drug Discovery.

    Science.gov (United States)

    Bajorath, Jürgen

    2017-01-01

    In recent years, there has been unprecedented growth in compound activity data in the public domain. These compound data provide an indispensable resource for drug discovery in academic environments as well as in the pharmaceutical industry. To handle large volumes of heterogeneous and complex compound data and extract discovery-relevant knowledge from these data, advanced computational mining approaches are required. Herein, major public compound data repositories are introduced, data confidence criteria reviewed, and selected data mining approaches discussed.

  3. Bioinformatics for cancer immunotherapy target discovery

    DEFF Research Database (Denmark)

    Olsen, Lars Rønn; Campos, Benito; Barnkob, Mike Stein

    2014-01-01

    cancer immunotherapies has yet to be fulfilled. The insufficient efficacy of existing treatments can be attributed to a number of biological and technical issues. In this review, we detail the current limitations of immunotherapy target selection and design, and review computational methods to streamline...... therapy target discovery in a bioinformatics analysis pipeline. We describe specialized bioinformatics tools and databases for three main bottlenecks in immunotherapy target discovery: the cataloging of potentially antigenic proteins, the identification of potential HLA binders, and the selection epitopes...

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

    Science.gov (United States)

    Drinkwater, Nyssa; McGowan, Sheena

    2014-08-01

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

  5. Applications of fiber-optics-based nanosensors to drug discovery.

    Science.gov (United States)

    Vo-Dinh, Tuan; Scaffidi, Jonathan; Gregas, Molly; Zhang, Yan; Seewaldt, Victoria

    2009-08-01

    Fiber-optic nanosensors are fabricated by heating and pulling optical fibers to yield sub-micron diameter tips and have been used for in vitro analysis of individual living mammalian cells. Immobilization of bioreceptors (e.g., antibodies, peptides, DNA) selective to targeting analyte molecules of interest provides molecular specificity. Excitation light can be launched into the fiber, and the resulting evanescent field at the tip of the nanofiber can be used to excite target molecules bound to the bioreceptor molecules. The fluorescence or surface-enhanced Raman scattering produced by the analyte molecules is detected using an ultra-sensitive photodetector. This article provides an overview of the development and application of fiber-optic nanosensors for drug discovery. The nanosensors provide minimally invasive tools to probe subcellular compartments inside single living cells for health effect studies (e.g., detection of benzopyrene adducts) and medical applications (e.g., monitoring of apoptosis in cells treated with anticancer drugs).

  6. Target discovery from data mining approaches.

    Science.gov (United States)

    Yang, Yongliang; Adelstein, S James; Kassis, Amin I

    2012-02-01

    Data mining of available biomedical data and information has greatly boosted target discovery in the 'omics' era. Target discovery is the key step in the biomarker and drug discovery pipeline to diagnose and fight human diseases. In biomedical science, the 'target' is a broad concept ranging from molecular entities (such as genes, proteins and miRNAs) to biological phenomena (such as molecular functions, pathways and phenotypes). Within the context of biomedical science, data mining refers to a bioinformatics approach that combines biological concepts with computer tools or statistical methods that are mainly used to discover, select and prioritize targets. In response to the huge demand of data mining for target discovery in the 'omics' era, this review explicates various data mining approaches and their applications to target discovery with emphasis on text and microarray data analysis. Two emerging data mining approaches, chemogenomic data mining and proteomic data mining, are briefly introduced. Also discussed are the limitations of various data mining approaches found in the level of database integration, the quality of data annotation, sample heterogeneity and the performance of analytical and mining tools. Tentative strategies of integrating different data sources for target discovery, such as integrated text mining with high-throughput data analysis and integrated mining with pathway databases, are introduced. Published by Elsevier Ltd.

  7. Insecticide discovery: an evaluation and analysis.

    Science.gov (United States)

    Sparks, Thomas C

    2013-09-01

    There is an on-going need for the discovery and development of new insecticides due to the loss of existing products through the development of resistance, the desire for products with more favorable environmental and toxicological profiles, shifting pest spectrums, and changing agricultural practices. Since 1960, the number of research-based companies in the US and Europe involved in the discovery of new insecticidal chemistries has been declining. In part this is a reflection of the increasing costs of the discovery and development of new pesticides. Likewise, the number of compounds that need to be screened for every product developed has, until recently, been climbing. In the past two decades the agrochemical industry has been able to develop a range of new products that have more favorable mammalian vs. insect selectivity. This review provides an analysis of the time required for the discovery, or more correctly the building process, for a wide range of insecticides developed during the last 60 years. An examination of the data around the time requirements for the discovery of products based on external patents, prior internal products, or entirely new chemistry provides some unexpected observations. In light of the increasing costs of discovery and development, coupled with fewer companies willing or able to make the investment, insecticide resistance management takes on greater importance as a means to preserve existing and new insecticides. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Shuttle Discovery Landing at Edwards

    Science.gov (United States)

    1989-01-01

    The STS-29 Space Shuttle Discovery mission lands at NASA's then Ames-Dryden Flight Research Facility, Edwards AFB, California, early Saturday morning, 18 March 1989. Touchdown was at 6:35:49 a.m. PST and wheel stop was at 6:36:40 a.m. on runway 22. Controllers chose the concrete runway for the landing in order to make tests of braking and nosewheel steering. The STS-29 mission was very successful, completing the launch of a Tracking and Data Relay communications satellite, as well as a range of scientific experiments. Discovery's five-man crew was led by Commander Michael L. Coats, and included pilot John E. Blaha and mission specialists James P. Bagian, Robert C. Springer, and James F. Buchli. Space Shuttles are the main element of America's Space Transportation System and are used for space research and other space applications. The shuttles are the first vehicles capable of being launched into space and returning to Earth on a routine basis. Space Shuttles are used as orbiting laboratories in which scientists and mission specialists conduct a wide variety of scientific experiments. Crews aboard shuttles place satellites in orbit, rendezvous with satellites to carry out repair missions and return them to space, and retrieve satellites and return them to Earth for refurbishment and reuse. Space Shuttles are true aerospace vehicles. They leave Earth and its atmosphere under rocket power provided by three liquid-propellant main engines with two solid-propellant boosters attached plus an external liquid-fuel tank. After their orbital missions, they streak back through the atmosphere and land like airplanes. The returning shuttles, however, land like gliders, without power and on runways. Other rockets can place heavy payloads into orbit, but, they can only be used once. Space Shuttles are designed to be continually reused. When Space Shuttles are used to transport complete scientific laboratories into space, the laboratories remain inside the payload bay throughout

  9. Electrochemistry "Discovery" Course for Undergraduates

    Science.gov (United States)

    May, Michael Alan; Gupta, Vijay K.

    1997-07-01

    We developed a chemistry selected topics course at Central State University, "Introduction to Laboratory Techniques in Electrochemistry" to: (1) give undergraduates hands-on experience with electrochemical measurements, (2) prepare students for summer research in Fuel Cell and Battery technology. Since students "learn by doing", the course is suitable for undergraduates from sophomore to senior levels. Students complete 6 laboratories, based on a "less is more" philosophy which emphasizes analytic and creative process rather than mandatory topical coverage. Eight electrochemical experiments are available: Construction of Zinc-Copper battery stacks, Lead Acid Battery discharge-charge cycles, Conductimetric titration of aspirin with Ammonium Hydroxide, Ion Selective Electrode determination of Fluoride in water, Cyclic Voltammetry of Potassium Ferricyanide solution, Cyclic Voltammetry of Sulfuric acid on Platinum working electrode, Anodic Stripping Voltammetry of Lead ion in solution, Differential Pulse Polarography of Lead ion in solution. Topics discussed in lecture include: chemical definitions, electrical definitions, Oxidation-Reduction reactions, Electrochemical series, Electrodes, Electrochemical Cells, direct Coulometry, electrolysis, electrochemical process efficiency, equilibrium Potentiometry, real Cell Voltages, Ion Selective Electrode types and designs, reference electrode designs, working electrode materials, pH buffers, Cyclic Voltammetry, Anodic Stripping Voltammetry, Polarography, differential pulse Polarography, and simple electrochemical instrumentation circuits.

  10. Target discovery of acivicin in cancer cells elucidates its mechanism of growth inhibition†Electronic supplementary information (ESI) available: Synthesis, cloning, protein expression, purification and biochemical assays. See DOI: 10.1039/c4sc02339k.

    Science.gov (United States)

    Kreuzer, Johannes; Bach, Nina C; Forler, Daniel; Sieber, Stephan A

    2014-12-01

    Acivicin is a natural product with diverse biological activities. Several decades ago its clinical application in cancer treatment was explored but failed due to unacceptable toxicity. The causes behind the desired and undesired biological effects have never been elucidated and only limited information about acivicin-specific targets is available. In order to elucidate the target spectrum of acivicin in more detail we prepared functionalized derivatives and applied them for activity based proteomic profiling (ABPP) in intact cancer cells. Target deconvolution by quantitative mass spectrometry (MS) revealed a preference for specific aldehyde dehydrogenases. Further in depth target validation confirmed that acivicin inhibits ALDH4A1 activity by binding to the catalytic site. In accordance with this, downregulation of ALDH4A1 by siRNA resulted in a severe inhibition of cell growth and might thus provide an explanation for the cytotoxic effects of acivicin.

  11. Chemical reporters for biological discovery.

    Science.gov (United States)

    Grammel, Markus; Hang, Howard C

    2013-08-01

    Functional tools are needed to understand complex biological systems. Here we review how chemical reporters in conjunction with bioorthogonal labeling methods can be used to image and retrieve nucleic acids, proteins, glycans, lipids and other metabolites in vitro, in cells as well as in whole organisms. By tagging these biomolecules, researchers can now monitor their dynamics in living systems and discover specific substrates of cellular pathways. These advances in chemical biology are thus providing important tools to characterize biological pathways and are poised to facilitate our understanding of human diseases.

  12. History, Discovery, and Classification of lncRNAs.

    Science.gov (United States)

    Jarroux, Julien; Morillon, Antonin; Pinskaya, Marina

    2017-01-01

    The RNA World Hypothesis suggests that prebiotic life revolved around RNA instead of DNA and proteins. Although modern cells have changed significantly in 4 billion years, RNA has maintained its central role in cell biology. Since the discovery of DNA at the end of the nineteenth century, RNA has been extensively studied. Many discoveries such as housekeeping RNAs (rRNA, tRNA, etc.) supported the messenger RNA model that is the pillar of the central dogma of molecular biology, which was first devised in the late 1950s. Thirty years later, the first regulatory non-coding RNAs (ncRNAs) were initially identified in bacteria and then in most eukaryotic organisms. A few long ncRNAs (lncRNAs) such as H19 and Xist were characterized in the pre-genomic era but remained exceptions until the early 2000s. Indeed, when the sequence of the human genome was published in 2001, studies showed that only about 1.2% encodes proteins, the rest being deemed "non-coding." It was later shown that the genome is pervasively transcribed into many ncRNAs, but their functionality remained controversial. Since then, regulatory lncRNAs have been characterized in many species and were shown to be involved in processes such as development and pathologies, revealing a new layer of regulation in eukaryotic cells. This newly found focus on lncRNAs, together with the advent of high-throughput sequencing, was accompanied by the rapid discovery of many novel transcripts which were further characterized and classified according to specific transcript traits.In this review, we will discuss the many discoveries that led to the study of lncRNAs, from Friedrich Miescher's "nuclein" in 1869 to the elucidation of the human genome and transcriptome in the early 2000s. We will then focus on the biological relevance during lncRNA evolution and describe their basic features as genes and transcripts. Finally, we will present a non-exhaustive catalogue of lncRNA classes, thus illustrating the vast complexity of

  13. Recent lab-on-chip developments for novel drug discovery.

    Science.gov (United States)

    Khalid, Nauman; Kobayashi, Isao; Nakajima, Mitsutoshi

    2017-07-01

    Microelectromechanical systems (MEMS) and micro total analysis systems (μTAS) revolutionized the biochemical and electronic industries, and this miniaturization process became a key driver for many markets. Now, it is a driving force for innovations in life sciences, diagnostics, analytical sciences, and chemistry, which are called 'lab-on-a-chip, (LOC)' devices. The use of these devices allows the development of fast, portable, and easy-to-use systems with a high level of functional integration for applications such as point-of-care diagnostics, forensics, the analysis of biomolecules, environmental or food analysis, and drug development. In this review, we report on the latest developments in fabrication methods and production methodologies to tailor LOC devices. A brief overview of scale-up strategies is also presented together with their potential applications in drug delivery and discovery. The impact of LOC devices on drug development and discovery has been extensively reviewed in the past. The current research focuses on fast and accurate detection of genomics, cell mutations and analysis, drug delivery, and discovery. The current research also differentiates the LOC devices into new terminology of microengineering, like organ-on-a-chip, stem cells-on-a-chip, human-on-a-chip, and body-on-a-chip. Key challenges will be the transfer of fabricated LOC devices from lab-scale to industrial large-scale production. Moreover, extensive toxicological studies are needed to justify the use of microfabricated drug delivery vehicles in biological systems. It will also be challenging to transfer the in vitro findings to suitable and promising in vivo models. WIREs Syst Biol Med 2017, 9:e1381. doi: 10.1002/wsbm.1381 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

  14. Internet Naming and Discovery Architecture and Economics

    CERN Document Server

    Khoury, Joud S

    2013-01-01

    Naming is an integral building block within data networks and systems and is becoming ever more important as complex data-centric usage models emerge. Internet Naming and Discovery is timely in developing a unified model for studying the topic of naming and discovery. It details the architectural and economic tools needed for designing naming and discovery schemes within the broader context of internetwork architecture.   Readers will find in this book a historic overview of the Internet and a comprehensive survey of the literature, followed by and an in-depth examination of naming and discovery. Specific topics covered include: ·         formal definitions of name, address, identifier, locator, binding, routing, discovery, mapping, and resolution; ·         a discussion of the properties of names and bindings, along with illustrative case studies; ·         taxonomy that helps in organizing the solution space, and more importantly in identifying new avenues for contributing to the...

  15. The Discovery of Subatomic Particles Revised Edition

    Science.gov (United States)

    Weinberg, Steven

    2003-09-01

    This commentary on the discovery of the atom's constituents provides an historical account of key events in the physics of the twentieth century that led to the discoveries of the electron, proton and neutron. Steven Weinberg introduces the fundamentals of classical physics that played crucial roles in these discoveries. Connections are shown throughout the book between the historic discoveries of subatomic particles and contemporary research at the frontiers of physics, including the most current discoveries of new elementary particles. Steven Weinberg was Higgins Professor of Physics at Harvard before moving to The University of Texas at Austin, where he founded its Theory Group. At Texas he holds the Josey Regental Chair of Science and is a member of the Physics and Astronomy Departments. His research has spanned a broad range of topics in quantum field theory, elementary particle physics, and cosmology, and has been honored with numerous awards, including the Nobel Prize in Physics, the National Medal of Science, the Heinemann Prize in Mathematical Physics, the Cresson Medal of the Franklin Institute, the Madison Medal of Princeton University, and the Oppenheimer Prize. In addition to the well-known treatise, Gravitation and Cosmololgy, he has written several books for general readers, including the prize-winning The First Three Minutes (now translated into 22 foreign languages), and most recently Dreams of a Final Theory (Pantheon Books, 1993). He has also written a textbook The Quantum Theory of Fields, Vol.I, Vol. II, and Vol. III (Cambridge).

  16. Lifeomics leads the age of grand discoveries.

    Science.gov (United States)

    He, Fuchu

    2013-03-01

    When our knowledge of a field accumulates to a certain level, we are bound to see the rise of one or more great scientists. They will make a series of grand discoveries/breakthroughs and push the discipline into an 'age of grand discoveries'. Mathematics, geography, physics and chemistry have all experienced their ages of grand discoveries; and in life sciences, the age of grand discoveries has appeared countless times since the 16th century. Thanks to the ever-changing development of molecular biology over the past 50 years, contemporary life science is once again approaching its breaking point and the trigger for this is most likely to be 'lifeomics'. At the end of the 20th century, genomics wrote out the 'script of life'; proteomics decoded the script; and RNAomics, glycomics and metabolomics came into bloom. These 'omics', with their unique epistemology and methodology, quickly became the thrust of life sciences, pushing the discipline to new high. Lifeomics, which encompasses all omics, has taken shape and is now signalling the dawn of a new era, the age of grand discoveries.

  17. Target-oriented discovery of a new esterase-producing strain Enterobacter sp. ECU1107 for whole cell-catalyzed production of (2S,3R)-3-phenylglycidate as a chiral synthon of Taxol.

    Science.gov (United States)

    Zhou, Dong-Jie; Pan, Jiang; Yu, Hui-Lei; Zheng, Gao-Wei; Xu, Jian-He

    2013-07-01

    A new strain, Enterobacter sp. ECU1107, was identified among over 200 soil isolates using a two-step screening strategy for the enantioselective synthesis of (2S,3R)-3-phenylglycidate methyl ester (PGM), a key intermediate for production of a potent anticancer drug Taxol®. An organic-aqueous biphasic system was employed to reduce spontaneous hydrolysis of the substrate PGM and isooctane was found to be the most suitable organic solvent. The temperature and pH optima of the whole cell-mediated bioreaction were 40 °C and 6.0, respectively. Under these reaction conditions, the enantiomeric excess (ee(s)) of (2S,3R)-PGM recovered was greater than 99 % at approximately 50 % conversion. The total substrate loading in batch reaction could reach 600 mM. By using whole cells of Enterobacter sp. ECU1107, (2S,3R)-PGM was successfully prepared in decagram scale in a 1.0-l mechanically stirred reactor, affording the chiral epoxy ester in >99 % ee s and 43.5 % molar yield based on the initial load of racemic substrate.

  18. Discovery of a novel restriction endonuclease by genome comparison and application of a wheat-germ-based cell-free translation assay: PabI (5'-GTA/C) from the hyperthermophilic archaeon Pyrococcus abyssi.

    Science.gov (United States)

    Ishikawa, Ken; Watanabe, Miki; Kuroita, Toshihiro; Uchiyama, Ikuo; Bujnicki, Janusz M; Kawakami, Bunsei; Tanokura, Masaru; Kobayashi, Ichizo

    2005-07-21

    To search for restriction endonucleases, we used a novel plant-based cell-free translation procedure that bypasses the toxicity of these enzymes. To identify candidate genes, the related genomes of the hyperthermophilic archaea Pyrococcus abyssi and Pyrococcus horikoshii were compared. In line with the selfish mobile gene hypothesis for restriction-modification systems, apparent genome rearrangement around putative restriction genes served as a selecting criterion. Several candidate restriction genes were identified and then amplified in such a way that they were removed from their own translation signal. During their cloning into a plasmid, the genes became connected with a plant translation signal. After in vitro transcription by T7 RNA polymerase, the mRNAs were separated from the template DNA and translated in a wheat-germ-based cell-free protein synthesis system. The resulting solution could be directly assayed for restriction activity. We identified two deoxyribonucleases. The novel enzyme was denoted as PabI, purified and found to recognize 5'-GTAC and leave a 3'-TA overhang (5'-GTA/C), a novel restriction enzyme-generated terminus. PabI is active up to 90 degrees C and optimally active at a pH of around 6 and in NaCl concentrations ranging from 100 to 200 mM. We predict that it has a novel 3D structure.

  19. Discovery of a novel restriction endonuclease by genome comparison and application of a wheat-germ-based cell-free translation assay: PabI (5′-GTA/C) from the hyperthermophilic archaeon Pyrococcus abyssi

    Science.gov (United States)

    Ishikawa, Ken; Watanabe, Miki; Kuroita, Toshihiro; Uchiyama, Ikuo; Bujnicki, Janusz M.; Kawakami, Bunsei; Tanokura, Masaru; Kobayashi, Ichizo

    2005-01-01

    To search for restriction endonucleases, we used a novel plant-based cell-free translation procedure that bypasses the toxicity of these enzymes. To identify candidate genes, the related genomes of the hyperthermophilic archaea Pyrococcus abyssi and Pyrococcus horikoshii were compared. In line with the selfish mobile gene hypothesis for restriction–modification systems, apparent genome rearrangement around putative restriction genes served as a selecting criterion. Several candidate restriction genes were identified and then amplified in such a way that they were removed from their own translation signal. During their cloning into a plasmid, the genes became connected with a plant translation signal. After in vitro transcription by T7 RNA polymerase, the mRNAs were separated from the template DNA and translated in a wheat-germ-based cell-free protein synthesis system. The resulting solution could be directly assayed for restriction activity. We identified two deoxyribonucleases. The novel enzyme was denoted as PabI, purified and found to recognize 5′-GTAC and leave a 3′-TA overhang (5′-GTA/C), a novel restriction enzyme-generated terminus. PabI is active up to 90°C and optimally active at a pH of around 6 and in NaCl concentrations ranging from 100 to 200 mM. We predict that it has a novel 3D structure. PMID:16040595

  20. Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)–Mixed Lineage Leukemia (MLL) Protein–Protein Interaction

    Energy Technology Data Exchange (ETDEWEB)

    Karatas, Hacer; Li, Yangbing; Liu, Liu; Ji, Jiao; Lee, Shirley; Chen, Yong; Yang, Jiuling; Huang, Liyue; Bernard, Denzil; Xu, Jing; Townsend, Elizabeth C.; Cao, Fang; Ran, Xu; Li, Xiaoqin; Wen, Bo; Sun, Duxin; Stuckey, Jeanne A; Lei, Ming; Dou, Yali; Wang, Shaomeng (Michigan)

    2017-06-06

    We report herein the design, synthesis, and evaluation of macrocyclic peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the WDR5–mixed lineage leukemia (MLL) protein–protein interaction. Compound 18 (MM-589) binds to WDR5 with an IC50 value of 0.90 nM (Ki value <1 nM) and inhibits the MLL H3K4 methyltransferase (HMT) activity with an IC50 value of 12.7 nM. Compound 18 potently and selectively inhibits cell growth in human leukemia cell lines harboring MLL translocations and is >40 times better than the previously reported compound MM-401. Cocrystal structures of 16 and 18 complexed with WDR5 provide structural basis for their high affinity binding to WDR5. Additionally, we have developed and optimized a new AlphaLISA-based MLL HMT functional assay to facilitate the functional evaluation of these designed compounds. Compound 18 represents the most potent inhibitor of the WDR5–MLL interaction reported to date, and further optimization of 18 may yield a new therapy for acute leukemia.

  1. Context-sensitive service discovery experimental prototype and evaluation

    DEFF Research Database (Denmark)

    Balken, Robin; Haukrogh, Jesper; L. Jensen, Jens

    2007-01-01

    the network in domains that handle the complex distributed service discovery, which is based on dynamically changing context information. In the prototype, a method for performing context-sensitive service discovery has been realised. The service discovery part utilizes UPnP, which has been expanded in order...... to increase network scalability. The experimental analysis of service discovery times for different scenarios is used to optimize parameter settings of the service discovery system in order to achieve short response times....

  2. [Human babesiosis--recent discoveries].

    Science.gov (United States)

    Mitrović, Sanja; Kranjcić-Zec, Ivana; Arsić-Arsenijević, Valentina; Dzamić, Aleksandar; Radonjić, Ivana

    2004-01-01

    Babesiosis is caused by intraerythrocytic parasites of the genus Babesia, which is a common animal infection worldwide. This protozoa requires both a competent vertebrate and a nonvertebrate host (Ixodes sp. etc.) to maintain the transmission cycle. Human babesiosis is predominantly caused by Babesia microti (rodent-borne piroplasm, an emerging zoonosis in humans in North America) and by Babesia divergens (bovine pathogen, in Europe). Occasionally, infection in America is caused also by a newly recognized species, so-called WA1 piroplasm. The spectrum of human babesiosis in the USA is broad, and ranges from an apparently silent infection to a fulminant. In Europe, babesiosis is considerably rarer, but more lethal (42% mortality rate in Europe and 5% in the USA, for clinically apparent infections) and mostly in splenectomized patients. Various determinants are involved in the severity of infection, such as age, immunocompetence and coinfection with other pathogens (Borrelia burgdorferi). B. microti antigens can trigger specific activation of T-cells and the infection can be effectively controlled by a Th1-dominant CD4+ T-cell response. The diagnosis of babesiosis should include examination of blood smears stained by Giemsa, as well as serologic evaluation with indirect immunofluorescent antibody tests and possibly PCR. The treatment of babesiosis depends on severity of cases; if it is mild it resolves spontaneously, whereas very severe cases with B. divergens require prompt treatment that includes erythrocyte exchange transfuision along with intravenous clindamycin and oral quinine to arrest hemolysis and prevent renalfailure. This paper offers an overview of recent developments in the investigation of Babesia sp. and babesiosis.

  3. Chronic Trypanosoma cruzi-elicited cardiomyopathy: from the discovery to the proposal of rational therapeutic interventions targeting cell adhesion molecules and chemokine receptors--how to make a dream come true.

    Science.gov (United States)

    Lannes-Vieira, Joseli; Silverio, Jaline Coutinho; Pereira, Isabela Resende; Vinagre, Nathália Ferreira; Carvalho, Cristiano Marcelo Espinola; Paiva, Cláudia Neto; Silva da, Andréa Alice

    2009-07-01

    One hundred years ago, Carlos Chagas discovered a new disease, the American trypanosomiasis. Chagas and co-workers later characterised the disease's common manifestation, chronic cardiomyopathy, and suggested that parasitic persistence coupled with inflammation was the key underlying pathogenic mechanism. Better comprehension of the molecular mechanisms leading to clinical heart afflictions is a prerequisite to developing new therapies that ameliorate inflammation and improve heart function without hampering parasite control. Here, we review recent data showing that distinct cell adhesion molecules, chemokines and chemokine receptors participate in anti-parasite immunity and/or detrimental leukocyte trafficking to the heart. Moreover, we offer evidence that CC-chemokine receptors may be attractive therapeutic targets aiming to regain homeostatic balance in parasite/host interaction thereby improving prognosis, supporting that it is becoming a non-phantasious proposal.

  4. Bioinformatics for discovery of microbiome variation

    DEFF Research Database (Denmark)

    Brejnrod, Asker Daniel

    two conditions. The purpose is to assess the false discovery rate, recovery of truly differential abundant bacteria and the impact of beta diversity exploration strategies commonly used in microbiome research. We assess these differences by simulation and by making biological assumptions about...... of various molecular methods to build hypotheses about the impact of a copper contaminated soil. The introduction is a broad introduction to the field of microbiome research with a focus on the technologies that enable these discoveries and how some of the broader issues have related to this thesis...... 1 ,“Large-scale benchmarking reveals false discoveries and count transformation sensitivity in 16S rRNA gene amplicon data analysis methods used in microbiome studies”, benchmarked the performance of a variety of popular statistical methods for discovering differentially abundant bacteria . between...

  5. A perfect launch of Space Shuttle Discovery

    Science.gov (United States)

    2000-01-01

    Space Shuttle Discovery lifts off Launch Pad 39A against a backdrop of xenon lights (just above the orbiter' nose and at left). On the Mobile Launcher Platform beneath, water begins flooding the area for flame and sound control. The perfect on- time liftoff occurred at 7:17 p.m. EDT, sending a crew of seven on the 100th launch in the history of the Shuttle program. Discovery carries a payload that includes the Integrated Truss Structure Z-1, first of 10 trusses that will form the backbone of the Space Station, and the third Pressurized Mating Adapter that will provide a Shuttle docking port for solar array installation on the sixth Station flight and Lab installation on the seventh Station flight. Discovery's landing is expected Oct. 22 at 2:10 p.m. EDT.

  6. John Herschel on the Discovery of Neptune

    Science.gov (United States)

    Kollerstrom, Nicholas

    2006-12-01

    The letters of John Herschel that concern the discovery of the planet Neptune have not been greatly discussed by historians of science. I have transcribed these in the course of archiving the British Neptune-discovery documents. Herschel tends to be depicted as a background figure in narrations of the story of Neptune's discovery, whereas the present account focuses upon his evolving view of the topic: the rival merits of the two main protagonists, and the startling manner in which an obscure branch of mathematics (perturbation theory) was able to pinpoint the position of a new sphere in the sky. As the son of the man who found Uranus, his views have a special relevance. Also, I suggest that his eloquent prose style may still be enjoyed today.

  7. Virtual drug discovery: beyond computational chemistry?

    Science.gov (United States)

    Gilardoni, Francois; Arvanites, Anthony C

    2010-02-01

    This editorial looks at how a fully integrated structure that performs all aspects in the drug discovery process, under one company, is slowly disappearing. The steps in the drug discovery paradigm have been slowly increasing toward virtuality or outsourcing at various phases of product development in a company's candidate pipeline. Each step in the process, such as target identification and validation and medicinal chemistry, can be managed by scientific teams within a 'virtual' company. Pharmaceutical companies to biotechnology start-ups have been quick in adopting this new research and development business strategy in order to gain flexibility, access the best technologies and technical expertise, and decrease product developmental costs. In today's financial climate, the term virtual drug discovery has an organizational meaning. It represents the next evolutionary step in outsourcing drug development.

  8. Discovery, Characterization, and Dynamics of Transiting Exoplanets

    DEFF Research Database (Denmark)

    Van Eylen, Vincent

    2015-01-01

    Are we alone in the Universe? So far, the question remains unanswered, but a significant leap forward was achieved two decades ago, with the discovery of the first planets orbiting stars other than our Sun. Almost 2000 exoplanets have now been detected. They are diverse in radius, mass and orbital......, in this thesis I make use of the transit method, which is based on the observed brightness drop of a star as a planet crosses in front of it. This thesis consists of two parts. The first part focuses on the discovery of new planets and the understanding of exoplanet properties. I report the discovery...... results of this study, constraining the masses and bulk compositions of three planets. The second part of this thesis focuses on dynamics of exoplanets. All the solar system planets orbit in nearly the same plane, and that plane is also aligned with the equatorial plane of the Sun. That is not true...

  9. Protein chemical synthesis in drug discovery.

    Science.gov (United States)

    Liu, Fa; Mayer, John P

    2015-01-01

    The discovery of novel therapeutics to combat human disease has traditionally been among the most important goals of research chemists. After a century of innovation, state-of-the-art chemical protein synthesis is now capable of efficiently assembling proteins of up to several hundred residues in length from individual amino acids. By virtue of its unique ability to incorporate non-native structural elements, chemical protein synthesis has been seminal in the recent development of several novel drug discovery technologies. In this chapter, we review the key advances in peptide and protein chemistry which have enabled our current synthetic capabilities. We also discuss the synthesis of D-proteins and their applications in mirror image phage-display and racemic protein crystallography, the synthesis of enzymes for structure-based drug discovery, and the direct synthesis of homogenous protein pharmaceuticals.

  10. Neutron Diffraction and Inorganic Materials Discovery

    International Nuclear Information System (INIS)

    Rosseinsky, M.J.

    2005-01-01

    Full text: The discovery of complex inorganic materials is an important academic and technological challenge because of the opportunities these systems offer for observation of new phenomena, and the questions they pose for fundamental understanding. This presentation will illustrate the key role of neutron powder diffraction in enabling the discovery of new classes of materials, and in evaluating their properties and the conditions under which they need to be processed to optimise their behaviour in devices for applications. New chemistry is illustrated by the transition metal oxide hydrides, where both structure and ionic mobility required neutron scattering characterisation. The relationship between chemistry, structure and properties will be addressed by considering the difficulties in inducing superconductivity in analogues of magnesium diboride. The role of both neutron and X-ray diffraction in evaluating the processing of microwave dielectric ceramics will be highlighted, with the discovery of new phases shown to be a useful bonus in this type of in-situ study. (author)

  11. Predictors of timing of pregnancy discovery.

    Science.gov (United States)

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

    2018-04-01

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

  12. From the nucleus discovery to DWBA

    International Nuclear Information System (INIS)

    Fernandez, B.

    2007-01-01

    The author presents a brief review of the main events in the field of nuclear reactions that are acknowledged as milestones because of their importance due to either experimental setting or physical interpretation. It is shown that the pace of discoveries has been strongly dependent on the technical progress in detection means at the beginning of nuclear physics and now is linked to the development of simulation means. The discovery of the neutron, the development of the Geiger counter, the theory of the compound nucleus or the first direct reactions are among these milestones

  13. The discovery of the tau lepton

    International Nuclear Information System (INIS)

    Perl, M.L.

    1992-09-01

    The discovery of the tau lepton and the third generation of fermions came from the convergence of three physics streams in the late 1960's and early 1970's. These streams were: the failed attempts by myself and others to understand the connection between the electron and the muon, the development of electron-positron storage rings, and the development of the theory of sequential leptons. In this paper I give the history of the discovery of the tau and the measurement of its major properties-the properties which established the tau as a sequential lepton

  14. Net present value approaches for drug discovery.

    Science.gov (United States)

    Svennebring, Andreas M; Wikberg, Jarl Es

    2013-12-01

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

  15. The centenary of discovery of radium

    International Nuclear Information System (INIS)

    Mazeron, J.-J.; Gerbaulet, A.

    1998-01-01

    Henri Becquerel presented the discovery of radium by Pierre and Marie Curie at the Paris Academy of Science on 26th December 1898. One century later, radium has been abandoned, mainly for radiation protection difficulties. It is, however, likely that modern techniques of brachytherapy have inherited to those designed for radium sources, and that radium has cured thousands and thousands patients all over the world for about eighty years. The history of discovery and medical use of radium is summarised. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  16. The discovery of elements 113 to 118

    Directory of Open Access Journals (Sweden)

    Utyonkov Vladimir

    2016-01-01

    Full Text Available Discovery and investigation of the “Island of stability” of superheavy nuclei at the separator DGFRS in the 238U-249Cf+ 48Ca reactions is reviewed. The results are compared with the data obtained in chemistry experiments and at the separators SHIP, BGS, TASCA, and GARIS. The synthesis of the heaviest nuclei, their decay properties, and methods of identification are discussed and compared with the criteria that must be satisfied for claiming the discovery of a new chemical element. The role of shell effects in the stability of superheavy nuclei is demonstrated by comparison of the experimental results with empirical systematics and theoretical data.

  17. Effective Online Group Discovery in Trajectory Databases

    DEFF Research Database (Denmark)

    Li, Xiaohui; Ceikute, Vaida; Jensen, Christian S.

    2013-01-01

    GPS-enabled devices are pervasive nowadays. Finding movement patterns in trajectory data stream is gaining in importance. We propose a group discovery framework that aims to efficiently support the online discovery of moving objects that travel together. The framework adopts a sampling...... based on their cardinality and duration, and the top-$k$ groups are returned. To avoid returning similar subgroups in a result, notions of domination and similarity are introduced that enable the pruning of low-interest groups. Empirical studies on real and synthetic data sets offer insight...

  18. Using Discovery Learning to Encourage Creative Thinking

    Directory of Open Access Journals (Sweden)

    Mardia Hi. Rahman

    2017-10-01

    Full Text Available Creative thinking ability development is needed to be implemented by every educator including lecturers to their students. Therefore, they need to seriously act and design their learning process. One of the ways to develop student’s creative thinking is using discovery learning model. This research is conducted in physics education study program in 2016 with students who took learning and teaching class as research subject. From the research analysis result and discussion, it can be concluded that discovery learning model can encourage students’ creative thinking ability in learning and teaching strategy subject.

  19. Epithelial cell polarity, stem cells and cancer

    DEFF Research Database (Denmark)

    Martin-Belmonte, Fernando; Perez-Moreno, Mirna

    2011-01-01

    After years of extensive scientific discovery much has been learned about the networks that regulate epithelial homeostasis. Loss of expression or functional activity of cell adhesion and cell polarity proteins (including the PAR, crumbs (CRB) and scribble (SCRIB) complexes) is intricately related......, deregulation of adhesion and polarity proteins can cause misoriented cell divisions and increased self-renewal of adult epithelial stem cells. In this Review, we highlight some advances in the understanding of how loss of epithelial cell polarity contributes to tumorigenesis....

  20. 10 CFR 2.1018 - Discovery.

    Science.gov (United States)

    2010-01-01

    ... production of, copies of documentary material for which bibliographic headers only have been submitted..., such as the names of witnesses and the subjects they plan to address; and (vii) Interrogatories and... depositions upon written questions may be authorized by order of the discovery master appointed under...

  1. Discovery Learning for Mathematical Literacy Ability

    Science.gov (United States)

    Tokada, D.; Herman, T.; Suhendra

    2017-09-01

    The background of this research is students’ mathematical literacy ability which is still less so most students find difficulty in solving mathematical problem in daily life. Learning which tend to be teacher centered not give change to students to develop their own ideas so the students do not master the concept well. Discovery learning is one of learning which train students how to discover mathematical concept and to train students to express their ideas. This study is quasi experimental study which is aimed to find out the enhancement of mathematical literacy ability of eighth grade students with discovery learning. This research used nonequivalent control group design. The population in this research were all students of the eight grade Junior High School in Tana Toraja. This research conclude that mathematics learning with discovery learning method in eight grade students of Junior High School can enhance the ability of mathematical literacy more significant. Discovery learning give change to students to construct their own knowledge so they can understand mathematical problem until its solution.

  2. Streaming Process Discovery and Conformance Checking

    DEFF Research Database (Denmark)

    Burattin, Andrea

    2018-01-01

    Streaming process discovery, streaming conformance checking, and streaming process mining in general (also known as online process mining) are disciplines which analyze event streams to extract a process model or to assess their conformance with respect to a given reference model. The main...

  3. Discovery Learning: Zombie, Phoenix, or Elephant?

    Science.gov (United States)

    Bakker, Arthur

    2018-01-01

    Discovery learning continues to be a topic of heated debate. It has been called a zombie, and this special issue raises the question whether it may be a phoenix arising from the ashes to which the topic was burnt. However, in this commentary I propose it is more like an elephant--a huge topic approached by many people who address different…

  4. The next generation of targeted mutation discovery

    NARCIS (Netherlands)

    Harakalova, M.

    2013-01-01

    Sequencing technologies (NGS) now allows efficient analysis of the complete protein-coding regions of genomes (exomes) for multiple samples in a single sequencing run. In Chapter 2, we present our results with a genomic DNA pooling strategy for rare variant discovery on a NGS platform. The high

  5. Bioenergy Knowledge Discovery Framework (KDF) Fact Sheet

    Energy Technology Data Exchange (ETDEWEB)

    None

    2013-07-29

    The Bioenergy Knowledge Discovery Framework (KDF) is an online collaboration and geospatial analysis tool that allows researchers, policymakers, and investors to explore and engage the latest bioenergy research. This publication describes how the KDF harnesses Web 2.0 and social networking technologies to build a collective knowledge system that facilitates collaborative production, integration, and analysis of bioenergy-related information.

  6. Discovery and preclinical development of new antibiotics.

    Science.gov (United States)

    Hughes, Diarmaid; Karlén, Anders

    2014-05-01

    Antibiotics are the medical wonder of our age, but an increasing frequency of resistance among key pathogens is rendering them less effective. If this trend continues the consequences for cancer patients, organ transplant patients, and indeed the general community could be disastrous. The problem is complex, involving abuse and overuse of antibiotics (selecting for an increasing frequency of resistant bacteria), together with a lack of investment in discovery and development (resulting in an almost dry drug development pipeline). Remedial approaches to the problem should include taking measures to reduce the selective pressures for resistance development, and taking measures to incentivize renewed investment in antibiotic discovery and development. Bringing new antibiotics to the clinic is critical because this is currently the only realistic therapy that can ensure the level of infection control required for many medical procedures. Here we outline the complex process involved in taking a potential novel antibiotic from the initial discovery of a hit molecule, through lead and candidate drug development, up to its entry into phase I clinical trials. The stringent criteria that a successful drug must meet, balancing high efficacy in vivo against a broad spectrum of pathogens, with minimal liabilities against human targets, explain why even with sufficient investment this process is prone to a high failure rate. This emphasizes the need to create a well-funded antibiotic discovery and development pipeline that can sustain the continuous delivery of novel candidate drugs into clinical trials, to ensure the maintenance of the advanced medical procedures we currently take for granted.

  7. 36 CFR 1150.63 - Discovery.

    Science.gov (United States)

    2010-07-01

    ... satisfactory to the judge, the judge may decide the fact or issue relating to the material requested to be... appropriate circumstances, but not as a matter of course, the judge may entertain motions for permission for... for discovery shall be granted only to the extent and upon such terms as the judge in his/her...

  8. Knowledge Discovery and Data Mining: An Overview

    Science.gov (United States)

    Fayyad, U.

    1995-01-01

    The process of knowledge discovery and data mining is the process of information extraction from very large databases. Its importance is described along with several techniques and considerations for selecting the most appropriate technique for extracting information from a particular data set.

  9. Secure Service Discovery in Home Networks

    NARCIS (Netherlands)

    Scholten, Johan; van Dijk, H.W.; De Cock, Danny; Preneel, Bart; Kung, Antonio; d'Hooge, Michel

    2006-01-01

    This paper presents an architecture for secure service discovery for use in home networks. We give an overview and rationale of a cluster-based home network architecture that bridges different, often vendor specific, network technologies. We show how it integrates security, communication, and

  10. Computational approaches to natural product discovery

    NARCIS (Netherlands)

    Medema, M.H.; Fischbach, M.A.

    2015-01-01

    Starting with the earliest Streptomyces genome sequences, the promise of natural product genome mining has been captivating: genomics and bioinformatics would transform compound discovery from an ad hoc pursuit to a high-throughput endeavor. Until recently, however, genome mining has advanced

  11. Visualizing the process of knowledge discovery

    Science.gov (United States)

    Han, Jianchao; Cercone, Nick

    2000-10-01

    Most existing visualization systems stress either the original data visualization of the discovered knowledge visualization, such as decision tree, neural network, rules, etc., but lack the abilities to visualize the entire process of knowledge discovery. We propose an interactive model, RuleViz, for visualizing the process of knowledge discovery and data mining. The RuleViz model consists of five components, each of which can be interacted and visualized by using different visualization techniques. According to this model, two interactive systems, AViz and CViz, for visualizing the process of discovering numerical association rules and the process of learning classification rules have been implemented, respectively. To preprocess the data, each system provides users with three approaches for discretizing numerical attributes and the corresponding rule discovery algorithms. The discretization approaches and the algorithms for discovering association rules and learning classification rules are presented, and the approaches to visualizing discretized data and discovered rules are developed. The discovery of numerical association rules in AViz is based on image-based mining algorithm, while, in CViz, the classification rules are learned in terms of a logical rule induction algorithm. We also demonstrate our experimental results with AViz and CViz on the census data sets, UCl data sets, and artificial data sets.

  12. The discovery and development of antiretroviral agents

    NARCIS (Netherlands)

    Lange, Joep M. A.; Ananworanich, Jintanat

    2014-01-01

    Since the discovery of HIV as the causative agent of AIDS in 1983/1984, remarkable progress has been made in finding antiretroviral drugs (ARVs) that are effective against it. A major breakthrough occurred in 1996 when it was found that triple drug therapy (HAART) could durably suppress viral

  13. 7 CFR 283.12 - Discovery.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 4 2010-01-01 2010-01-01 false Discovery. 283.12 Section 283.12 Agriculture Regulations of the Department of Agriculture (Continued) FOOD AND NUTRITION SERVICE, DEPARTMENT OF AGRICULTURE...) Supplementation of response. A party who knows or later learns that a response is incorrect is under a duty to...

  14. The Discovery of the Double Helix

    CERN Multimedia

    CERN. Geneva

    2011-01-01

    Professor James D. Watson has kindly agreed to make a presentation on the 1953 finding of the Double Helix at the Cavendish Laboratory by Francis Crick and himself. Being one of the greatest scientific discoveries in human history, little else needs to be added.

  15. Cognitive Neuroscience Discoveries and Educational Practices

    Science.gov (United States)

    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…

  16. Translating Genomic Discoveries to Cure Ultrahypermutant ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Translating Genomic Discoveries to Cure Ultrahypermutant Mismatch Repair Deficient Brain Tumours. Malignant brain tumours are the most common cause of death among children with cancer, but there is no known cure. This project will advance research in this important field. Inherited mutations and childhood cancer.

  17. (Self-) Discovery Service: Helping Students Help Themselves

    Science.gov (United States)

    Debonis, Rocco; O'Donnell, Edward; Thomes, Cynthia

    2012-01-01

    EBSCO Discovery Service (EDS) has been heavily used by UMUC students since its implementation in fall 2011, but experience has shown that it is not always the most appropriate source for satisfying students' information needs and that they often need assistance in understanding how the tool works and how to use it effectively. UMUC librarians have…

  18. Rough – Granular Computing knowledge discovery models

    Directory of Open Access Journals (Sweden)

    Mohammed M. Eissa

    2016-11-01

    Full Text Available Medical domain has become one of the most important areas of research in order to richness huge amounts of medical information about the symptoms of diseases and how to distinguish between them to diagnose it correctly. Knowledge discovery models play vital role in refinement and mining of medical indicators to help medical experts to settle treatment decisions. This paper introduces four hybrid Rough – Granular Computing knowledge discovery models based on Rough Sets Theory, Artificial Neural Networks, Genetic Algorithm and Rough Mereology Theory. A comparative analysis of various knowledge discovery models that use different knowledge discovery techniques for data pre-processing, reduction, and data mining supports medical experts to extract the main medical indicators, to reduce the misdiagnosis rates and to improve decision-making for medical diagnosis and treatment. The proposed models utilized two medical datasets: Coronary Heart Disease dataset and Hepatitis C Virus dataset. The main purpose of this paper was to explore and evaluate the proposed models based on Granular Computing methodology for knowledge extraction according to different evaluation criteria for classification of medical datasets. Another purpose is to make enhancement in the frame of KDD processes for supervised learning using Granular Computing methodology.

  19. Social Relationship Discovery Via Call Records

    Directory of Open Access Journals (Sweden)

    Zhao Wen-Zhe

    2017-01-01

    Full Text Available Telecom users constitute a huge, but relatively sparse social network. Community discovery has been a research topic of data mining. Traditional algorithms are greatly influenced by outliers. This paper presents a new algorithm based on social triangle theory. Experiments show that the new algorithm is effective.

  20. Communication in Drug Development: "Translating" Scientific Discovery.

    Science.gov (United States)

    Settleman, Jeff; Cohen, Robert L

    2016-03-10

    The discovery and development of new medicines that promote human health and potentially extend natural life remains a remarkably challenging endeavor. In this Commentary, we identify key elements of communication required to successfully translate promising biological findings to novel approved drug therapies and discuss the attendant challenges and opportunities. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. 41 CFR 105-70.021 - Discovery.

    Science.gov (United States)

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Discovery. 105-70.021 Section 105-70.021 Public Contracts and Property Management Federal Property Management Regulations System..., papers, and other data and documentary evidence. Nothing contained herein shall be interpreted to require...

  2. 5 CFR 185.122 - Discovery.

    Science.gov (United States)

    2010-01-01

    ... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Discovery. 185.122 Section 185.122 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PROGRAM FRAUD CIVIL REMEDIES..., answers, records, accounts, papers, and other data and documentary evidence. Nothing contained herein...

  3. Zavoisky and the Discovery of EPR

    Indian Academy of Sciences (India)

    IAS Admin

    The name of the Soviet physicist Evgenii Konstantinovich. Zavoisky (1907–1976) belongs to the history of science due to his discovery of a fundamental physical phenomenon – elec- tron paramagnetic resonance (EPR) and a series of brilliant works in nuclear physics, controlled thermonuclear fusion and physical ...

  4. Biological Awareness: Statements for Self-Discovery.

    Science.gov (United States)

    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,…

  5. Computer-Assisted Discovery and Proof

    Energy Technology Data Exchange (ETDEWEB)

    Bailey, David H.; Borwein, Jonathan M.

    2007-12-10

    With the advent of powerful, widely-available mathematical software, combined with ever-faster computer hardware, we are approaching a day when both the discovery and proof of mathematical facts can be done in a computer-assisted manner. his article presents several specific examples of this new paradigm in action.

  6. 21 CFR 17.23 - Discovery.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Discovery. 17.23 Section 17.23 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL CIVIL MONEY PENALTIES.... Nothing contained in this section may be interpreted to require the creation of a document, except that...

  7. Conference Abstracts: Translational Science and Drug Discovery ...

    African Journals Online (AJOL)

    Abstracts prsented at the "Translational Science and Drug Discovery: Impact on Health, Wellness, Environment and Economics" conference, July 27-29th, 2015, at the Hennessy Park Hotel, Ebène Cybercity, Mauritius. The conference was hosted by the Society for Free radical Research Africa and the International ...

  8. INTEGRATE: gene fusion discovery using whole genome and transcriptome data.

    Science.gov (United States)

    Zhang, Jin; White, Nicole M; Schmidt, Heather K; Fulton, Robert S; Tomlinson, Chad; Warren, Wesley C; Wilson, Richard K; Maher, Christopher A

    2016-01-01

    While next-generation sequencing (NGS) has become the primary technology for discovering gene fusions, we are still faced with the challenge of ensuring that causative mutations are not missed while minimizing false positives. Currently, there are many computational tools that predict structural variations (SV) and gene fusions using whole genome (WGS) and transcriptome sequencing (RNA-seq) data separately. However, as both WGS and RNA-seq have their limitations when used independently, we hypothesize that the orthogonal validation from integrating both data could generate a sensitive and specific approach for detecting high-confidence gene fusion predictions. Fortunately, decreasing NGS costs have resulted in a growing quantity of patients with both data available. Therefore, we developed a gene fusion discovery tool, INTEGRATE, that leverages both RNA-seq and WGS data to reconstruct gene fusion junctions and genomic breakpoints by split-read mapping. To evaluate INTEGRATE, we compared it with eight additional gene fusion discovery tools using the well-characterized breast cell line HCC1395 and peripheral blood lymphocytes derived from the same patient (HCC1395BL). The predictions subsequently underwent a targeted validation leading to the discovery of 131 novel fusions in addition to the seven previously reported fusions. Overall, INTEGRATE only missed six out of the 138 validated fusions and had the highest accuracy of the nine tools evaluated. Additionally, we applied INTEGRATE to 62 breast cancer patients from The Cancer Genome Atlas (TCGA) and found multiple recurrent gene fusions including a subset involving estrogen receptor. Taken together, INTEGRATE is a highly sensitive and accurate tool that is freely available for academic use. © 2016 Zhang et al.; Published by Cold Spring Harbor Laboratory Press.

  9. Discovery of S···C≡N Intramolecular Bonding in a Thiophenylcyanoacrylate-Based Dye: Realizing Charge Transfer Pathways and Dye···TiO 2 Anchoring Characteristics for Dye-Sensitized Solar Cells

    Energy Technology Data Exchange (ETDEWEB)

    Cole, Jacqueline M. [Cavendish; ISIS; Argonne National Laboratory, 9700 S. Cass Avenue, Argonne, Illinois 60439, United States; Department; Blood-Forsythe, Martin A. [Cavendish; Lin, Tze-Chia [Cavendish; Pattison, Philip [Swiss; Gong, Yun [Cavendish; Vázquez-Mayagoitia, Álvaro [Argonne National Laboratory, 9700 S. Cass Avenue, Argonne, Illinois 60439, United States; Waddell, Paul G. [Cavendish; Australian Centre for Neutron Scattering, Australian Nuclear Science; Zhang, Lei [Cavendish; Koumura, Nagatoshi [National Institute of Advanced Industrial Science and Technology, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan; Mori, Shogo [Division

    2017-07-25

    Donor-pi-acceptor dyes containing thiophenyl pi-conjugated units and cyanoacrylate acceptor groups are among the best-performing organic chromophores used in dye-sensitized solar cell (DSC) applications. Yet, the molecular origins of their high photovoltaic output have remained unclear until now. This synchrotron-based X-ray diffraction study elucidates these origins for the high-performance thiophenylcyanoacrylate-based dye MK-2 (7.7% DSC device efficiency) and its molecular building block, MK-44. The crystal structures of MK-2 and MK-44 are both determined, while a high-resolution charge-density mapping of the smaller molecule was also possible, enabling the nature of its bonding to be detailed. A strong S center dot center dot center dot C equivalent to N intramolecular interaction is discovered, which bears a bond critical point, thus proving that this interaction should be formally classified as a chemical bond. A topological analysis of the pi-conjugated portion of MK-44 shows that this S center dot center dot center dot C equivalent to N bonding underpins the highly efficient intramolecular charge transfer(ICT) in thiophenylcyanoacrylate dyes. This manifests as two bipartite ICT pathways bearing carboxylate and nitrile end points. In turn, these pathways dictate a preferred COO/CN anchoring mode for the dye as it adsorbs onto TiO2 surfaces, to form the dye TiO2 interface that constitutes the DSC working electrode. These results corroborate a recent proposal that all cyanoacrylate groups anchor onto TiO2 in this COO/CN binding configuration. Conformational analysis of the MK-44 and MK-2 crystal structures reveals that this S center dot center dot center dot C equivalent to N bonding will persist in MK-2. Accordingly, this newly discovered bond affords a rational explanation for the attractive photovoltaic properties of,MK-2. More generally, this study provides the first unequivocal evidence for an S center dot center dot center dot C equivalent to N

  10. Swedish Chemists and Discovery of the Elements

    Science.gov (United States)

    Thomsen, Volker

    1996-10-01

    All of the elements not already known from antiquity were discovered in Europe and North America. So which country ranks number one on the discovery list? The question occurred to me while leafing through reference 1 in search of thermodynamic data on silicon. Never having seen such a tabulation, I wondered if it might prove useful in teaching. The question has a sports-related flavor that will appeal to many students. Personally, I picked England or Germany for #1. The actual result is surprising. The ranking considering only up to atomic number 103 is as follows: Note: Where two or more independent discoveries have been made, each country is credited. In the "others" category Austria and Denmark each has two discoveries. The remaining countries, with one each, are Finland, Italy, Mexico, Poland, Romania, Russia, and Spain. The high place for the USA is primarily due to the work done at Berkeley and Los Alamos on the transuranics. Without these discoveries, the US would have tied with Switzerland at three elements. Perhaps the most interesting aspect of this tabulation is that Swedish chemists have discovered the most elements. Four chemists alone account for twelve of the 20 discoveries: Baron Jöns Jakob Berzelius (1779-1848) is credited with four elements. His pupil, friend, and assistant, Carl Gustav Mosander (1797-1858) discovered three. P. T. Cleve also found three elements and Karl Wilhelm Scheele (1742-1786) discovered two. Biographical research on the Swedish chemists is a suitable assignment at the introductory level. Reasons for the predominance of Swedish chemists presents a challenging student research topic in the history of chemistry. Another interesting question at the introductory level is, transuranics aside, who discovered the most elements? At the more advanced level the question becomes, why? Literature Cited: 1. Emsley, J. The Elements; Clarendon: Oxford, 1989.

  11. Discovery in a World of Mashups

    Science.gov (United States)

    King, T. A.; Ritschel, B.; Hourcle, J. A.; Moon, I. S.

    2014-12-01

    When the first digital information was stored electronically, discovery of what existed was through file names and the organization of the file system. With the advent of networks, digital information was shared on a wider scale, but discovery remained based on file and folder names. With a growing number of information sources, named based discovery quickly became ineffective. The keyword based search engine was one of the first types of a mashup in the world of Web 1.0. Embedded links from one document to another with prescribed relationships between files and the world of Web 2.0 was formed. Search engines like Google used the links to improve search results and a worldwide mashup was formed. While a vast improvement, the need for semantic (meaning rich) discovery was clear, especially for the discovery of scientific data. In response, every science discipline defined schemas to describe their type of data. Some core schemas where shared, but most schemas are custom tailored even though they share many common concepts. As with the networking of information sources, science increasingly relies on data from multiple disciplines. So there is a need to bring together multiple sources of semantically rich information. We explore how harvesting, conceptual mapping, facet based search engines, search term promotion, and style sheets can be combined to create the next generation of mashups in the emerging world of Web 3.0. We use NASA's Planetary Data System and NASA's Heliophysics Data Environment to illustrate how to create a multi-discipline mash-up.

  12. Inseparability of science history and discovery

    Directory of Open Access Journals (Sweden)

    J. M. Herndon

    2010-04-01

    Full Text Available Science is very much a logical progression through time. Progressing along a logical path of discovery is rather like following a path through the wilderness. Occasionally the path splits, presenting a choice; the correct logical interpretation leads to further progress, the wrong choice leads to confusion. By considering deeply the relevant science history, one might begin to recognize past faltering in the logical progression of observations and ideas and, perhaps then, to discover new, more precise understanding. The following specific examples of science faltering are described from a historical perspective: (1 Composition of the Earth's inner core; (2 Giant planet internal energy production; (3 Physical impossibility of Earth-core convection and Earth-mantle convection, and; (4 Thermonuclear ignition of stars. For each example, a revised logical progression is described, leading, respectively, to: (1 Understanding the endo-Earth's composition; (2 The concept of nuclear georeactor origin of geo- and planetary magnetic fields; (3 The invalidation and replacement of plate tectonics; and, (4 Understanding the basis for the observed distribution of luminous stars in galaxies. These revised logical progressions clearly show the inseparability of science history and discovery. A different and more fundamental approach to making scientific discoveries than the frequently discussed variants of the scientific method is this: An individual ponders and through tedious efforts arranges seemingly unrelated observations into a logical sequence in the mind so that causal relationships become evident and new understanding emerges, showing the path for new observations, for new experiments, for new theoretical considerations, and for new discoveries. Science history is rich in "seemingly unrelated observations" just waiting to be logically and causally related to reveal new discoveries.

  13. [The discovery of hypoglycemic sulfonamides].

    Science.gov (United States)

    Loubatières-Mariani, Marie-Madeleine

    2007-01-01

    and structural analogs and investigated the mechanism involved in the hypoglycemia. These results are reported in his "Doctorat ès-Sciences" thesis (1946). He observed that 2254 RP was ineffective on glycemia in totally pancreatectomized dogs but was effective in partially pancreatectomized ones. The hypoglycemic effect in normal dog was dependent on the plasma sulfonamide concentration; this effect appeared whatever the route of administration and was unaffected by vagotomy. Furthermore, Loubatières performed cross-circulation experiments. In these experiments, the pancreatico-duodenal vein of a normal dog was anastomosed to the jugular vein of a receiver dog made diabetic by alloxan; in this case, the injection of 2254 RP into the donor induced a decrease in blood glucose levels in the receiver. In early 1946, Auguste Loubatières proposed that the hypoglycemic property of 2254 RP was due to its ability to stimulate insulin secretion through a direct action on pancreatic islets; he wrote in his thesis "A notre avis, le para-amino-benzène-sulfamido-isopropylthiodiazol (2254 RP) est donc un corps essentiellement insulino-sécréteur; son action s'exerce directement sur les îlots de Langerhans". He also proposed to use such hypoglycemic sulfonamides in certain forms of diabetes "que l'on peut qualifier de fonctionnels et qui sont la conséquence d'une paresse des mécanismes insulino-sécréteurs". In 1992, Jean-Claude Henquin demonstrated that the sequence of events triggered by 2254 RP at the level of islet beta-cells was similar to that induced by sulfonylureas of the first or second generation. Thus, the 2254 RP, proposed by Auguste Loubatières in the treatment of certain forms of diabetes, was the first of oral hypoglycemic sulfonamides currently used in the treatment of type 2 diabetes mellitus.

  14. Fusion genes and their discovery using high throughput sequencing.

    Science.gov (United States)

    Annala, M J; Parker, B C; Zhang, W; Nykter, M

    2013-11-01

    Fusion genes are hybrid genes that combine parts of two or more original genes. They can form as a result of chromosomal rearrangements or abnormal transcription, and have been shown to act as drivers of malignant transformation and progression in many human cancers. The biological significance of fusion genes together with their specificity to cancer cells has made them into excellent targets for molecular therapy. Fusion genes are also used as diagnostic and prognostic markers to confirm cancer diagnosis and monitor response to molecular therapies. High-throughput sequencing has enabled the systematic discovery of fusion genes in a wide variety of cancer types. In this review, we describe the history of fusion genes in cancer and the ways in which fusion genes form and affect cellular function. We also describe computational methodologies for detecting fusion genes from high-throughput sequencing experiments, and the most common sources of error that lead to false discovery of fusion genes. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  15. Proteomics for discovery of candidate colorectal cancer biomarkers

    Science.gov (United States)

    Álvarez-Chaver, Paula; Otero-Estévez, Olalla; Páez de la Cadena, María; Rodríguez-Berrocal, Francisco J; Martínez-Zorzano, Vicenta S

    2014-01-01

    Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in Europe and other Western countries, mainly due to the lack of well-validated clinically useful biomarkers with enough sensitivity and specificity to detect this disease at early stages. Although it is well known that the pathogenesis of CRC is a progressive accumulation of mutations in multiple genes, much less is known at the proteome level. Therefore, in the last years many proteomic studies have been conducted to find new candidate protein biomarkers for diagnosis, prognosis and as therapeutic targets for this malignancy, as well as to elucidate the molecular mechanisms of colorectal carcinogenesis. An important advantage of the proteomic approaches is the capacity to look for multiple differentially expressed proteins in a single study. This review provides an overview of the recent reports describing the different proteomic tools used for the discovery of new protein markers for CRC such as two-dimensional electrophoresis methods, quantitative mass spectrometry-based techniques or protein microarrays. Additionally, we will also focus on the diverse biological samples used for CRC biomarker discovery such as tissue, serum and faeces, besides cell lines and murine models, discussing their advantages and disadvantages, and summarize the most frequently identified candidate CRC markers. PMID:24744574

  16. 'Big data' approaches for novel anti-cancer drug discovery.

    Science.gov (United States)

    Benstead-Hume, Graeme; Wooller, Sarah K; Pearl, Frances M G

    2017-06-01

    The development of improved cancer therapies is frequently cited as an urgent unmet medical need. Recent advances in platform technologies and the increasing availability of biological 'big data' are providing an unparalleled opportunity to systematically identify the key genes and pathways involved in tumorigenesis. The discoveries made using these new technologies may lead to novel therapeutic interventions. Areas covered: The authors discuss the current approaches that use 'big data' to identify cancer drivers. These approaches include the analysis of genomic sequencing data, pathway data, multi-platform data, identifying genetic interactions such as synthetic lethality and using cell line data. They review how big data is being used to identify novel drug targets. The authors then provide an overview of the available data repositories and tools being used at the forefront of cancer drug discovery. Expert opinion: Targeted therapies based on the genomic events driving the tumour will eventually inform treatment protocols. However, using a tailored approach to treat all tumour patients may require developing a large repertoire of targeted drugs.

  17. Drug discovery and development for rare genetic disorders.

    Science.gov (United States)

    Sun, Wei; Zheng, Wei; Simeonov, Anton

    2017-09-01

    Approximately 7,000 rare diseases affect millions of individuals in the United States. Although rare diseases taken together have an enormous impact, there is a significant gap between basic research and clinical interventions. Opportunities now exist to accelerate drug development for the treatment of rare diseases. Disease foundations and research centers worldwide focus on better understanding rare disorders. Here, the state-of-the-art drug discovery strategies for small molecules and biological approaches for orphan diseases are reviewed. Rare diseases are usually genetic diseases; hence, employing pharmacogenetics to develop treatments and using whole genome sequencing to identify the etiologies for such diseases are appropriate strategies to exploit. Beginning with high throughput screening of small molecules, the benefits and challenges of target-based and phenotypic screens are discussed. Explanations and examples of drug repurposing are given; drug repurposing as an approach to quickly move programs to clinical trials is evaluated. Consideration is given to the category of biologics which include gene therapy, recombinant proteins, and autologous transplants. Disease models, including animal models and induced pluripotent stem cells (iPSCs) derived from patients, are surveyed. Finally, the role of biomarkers in drug discovery and development, as well as clinical trials, is elucidated. © 2017 Wiley Periodicals, Inc.

  18. Amyotrophic lateral sclerosis: an emerging era of collaborative gene discovery.

    Directory of Open Access Journals (Sweden)

    Katrina Gwinn

    2007-12-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is the most common form of motor neuron disease (MND. It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA, phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS.

  19. Discovery of novel bacterial toxins by genomics and computational biology.

    Science.gov (United States)

    Doxey, Andrew C; Mansfield, Michael J; Montecucco, Cesare

    2018-06-01

    Hundreds and hundreds of bacterial protein toxins are presently known. Traditionally, toxin identification begins with pathological studies of bacterial infectious disease. Following identification and cultivation of a bacterial pathogen, the protein toxin is purified from the culture medium and its pathogenic activity is studied using the methods of biochemistry and structural biology, cell biology, tissue and organ biology, and appropriate animal models, supplemented by bioimaging techniques. The ongoing and explosive development of high-throughput DNA sequencing and bioinformatic approaches have set in motion a revolution in many fields of biology, including microbiology. One consequence is that genes encoding novel bacterial toxins can be identified by bioinformatic and computational methods based on previous knowledge accumulated from studies of the biology and pathology of thousands of known bacterial protein toxins. Starting from the paradigmatic cases of diphtheria toxin, tetanus and botulinum neurotoxins, this review discusses traditional experimental approaches as well as bioinformatics and genomics-driven approaches that facilitate the discovery of novel bacterial toxins. We discuss recent work on the identification of novel botulinum-like toxins from genera such as Weissella, Chryseobacterium, and Enteroccocus, and the implications of these computationally identified toxins in the field. Finally, we discuss the promise of metagenomics in the discovery of novel toxins and their ecological niches, and present data suggesting the existence of uncharacterized, botulinum-like toxin genes in insect gut metagenomes. Copyright © 2018. Published by Elsevier Ltd.

  20. Advancing cancer drug discovery towards more agile development of targeted combination therapies.

    Science.gov (United States)

    Carragher, Neil O; Unciti-Broceta, Asier; Cameron, David A

    2012-01-01

    Current drug-discovery strategies are typically 'target-centric' and are based upon high-throughput screening of large chemical libraries against nominated targets and a selection of lead compounds with optimized 'on-target' potency and selectivity profiles. However, high attrition of targeted agents in clinical development suggest that combinations of targeted agents will be most effective in treating solid tumors if the biological networks that permit cancer cells to subvert monotherapies are identified and retargeted. Conventional drug-discovery and development strategies are suboptimal for the rational design and development of novel drug combinations. In this article, we highlight a series of emerging technologies supporting a less reductionist, more agile, drug-discovery and development approach for the rational design, validation, prioritization and clinical development of novel drug combinations.

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

    Science.gov (United States)

    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).

  2. Aneuploidy in stem cells

    NARCIS (Netherlands)

    Garcia-Martinez, Jorge; Bakker, Bjorn; Schukken, Klaske M; Simon, Judith E; Foijer, Floris

    2016-01-01

    Stem cells hold enormous promise for regenerative medicine as well as for engineering of model systems to study diseases and develop new drugs. The discovery of protocols that allow for generating induced pluripotent stem cells (IPSCs) from somatic cells has brought this promise steps closer to

  3. Space Shuttle Discovery arrives at Launch Pad 39A

    Science.gov (United States)

    2001-01-01

    KENNEDY SPACE CENTER, Fla. -- Space Shuttle Discovery arrives at Launch Pad 39A after an early morning rollout from the Vehicle Assembly Building. Discovery is scheduled to launch Aug. 3 on mission STS-105.

  4. Do giant oilfield discoveries fuel internal armed conflicts?

    OpenAIRE

    Yu-Hsiang Lei; Guy Michaels

    2011-01-01

    We use new data to examine the effects of giant oilfield discoveries around the world since 1946. On average, these discoveries increase per capita oil production and oil exports by up to 50 percent. But these giant oilfield discoveries also have a dark side: they increase the incidence of internal armed conflict by about 5-8 percentage points. This increased incidence of conflict due to giant oilfield discoveries is especially high for countries that had already experienced armed conflicts o...

  5. Boesenbergia rotunda: From Ethnomedicine to Drug Discovery

    Directory of Open Access Journals (Sweden)

    Tan Eng-Chong

    2012-01-01

    Full Text Available Boesenbergia rotunda is a herb from the Boesenbergia genera under the Zingiberaceae family. B. rotunda is widely found in Asian countries where it is commonly used as a food ingredient and in ethnomedicinal preparations. The popularity of its ethnomedicinal usage has drawn the attention of scientists worldwide to further investigate its medicinal properties. Advancement in drug design and discovery research has led to the development of synthetic drugs from B. rotunda metabolites via bioinformatics and medicinal chemistry studies. Furthermore, with the advent of genomics, transcriptomics, proteomics, and metabolomics, new insights on the biosynthetic pathways of B. rotunda metabolites can be elucidated, enabling researchers to predict the potential bioactive compounds responsible for the medicinal properties of the plant. The vast biological activities exhibited by the compounds obtained from B. rotunda warrant further investigation through studies such as drug discovery, polypharmacology, and drug delivery using nanotechnology.

  6. Mass Spectrometry-Based Biomarker Discovery.

    Science.gov (United States)

    Zhou, Weidong; Petricoin, Emanuel F; Longo, Caterina

    2017-01-01

    The discovery of candidate biomarkers within the entire proteome is one of the most important and challenging goals in proteomic research. Mass spectrometry-based proteomics is a modern and promising technology for semiquantitative and qualitative assessment of proteins, enabling protein sequencing and identification with exquisite accuracy and sensitivity. For mass spectrometry analysis, protein extractions from tissues or body fluids and subsequent protein fractionation represent an important and unavoidable step in the workflow for biomarker discovery. Following extraction of proteins, the protein mixture must be digested, reduced, alkylated, and cleaned up prior to mass spectrometry. The aim of our chapter is to provide comprehensible and practical lab procedures for sample digestion, protein fractionation, and subsequent mass spectrometry analysis.

  7. Discovery and Selection of Semantic Web Services

    CERN Document Server

    Wang, Xia

    2013-01-01

    For advanced web search engines to be able not only to search for semantically related information dispersed over different web pages, but also for semantic services providing certain functionalities, discovering semantic services is the key issue. Addressing four problems of current solution, this book presents the following contributions. A novel service model independent of semantic service description models is proposed, which clearly defines all elements necessary for service discovery and selection. It takes service selection as its gist and improves efficiency. Corresponding selection algorithms and their implementation as components of the extended Semantically Enabled Service-oriented Architecture in the Web Service Modeling Environment are detailed. Many applications of semantic web services, e.g. discovery, composition and mediation, can benefit from a general approach for building application ontologies. With application ontologies thus built, services are discovered in the same way as with single...

  8. Golden Jubilee photos: A gargantuan discovery

    CERN Multimedia

    2004-01-01

    In July 1973, a groundbreaking discovery was announced in CERN's Main Auditorium: the Gargamelle group had found proof of the weak neutral current. The discovery confirmed the electroweak theory, which had predicted that the weak force and the electromagnetic force were different facets of the same interaction. This paved the way for the Grand Unified Theory, which holds that just after the birth of the Universe all forces were actually the same... Gargamelle, whose "body" now reposes in the Microcosm garden, was a huge bubble chamber weighing around 1000 tonnes, filled with 18 tonnes of liquid freon. Its size, worthy of the giant Gargantua - the son of Gargamelle - was mighty enough to catch neutrinos, the elusive neutral particles which career through space without leaving any tracks. In the photograph, an unseen neutrino interacts with an electron and emerges as a neutrino instead of changing into a muon - what is seen (vertically) is the track of the electron. This lepton event offers p...

  9. Panorama 2014 - New oil and gas discoveries

    International Nuclear Information System (INIS)

    Vially, Roland; Hureau, Geoffroy

    2013-12-01

    Spending on exploration increased significantly in 2012, and this growth should continue into 2013. Over a period of ten years, exploration budgets have increased five-fold, leading to major discoveries in regions as yet unexplored. In 2012, 25 billion barrels of oil equivalent (Gboe) were revealed. This is more than the average for the whole decade, but less than the amount for the previous year. Although knowledge of the volumes that have been discovered is still very fragmented, they should continue to fall into 2013. The main reason lies in the fact that spending on exploration is being shifted towards assessing discoveries made in previous years in the particularly prolific basins of Brazil and East Africa, while the exploration of border regions - such as the West African pre-salt formation - is still only in its early stages. (authors)

  10. Biopharmaceutical discovery and production in yeast.

    Science.gov (United States)

    Meehl, Michael A; Stadheim, Terrance A

    2014-12-01

    The selection of an expression platform for recombinant biopharmaceuticals is often centered upon suitable product titers and critical quality attributes, including post-translational modifications. Although notable differences between microbial, yeast, plant, and mammalian host systems exist, recent advances have greatly mitigated any inherent liabilities of yeasts. Yeast expression platforms are important to both the supply of marketed biopharmaceuticals and the pipelines of novel therapeutics. In this review, recent advances in yeast-based expression of biopharmaceuticals will be discussed. The advantages of using glycoengineered yeast as a production host and in the discovery space will be illustrated. These advancements, in turn, are transforming yeast platforms from simple production systems to key technological assets in the discovery and selection of biopharmaceutical lead candidates. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Bayesian centroid estimation for motif discovery.

    Science.gov (United States)

    Carvalho, Luis

    2013-01-01

    Biological sequences may contain patterns that signal important biomolecular functions; a classical example is regulation of gene expression by transcription factors that bind to specific patterns in genomic promoter regions. In motif discovery we are given a set of sequences that share a common motif and aim to identify not only the motif composition, but also the binding sites in each sequence of the set. We propose a new centroid estimator that arises from a refined and meaningful loss function for binding site inference. We discuss the main advantages of centroid estimation for motif discovery, including computational convenience, and how its principled derivation offers further insights about the posterior distribution of binding site configurations. We also illustrate, using simulated and real datasets, that the centroid estimator can differ from the traditional maximum a posteriori or maximum likelihood estimators.

  12. Bayesian centroid estimation for motif discovery.

    Directory of Open Access Journals (Sweden)

    Luis Carvalho

    Full Text Available Biological sequences may contain patterns that signal important biomolecular functions; a classical example is regulation of gene expression by transcription factors that bind to specific patterns in genomic promoter regions. In motif discovery we are given a set of sequences that share a common motif and aim to identify not only the motif composition, but also the binding sites in each sequence of the set. We propose a new centroid estimator that arises from a refined and meaningful loss function for binding site inference. We discuss the main advantages of centroid estimation for motif discovery, including computational convenience, and how its principled derivation offers further insights about the posterior distribution of binding site configurations. We also illustrate, using simulated and real datasets, that the centroid estimator can differ from the traditional maximum a posteriori or maximum likelihood estimators.

  13. Accelerating the Rate of Astronomical Discovery

    Science.gov (United States)

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

    2010-05-01

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

  14. Identifying and quantifying heterogeneity in high content analysis: application of heterogeneity indices to drug discovery.

    Directory of Open Access Journals (Sweden)

    Albert H Gough

    Full Text Available One of the greatest challenges in biomedical research, drug discovery and diagnostics is understanding how seemingly identical cells can respond differently to perturbagens including drugs for disease treatment. Although heterogeneity has become an accepted characteristic of a population of cells, in drug discovery it is not routinely evaluated or reported. The standard practice for cell-based, high content assays has been to assume a normal distribution and to report a well-to-well average value with a standard deviation. To address this important issue we sought to define a method that could be readily implemented to identify, quantify and characterize heterogeneity in cellular and small organism assays to guide decisions during drug discovery and experimental cell/tissue profiling. Our study revealed that heterogeneity can be effectively identified and quantified with three indices that indicate diversity, non-normality and percent outliers. The indices were evaluated using the induction and inhibition of STAT3 activation in five cell lines where the systems response including sample preparation and instrument performance were well characterized and controlled. These heterogeneity indices provide a standardized method that can easily be integrated into small and large scale screening or profiling projects to guide interpretation of the biology, as well as the development of therapeutics and diagnostics. Understanding the heterogeneity in the response to perturbagens will become a critical factor in designing strategies for the development of therapeutics including targeted polypharmacology.

  15. Graph-Based Methods for Discovery Browsing with Semantic Predications

    DEFF Research Database (Denmark)

    Wilkowski, Bartlomiej; Fiszman, Marcelo; Miller, Christopher M

    2011-01-01

    We present an extension to literature-based discovery that goes beyond making discoveries to a principled way of navigating through selected aspects of some biomedical domain. The method is a type of "discovery browsing" that guides the user through the research literature on a specified phenomen...

  16. 49 CFR 1313.10 - Procedures for complaints and discovery.

    Science.gov (United States)

    2010-10-01

    ...) Discovery petition. A discovery petition must note on the front page “Petition for Discovery of Rail... perform its common carrier obligation, the nexus between the information sought and the common carrier.... Immediately upon the filing of a complaint, the rail carrier filing the contract summary shall forward to the...

  17. Parasites and infectious disease: discovery by serendipity, and otherwise

    National Research Council Canada - National Science Library

    Esch, Gerald W

    2007-01-01

    ... in generating breakthrough scientific discoveries, ranging from immunology to ecology, and from malaria and trypanosomiasis to schistosomiasis and Lyme disease. Some of these discoveries were made serendipitously and others only after relentless effort pointed to a specific solution. This engaging and lively introduction to discovery in parasit...

  18. A Taxonomy of Self-configuring Service Discovery Systems

    NARCIS (Netherlands)

    Sundramoorthy, V.; Hartel, Pieter H.; Scholten, Johan

    2007-01-01

    We analyze the fundamental concepts and issues in service discovery. This analysis places service discovery in the context of distributed systems by describing service discovery as a third generation naming system. We also describe the essential architectures and the functionalities in service

  19. An extended dual search space model of scientific discovery learning

    NARCIS (Netherlands)

    van Joolingen, Wouter; de Jong, Anthonius J.M.

    1997-01-01

    This article describes a theory of scientific discovery learning which is an extension of Klahr and Dunbar''s model of Scientific Discovery as Dual Search (SDDS) model. We present a model capable of describing and understanding scientific discovery learning in complex domains in terms of the SDDS

  20. The Neutron's Discovery - 80 Years on

    Science.gov (United States)

    Rogers, John D.

    A brief review is given of selected highlights in scientific developments from the birth of modern nuclear physics at the end of the 19th century to the discovery of the neutron in 1932. This is followed by some important milestones in neutron and reactor physics that have led to our current understanding and implementation of nuclear technologies. The beginnings can be traced back to the discovery of X-rays by Roentgen, the identification of natural radioactivity by Becquerel and the discovery of the electron by Thomson, towards the end of the 19th Century. Rutherford was a key figure in experimental physics who determined the structure of the atom and who inspired his students at McGill, Manchester and Cambridge Universities (many of whom would become Nobel laureates) in the pursuit of their physics research. One of Rutherford's students, James Chadwick, had studied the work carried out by Bothe and Becker on alpha particle-induced disintegration of light elements which had led to their observation of high energy penetrating radiation that neither they nor the Joliot-Curies could identify. Chadwick knew that the only possible explanation was the emission of a neutron in the nuclear reaction. He carried out tests in the Cavendish Laboratory and submitted his now classical paper identifying the neutron to the periodical Nature in 1932. The discovery of the neutron and of nuclear fission in 1939 opened up new areas for scientific investigation, in, for example, astrophysics, geology, neutron and nuclear physics. The prospects for nuclear power in particular appeared to be unlimited and both civil and military applications have been actively pursued. Many new experimental facilities have been designed and built to provide intense sources of neutrons for research purposes. Work carried out in such centres is included in the programme of the 7th International Topical Meeting on Neutron Radiography, an important forum for discussion of the latest research work of this

  1. Computational functional group mapping for drug discovery

    OpenAIRE

    Guvench, Olgun

    2016-01-01

    Computational functional group mapping (cFGM) is emerging as a high-impact complement to existing widely used experimental and computational structure-based drug discovery methods. cFGM provides comprehensive atomic-resolution 3D maps of the affinity of functional groups that can constitute drug-like molecules for a given target, typically a protein. These 3D maps can be intuitively and interactively visualized by medicinal chemists to rapidly design synthetically accessible ligands. Given th...

  2. From Discovery to Impact - Near Earth Asteroids

    Directory of Open Access Journals (Sweden)

    Miloš Tichý

    2012-10-01

    Full Text Available The Near-Earth Objects (NEOs are the most important of the small bodies of the solar system, having the capability of close approaches to the Earth and the chance to collide with the Earth.  We present here the current system of discovery of these dangerous objects, standards for selecting useful and important targets for NEO follow-up astrometry, system of impact probabilities calculations, and also determination of impact site and evacuation area.

  3. Photovoltaic Technology and Applications | Othieno | Discovery and ...

    African Journals Online (AJOL)

    La technologie photovoltaïque est donc passée en revue et des recommandations sont faites sur leur application pour l'électrification rurale dans les pays en voie de développement. Mots clés: énergie solaire, matériaux photovoltaïques, électrification rurale, énergie, coût, application (Discovery and innovation: 14(1-2): ...

  4. The Discovery of the Top Quark

    Science.gov (United States)

    Sinervo, P.K.

    1995-12-01

    The top quark and the Higgs boson are the heaviest elementary particles predicted by the standard model. The four lightest quark flavours, the up, down, strange and charm quarks, were well-established by the mid-1970's. The discovery in 1977 of the {Tau} resonances, a new family of massive hadrons, required the introduction of the fifth quark flavour. Experimental and theoretical studies have indicated that this quark also has a heavier partner, the top quark.

  5. Bioenergy Knowledge Discovery Framework Fact Sheet

    Energy Technology Data Exchange (ETDEWEB)

    None

    2017-07-01

    The Bioenergy Knowledge Discovery Framework (KDF) supports the development of a sustainable bioenergy industry by providing access to a variety of data sets, publications, and collaboration and mapping tools that support bioenergy research, analysis, and decision making. In the KDF, users can search for information, contribute data, and use the tools and map interface to synthesize, analyze, and visualize information in a spatially integrated manner.

  6. Discovery Monday - Behind the plug: communication networks

    CERN Multimedia

    2004-01-01

    Ever wondered what happens to your email when you click "send"? And when you make a phone call, how does your voice travel down the wire? Find out more about communication networks and their applications. Do not miss the next Discovery Monday in Microcosm on 1st March (see Bulletin 9/2004)! Monday 1st March from 7.30pm to 9.00pm, in Microcosm. Entrance Free.

  7. Discovery and Development of Calcium Channel Blockers

    OpenAIRE

    Godfraind, Théophile

    2017-01-01

    In the mid 1960s, experimental work on molecules under screening as coronary dilators allowed the discovery of the mechanism of calcium entry blockade by drugs later named calcium channel blockers. This paper summarizes scientific research on these small molecules interacting directly with L-type voltage-operated calcium channels. It also reports on experimental approaches translated into understanding of their therapeutic actions. The importance of calcium in muscle contraction was discovere...

  8. Recent archaeological discoveries in East Kalimantan, Indonesia

    OpenAIRE

    Chazine, Jean-Michel; Ferrie, Jean-Georges

    2008-01-01

    International audience; Since 1992, thanks to the exceptional interest generated by caving teams crossing Kalimantan from west to east in 1988, a large quantity of archaeological discoveries has been revealed. A Franco-Indonesian team has surveyed caves and rockshelters in East Kalimantan to shed some light on an archaeologically unknown territory. Altogether, more than 100 caves have been visited and checked, of which over 30 contain undoubtable rock paintings. These sites are located in two...

  9. Important discoveries from analysing bacterial phenotypes

    OpenAIRE

    Bochner, Barry R; Giovannetti, Luciana; Viti, Carlo

    2008-01-01

    The ability to test hundreds to thousands of cellular phenotypes in a single experiment has opened up new avenues of investigation and exploration and led to important discoveries in very diverse applications of microbiological research and development. The information provided by global phenotyping is complementary to, and often more easily interpretable than information provided by global molecular analytical methods such as gene chips and proteomics. This report summarizes advances present...

  10. Proteomics and Mass Spectrometry for Cancer Biomarker Discovery

    Science.gov (United States)

    Lu, Ming; Faull, Kym F.; Whitelegge, Julian P.; He, Jianbo; Shen, Dejun; Saxton, Romaine E.; Chang, Helena R.

    2007-01-01

    Proteomics is a rapidly advancing field not only in the field of biology but also in translational cancer research. In recent years, mass spectrometry and associated technologies have been explored to identify proteins or a set of proteins specific to a given disease, for the purpose of disease detection and diagnosis. Such biomarkers are being investigated in samples including cells, tissues, serum/plasma, and other types of body fluids. When sufficiently refined, proteomic technologies may pave the way for early detection of cancer or individualized therapy for cancer. Mass spectrometry approaches coupled with bioinformatic tools are being developed for biomarker discovery and validation. Understanding basic concepts and application of such technology by investigators in the field may accelerate the clinical application of protein biomarkers in disease management. PMID:19662217

  11. High throughput electrophysiology: new perspectives for ion channel drug discovery

    DEFF Research Database (Denmark)

    Willumsen, Niels J; Bech, Morten; Olesen, Søren-Peter

    2003-01-01

    Proper function of ion channels is crucial for all living cells. Ion channel dysfunction may lead to a number of diseases, so-called channelopathies, and a number of common diseases, including epilepsy, arrhythmia, and type II diabetes, are primarily treated by drugs that modulate ion channels....... A cornerstone in current drug discovery is high throughput screening assays which allow examination of the activity of specific ion channels though only to a limited extent. Conventional patch clamp remains the sole technique with sufficiently high time resolution and sensitivity required for precise and direct...... characterization of ion channel properties. However, patch clamp is a slow, labor-intensive, and thus expensive, technique. New techniques combining the reliability and high information content of patch clamping with the virtues of high throughput philosophy are emerging and predicted to make a number of ion...

  12. Towards discovery-driven translational research in breast cancer

    DEFF Research Database (Denmark)

    Celis, Julio E; Moreira, José M A; Gromova, Irina

    2005-01-01

    Discovery-driven translational research in breast cancer is moving steadily from the study of cell lines to the analysis of clinically relevant samples that, together with the ever increasing number of novel and powerful technologies available within genomics, proteomics and functional genomics......, promise to have a major impact on the way breast cancer will be diagnosed, treated and monitored in the future. Here we present a brief report on long-term ongoing strategies at the Danish Centre for Translational Breast Cancer Research to search for markers for early detection and targets for therapeutic...... intervention, to identify signalling pathways affected in individual tumours, as well as to integrate multiplatform 'omic' data sets collected from tissue samples obtained from individual patients. The ultimate goal of this initiative is to coalesce knowledge-based complementary procedures into a systems...

  13. Systems Pharmacology in Small Molecular Drug Discovery.

    Science.gov (United States)

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-02-18

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

  14. Discovery and History of Amino Acid Fermentation.

    Science.gov (United States)

    Hashimoto, Shin-Ichi

    There has been a strong demand in Japan and East Asia for L-glutamic acid as a seasoning since monosodium glutamate was found to present umami taste in 1907. The discovery of glutamate fermentation by Corynebacterium glutamicum in 1956 enabled abundant and low-cost production of the amino acid, creating a large market. The discovery also prompted researchers to develop fermentative production processes for other L-amino acids, such as lysine. Currently, the amino acid fermentation industry is so huge that more than 5 million metric tons of amino acids are manufactured annually all over the world, and this number continues to grow. Research on amino acid fermentation fostered the notion and skills of metabolic engineering which has been applied for the production of other compounds from renewable resources. The discovery of glutamate fermentation has had revolutionary impacts on both the industry and science. In this chapter, the history and development of glutamate fermentation, including the very early stage of fermentation of other amino acids, are reviewed.

  15. The Challenges of Interoperable Data Discovery

    Science.gov (United States)

    Meaux, Melanie F.

    2005-01-01

    The Global Change Master Directory (GCMD) assists the oceanographic community in data discovery and access through its online metadata directory. The directory also offers data holders a means to post and search their oceanographic data through the GCMD portals, i.e. online customized subset metadata directories. The Gulf of Maine Ocean Data Partnership (GoMODP) has expressed interest in using the GCMD portals to increase the visibility of their data holding throughout the Gulf of Maine region and beyond. The purpose of the Gulf of Maine Ocean Data Partnership (GoMODP) is to "promote and coordinate the sharing, linking, electronic dissemination, and use of data on the Gulf of Maine region". The participants have decided that a "coordinated effort is needed to enable users throughout the Gulf of Maine region and beyond to discover and put to use the vast and growing quantities of data in their respective databases". GoMODP members have invited the GCMD to discuss further collaborations in view of this effort. This presentation. will focus on the GCMD GoMODP Portal - demonstrating its content and use for data discovery, and will discuss the challenges of interoperable data discovery. interoperability among metadata standards and vocabularies will be discussed. A short overview of the lessons learned at the Marine Metadata Interoperability (MMI) metadata workshop held in Boulder, Colorado on August 9-11, 2005 will be given.

  16. Pathways to new drug discovery in neuropsychiatry.

    Science.gov (United States)

    Berk, Michael

    2012-11-29

    There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. In this commentary, the sources of this dilemma and potential avenues to redress the issue are explored. These include a critical review of diagnostic issues and of selection of participants for clinical trials, and the mechanisms for identifying new drugs and new drug targets. Historically, the vast majority of agents have been discovered serendipitously or have been modifications of existing agents. Serendipitous discoveries, based on astute clinical observation or data mining, remain a valid option, as is illustrated by the suggestion in the paper by Wahlqvist and colleagues that treatment with sulfonylurea and metformin reduces the risk of affective disorder. However, the identification of agents targeting disorder-related biomarkers is currently proving particularly fruitful. There is considerable hope for genetics as a purist, pathophysiologically valid pathway to drug discovery; however, it is unclear whether the science is ready to meet this promise. Fruitful paradigms will require a break from the orthodoxy, and creativity and risk may well be the fingerprints of success.See related article http://www.biomedcentral.com/1741-7015/10/150.

  17. Biomimicry as a basis for drug discovery.

    Science.gov (United States)

    Kolb, V M

    1998-01-01

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

  18. Systems Pharmacology in Small Molecular Drug Discovery

    Directory of Open Access Journals (Sweden)

    Wei Zhou

    2016-02-01

    Full Text Available Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity, target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

  19. Pathways to new drug discovery in neuropsychiatry

    Directory of Open Access Journals (Sweden)

    Berk Michael

    2012-11-01

    Full Text Available Abstract There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. In this commentary, the sources of this dilemma and potential avenues to redress the issue are explored. These include a critical review of diagnostic issues and of selection of participants for clinical trials, and the mechanisms for identifying new drugs and new drug targets. Historically, the vast majority of agents have been discovered serendipitously or have been modifications of existing agents. Serendipitous discoveries, based on astute clinical observation or data mining, remain a valid option, as is illustrated by the suggestion in the paper by Wahlqvist and colleagues that treatment with sulfonylurea and metformin reduces the risk of affective disorder. However, the identification of agents targeting disorder-related biomarkers is currently proving particularly fruitful. There is considerable hope for genetics as a purist, pathophysiologically valid pathway to drug discovery; however, it is unclear whether the science is ready to meet this promise. Fruitful paradigms will require a break from the orthodoxy, and creativity and risk may well be the fingerprints of success. See related article http://www.biomedcentral.com/1741-7015/10/150

  20. Performance Evaluation of Frequent Subgraph Discovery Techniques

    Directory of Open Access Journals (Sweden)

    Saif Ur Rehman

    2014-01-01

    Full Text Available Due to rapid development of the Internet technology and new scientific advances, the number of applications that model the data as graphs increases, because graphs have highly expressive power to model a complicated structure. Graph mining is a well-explored area of research which is gaining popularity in the data mining community. A graph is a general model to represent data and has been used in many domains such as cheminformatics, web information management system, computer network, and bioinformatics, to name a few. In graph mining the frequent subgraph discovery is a challenging task. Frequent subgraph mining is concerned with discovery of those subgraphs from graph dataset which have frequent or multiple instances within the given graph dataset. In the literature a large number of frequent subgraph mining algorithms have been proposed; these included FSG, AGM, gSpan, CloseGraph, SPIN, Gaston, and Mofa. The objective of this research work is to perform quantitative comparison of the above listed techniques. The performances of these techniques have been evaluated through a number of experiments based on three different state-of-the-art graph datasets. This novel work will provide base for anyone who is working to design a new frequent subgraph discovery technique.

  1. Molecular dynamics simulations and novel drug discovery.

    Science.gov (United States)

    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.

  2. Workshop on Discovery Lessons-Learned

    Science.gov (United States)

    Saunders, M. (Editor)

    1995-01-01

    As part of the Discovery Program's continuous improvement effort, a Discovery Program Lessons-Learned workshop was designed to review how well the Discovery Program is moving toward its goal of providing low-cost research opportunities to the planetary science community while ensuring continued U.S. leadership in solar system exploration. The principal focus of the workshop was on the recently completed Announcement of Opportunity (AO) cycle, but the program direction and program management were also open to comment. The objective of the workshop was to identify both the strengths and weaknesses of the process up to this point, with the goal of improving the process for the next AO cycle. The process for initializing the workshop was to solicit comments from the communities involved in the program and to use the feedback as the basis for establishing the workshop agenda. The following four sessions were developed after reviewing and synthesizing both the formal feedback received and informal feedback obtained during discussions with various participants: (1) Science and Return on Investment; (2) Technology vs. Risk; Mission Success and Other Factors; (3) Cost; and (4) AO.AO Process Changes and Program Management.

  3. Towards Robot Scientists for autonomous scientific discovery.

    Science.gov (United States)

    Sparkes, Andrew; Aubrey, Wayne; Byrne, Emma; Clare, Amanda; Khan, Muhammed N; Liakata, Maria; Markham, Magdalena; Rowland, Jem; Soldatova, Larisa N; Whelan, Kenneth E; Young, Michael; King, Ross D

    2010-01-04

    We review the main components of autonomous scientific discovery, and how they lead to the concept of a Robot Scientist. This is a system which uses techniques from artificial intelligence to automate all aspects of the scientific discovery process: it generates hypotheses from a computer model of the domain, designs experiments to test these hypotheses, runs the physical experiments using robotic systems, analyses and interprets the resulting data, and repeats the cycle. We describe our two prototype Robot Scientists: Adam and Eve. Adam has recently proven the potential of such systems by identifying twelve genes responsible for catalysing specific reactions in the metabolic pathways of the yeast Saccharomyces cerevisiae. This work has been formally recorded in great detail using logic. We argue that the reporting of science needs to become fully formalised and that Robot Scientists can help achieve this. This will make scientific information more reproducible and reusable, and promote the integration of computers in scientific reasoning. We believe the greater automation of both the physical and intellectual aspects of scientific investigations to be essential to the future of science. Greater automation improves the accuracy and reliability of experiments, increases the pace of discovery and, in common with conventional laboratory automation, removes tedious and repetitive tasks from the human scientist.

  4. Two kinds of knowledge in scientific discovery.

    Science.gov (United States)

    Bridewell, Will; Langley, Pat

    2010-01-01

    Research on computational models of scientific discovery investigates both the induction of descriptive laws and the construction of explanatory models. Although the work in law discovery centers on knowledge-lean approaches to searching a problem space, research on deeper modeling tasks emphasizes the pivotal role of domain knowledge. As an example, our own research on inductive process modeling uses information about candidate processes to explain why variables change over time. However, our experience with IPM, an artificial intelligence system that implements this approach, suggests that process knowledge is insufficient to avoid consideration of implausible models. To this end, the discovery system needs additional knowledge that constrains the model structures. We report on an extended system, SC-IPM, that uses such information to reduce its search through the space of candidates and to produce models that human scientists find more plausible. We also argue that although people carry out less extensive search than SC-IPM, they rely on the same forms of knowledge--processes and constraints--when constructing explanatory models. Copyright © 2009 Cognitive Science Society, Inc.

  5. Discovery and Development of Calcium Channel Blockers

    Science.gov (United States)

    Godfraind, Théophile

    2017-01-01

    In the mid 1960s, experimental work on molecules under screening as coronary dilators allowed the discovery of the mechanism of calcium entry blockade by drugs later named calcium channel blockers. This paper summarizes scientific research on these small molecules interacting directly with L-type voltage-operated calcium channels. It also reports on experimental approaches translated into understanding of their therapeutic actions. The importance of calcium in muscle contraction was discovered by Sidney Ringer who reported this fact in 1883. Interest in the intracellular role of calcium arose 60 years later out of Kamada (Japan) and Heibrunn (USA) experiments in the early 1940s. Studies on pharmacology of calcium function were initiated in the mid 1960s and their therapeutic applications globally occurred in the the 1980s. The first part of this report deals with basic pharmacology in the cardiovascular system particularly in isolated arteries. In the section entitled from calcium antagonists to calcium channel blockers, it is recalled that drugs of a series of diphenylpiperazines screened in vivo on coronary bed precontracted by angiotensin were initially named calcium antagonists on the basis of their effect in depolarized arteries contracted by calcium. Studies on arteries contracted by catecholamines showed that the vasorelaxation resulted from blockade of calcium entry. Radiochemical and electrophysiological studies performed with dihydropyridines allowed their cellular targets to be identified with L-type voltage-operated calcium channels. The modulated receptor theory helped the understanding of their variation in affinity dependent on arterial cell membrane potential and promoted the terminology calcium channel blocker (CCB) of which the various chemical families are introduced in the paper. In the section entitled tissue selectivity of CCBs, it is shown that characteristics of the drug, properties of the tissue, and of the stimuli are important factors of

  6. Discovery and Development of Calcium Channel Blockers.

    Science.gov (United States)

    Godfraind, Théophile

    2017-01-01

    In the mid 1960s, experimental work on molecules under screening as coronary dilators allowed the discovery of the mechanism of calcium entry blockade by drugs later named calcium channel blockers. This paper summarizes scientific research on these small molecules interacting directly with L-type voltage-operated calcium channels. It also reports on experimental approaches translated into understanding of their therapeutic actions. The importance of calcium in muscle contraction was discovered by Sidney Ringer who reported this fact in 1883. Interest in the intracellular role of calcium arose 60 years later out of Kamada (Japan) and Heibrunn (USA) experiments in the early 1940s. Studies on pharmacology of calcium function were initiated in the mid 1960s and their therapeutic applications globally occurred in the the 1980s. The first part of this report deals with basic pharmacology in the cardiovascular system particularly in isolated arteries. In the section entitled from calcium antagonists to calcium channel blockers, it is recalled that drugs of a series of diphenylpiperazines screened in vivo on coronary bed precontracted by angiotensin were initially named calcium antagonists on the basis of their effect in depolarized arteries contracted by calcium. Studies on arteries contracted by catecholamines showed that the vasorelaxation resulted from blockade of calcium entry. Radiochemical and electrophysiological studies performed with dihydropyridines allowed their cellular targets to be identified with L-type voltage-operated calcium channels. The modulated receptor theory helped the understanding of their variation in affinity dependent on arterial cell membrane potential and promoted the terminology calcium channel blocker (CCB) of which the various chemical families are introduced in the paper. In the section entitled tissue selectivity of CCBs, it is shown that characteristics of the drug, properties of the tissue, and of the stimuli are important factors of

  7. Discovery and Development of Calcium Channel Blockers

    Directory of Open Access Journals (Sweden)

    Théophile Godfraind

    2017-05-01

    Full Text Available In the mid 1960s, experimental work on molecules under screening as coronary dilators allowed the discovery of the mechanism of calcium entry blockade by drugs later named calcium channel blockers. This paper summarizes scientific research on these small molecules interacting directly with L-type voltage-operated calcium channels. It also reports on experimental approaches translated into understanding of their therapeutic actions. The importance of calcium in muscle contraction was discovered by Sidney Ringer who reported this fact in 1883. Interest in the intracellular role of calcium arose 60 years later out of Kamada (Japan and Heibrunn (USA experiments in the early 1940s. Studies on pharmacology of calcium function were initiated in the mid 1960s and their therapeutic applications globally occurred in the the 1980s. The first part of this report deals with basic pharmacology in the cardiovascular system particularly in isolated arteries. In the section entitled from calcium antagonists to calcium channel blockers, it is recalled that drugs of a series of diphenylpiperazines screened in vivo on coronary bed precontracted by angiotensin were initially named calcium antagonists on the basis of their effect in depolarized arteries contracted by calcium. Studies on arteries contracted by catecholamines showed that the vasorelaxation resulted from blockade of calcium entry. Radiochemical and electrophysiological studies performed with dihydropyridines allowed their cellular targets to be identified with L-type voltage-operated calcium channels. The modulated receptor theory helped the understanding of their variation in affinity dependent on arterial cell membrane potential and promoted the terminology calcium channel blocker (CCB of which the various chemical families are introduced in the paper. In the section entitled tissue selectivity of CCBs, it is shown that characteristics of the drug, properties of the tissue, and of the stimuli are

  8. Gene set-based module discovery in the breast cancer transcriptome

    Directory of Open Access Journals (Sweden)

    Zhang Michael Q

    2009-02-01

    Full Text Available Abstract Background Although microarray-based studies have revealed global view of gene expression in cancer cells, we still have little knowledge about regulatory mechanisms underlying the transcriptome. Several computational methods applied to yeast data have recently succeeded in identifying expression modules, which is defined as co-expressed gene sets under common regulatory mechanisms. However, such module discovery methods are not applied cancer transcriptome data. Results In order to decode oncogenic regulatory programs in cancer cells, we developed a novel module discovery method termed EEM by extending a previously reported module discovery method, and applied it to breast cancer expression data. Starting from seed gene sets prepared based on cis-regulatory elements, ChIP-chip data, and gene locus information, EEM identified 10 principal expression modules in breast cancer based on their expression coherence. Moreover, EEM depicted their activity profiles, which predict regulatory programs in each subtypes of breast tumors. For example, our analysis revealed that the expression module regulated by the Polycomb repressive complex 2 (PRC2 is downregulated in triple negative breast cancers, suggesting similarity of transcriptional programs between stem cells and aggressive breast cancer cells. We also found that the activity of the PRC2 expression module is negatively correlated to the expression of EZH2, a component of PRC2 which belongs to the E2F expression module. E2F-driven EZH2 overexpression may be responsible for the repression of the PRC2 expression modules in triple negative tumors. Furthermore, our network analysis predicts regulatory circuits in breast cancer cells. Conclusion These results demonstrate that the gene set-based module discovery approach is a powerful tool to decode regulatory programs in cancer cells.

  9. Directional genomic hybridization for chromosomal inversion discovery and detection.

    Science.gov (United States)

    Ray, F Andrew; Zimmerman, Erin; Robinson, Bruce; Cornforth, Michael N; Bedford, Joel S; Goodwin, Edwin H; Bailey, Susan M

    2013-04-01

    Chromosomal rearrangements are a source of structural variation within the genome that figure prominently in human disease, where the importance of translocations and deletions is well recognized. In principle, inversions-reversals in the orientation of DNA sequences within a chromosome-should have similar detrimental potential. However, the study of inversions has been hampered by traditional approaches used for their detection, which are not particularly robust. Even with significant advances in whole genome approaches, changes in the absolute orientation of DNA remain difficult to detect routinely. Consequently, our understanding of inversions is still surprisingly limited, as is our appreciation for their frequency and involvement in human disease. Here, we introduce the directional genomic hybridization methodology of chromatid painting-a whole new way of looking at structural features of the genome-that can be employed with high resolution on a cell-by-cell basis, and demonstrate its basic capabilities for genome-wide discovery and targeted detection of inversions. Bioinformatics enabled development of sequence- and strand-specific directional probe sets, which when coupled with single-stranded hybridization, greatly improved the resolution and ease of inversion detection. We highlight examples of the far-ranging applicability of this cytogenomics-based approach, which include confirmation of the alignment of the human genome database and evidence that individuals themselves share similar sequence directionality, as well as use in comparative and evolutionary studies for any species whose genome has been sequenced. In addition to applications related to basic mechanistic studies, the information obtainable with strand-specific hybridization strategies may ultimately enable novel gene discovery, thereby benefitting the diagnosis and treatment of a variety of human disease states and disorders including cancer, autism, and idiopathic infertility.

  10. Proteomics for Adverse Outcome Pathway Discovery using Human Kidney Cells?

    Science.gov (United States)

    An Adverse Outcome Pathway (AOP) is a conceptual framework that applies molecular-based data for use in risk assessment and regulatory decision support. AOP development is based on effects data of chemicals on biological processes (i.e., molecular initiating events, key intermedi...

  11. The neural crest and neural crest cells: discovery and significance ...

    Indian Academy of Sciences (India)

    The neural crest has long fascinated developmental biologists, and, increasingly over the past decades, evolutionary and evolutionary developmental biologists. The neural crest is the name given to the fold of ectoderm at the junction between neural and epidermal ectoderm in neurula-stage vertebrate embryos.

  12. Meeting report on the Alzheimer?s Drug Discovery Foundation 14th International Conference on Alzheimer?s Drug Discovery

    OpenAIRE

    Friedman, Lauren G; Price, Katherine; Lane, Rachel F; Carman, Aaron J; Dacks, Penny A; Shineman, Diana W; Fillit, Howard M

    2014-01-01

    The Alzheimer?s Drug Discovery Foundation?s 14th International Conference on Alzheimer?s Drug Discovery was held on 9 and 10 September in Jersey City, NJ, USA. This annual meeting highlights novel therapeutic approaches supported by the Alzheimer?s Drug Discovery Foundation in development for Alzheimer?s disease and related dementias.

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

    Science.gov (United States)

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

    2017-10-01

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

  14. A brief history of T cell help to B cells.

    Science.gov (United States)

    Crotty, Shane

    2015-03-01

    In celebration of the 50th anniversary of the discovery of B cells, I take a look back at the history of T cell help to B cells, which was discovered 47 years ago. In addition, I summarize and categorize the distinct molecules that are expressed by CD4(+) T cells that constitute 'help' to B cells, and particularly the molecules expressed by T follicular helper (TFH) cells, which are the specialized providers of help to B cells.

  15. Price discovery in a continuous-time setting

    DEFF Research Database (Denmark)

    Dias, Gustavo Fruet; Fernandes, Marcelo; Scherrer, Cristina

    We formulate a continuous-time price discovery model in which the price discovery measure varies (stochastically) at daily frequency. We estimate daily measures of price discovery using a kernel-based OLS estimator instead of running separate daily VECM regressions as standard in the literature. ...... show that our estimator is not only consistent, but also outperforms the standard daily VECM in finite samples. We illustrate our theoretical findings by studying the price discovery process of 10 actively traded stocks in the U.S. from 2007 to 2013.......We formulate a continuous-time price discovery model in which the price discovery measure varies (stochastically) at daily frequency. We estimate daily measures of price discovery using a kernel-based OLS estimator instead of running separate daily VECM regressions as standard in the literature. We...

  16. Discovery of stimulation-responsive immune enhancers with CRISPR activation

    Science.gov (United States)

    Simeonov, Dimitre R.; Gowen, Benjamin G.; Boontanrart, Mandy; Roth, Theodore L.; Gagnon, John D.; Mumbach, Maxwell R.; Satpathy, Ansuman T.; Lee, Youjin; Bray, Nicolas L.; Chan, Alice Y.; Lituiev, Dmytro S.; Nguyen, Michelle L.; Gate, Rachel E.; Subramaniam, Meena; Li, Zhongmei; Woo, Jonathan M.; Mitros, Therese; Ray, Graham J.; Curie, Gemma L.; Naddaf, Nicki; Chu, Julia S.; Ma, Hong; Boyer, Eric; Van Gool, Frederic; Huang, Hailiang; Liu, Ruize; Tobin, Victoria R.; Schumann, Kathrin; Daly, Mark J.; Farh, Kyle K; Ansel, K. Mark; Ye, Chun J.; Greenleaf, William J.; Anderson, Mark S.; Bluestone, Jeffrey A.; Chang, Howard Y.; Corn, Jacob E.; Marson, Alexander

    2017-01-01

    The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues1–3. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption4–6, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa)7 to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (TH17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs. PMID:28854172

  17. Discovery of stimulation-responsive immune enhancers with CRISPR activation

    Science.gov (United States)

    Simeonov, Dimitre R.; Gowen, Benjamin G.; Boontanrart, Mandy; Roth, Theodore L.; Gagnon, John D.; Mumbach, Maxwell R.; Satpathy, Ansuman T.; Lee, Youjin; Bray, Nicolas L.; Chan, Alice Y.; Lituiev, Dmytro S.; Nguyen, Michelle L.; Gate, Rachel E.; Subramaniam, Meena; Li, Zhongmei; Woo, Jonathan M.; Mitros, Therese; Ray, Graham J.; Curie, Gemma L.; Naddaf, Nicki; Chu, Julia S.; Ma, Hong; Boyer, Eric; van Gool, Frederic; Huang, Hailiang; Liu, Ruize; Tobin, Victoria R.; Schumann, Kathrin; Daly, Mark J.; Farh, Kyle K.; Ansel, K. Mark; Ye, Chun J.; Greenleaf, William J.; Anderson, Mark S.; Bluestone, Jeffrey A.; Chang, Howard Y.; Corn, Jacob E.; Marson, Alexander

    2017-09-01

    The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa) to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (TH17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs.

  18. The future of crystallography in drug discovery.

    Science.gov (United States)

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

    2014-02-01

    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. 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. 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

  19. Utility of Glioblastoma Patient-Derived Orthotopic Xenografts in Drug Discovery and Personalized Therapy.

    Science.gov (United States)

    Patrizii, Michele; Bartucci, Monica; Pine, Sharon R; Sabaawy, Hatem E

    2018-01-01

    Despite substantial effort and resources dedicated to drug discovery and development, new anticancer agents often fail in clinical trials. Among many reasons, the lack of reliable predictive preclinical cancer models is a fundamental one. For decades, immortalized cancer cell cultures have been used to lay the groundwork for cancer biology and the quest for therapeutic responses. However, cell lines do not usually recapitulate cancer heterogeneity or reveal therapeutic resistance cues. With the rapidly evolving exploration of cancer "omics," the scientific community is increasingly investigating whether the employment of short-term patient-derived tumor cell cultures (two- and three-dimensional) and/or patient-derived xenograft models might provide a more representative delineation of the cancer core and its therapeutic response. Patient-derived cancer models allow the integration of genomic with drug sensitivity data on a personalized basis and currently represent the ultimate approach for preclinical drug development and biomarker discovery. The proper use of these patient-derived cancer models might soon influence clinical outcomes and allow the implementation of tailored personalized therapy. When assessing drug efficacy for the treatment of glioblastoma multiforme (GBM), currently, the most reliable models are generated through direct injection of patient-derived cells or more frequently the isolation of glioblastoma cells endowed with stem-like features and orthotopically injecting these cells into the cerebrum of immunodeficient mice. Herein, we present the key strengths, weaknesses, and potential applications of cell- and animal-based models of GBM, highlighting our experience with the glioblastoma stem-like patient cell-derived xenograft model and its utility in drug discovery.

  20. Solar System Moons Discovery and Mythology

    CERN Document Server

    Blunck, Jürgen

    2010-01-01

    Starting from Mars outward this concise handbook provides thorough information on the satellites of the planets in the solar system. Each chapter begins with a section on the discovery and the naming of the planet's satellites or rings. This is followed by a section presenting the historic sources of those names. The book contains tables with the orbital and physical parameters of all satellites and is illustrated throughout with modern photos of the planets and their moons as well as historical and mythological drawings. The Cyrillic transcriptions of the satellite names are provided in a register. Readers interested in the history of astronomy and its mythological backgrounds will enjoy this beautiful volume.

  1. Studying Scientific Discovery by Computer Simulation.

    Science.gov (United States)

    1983-03-30

    MAR 83 UNCLASSIFIED CMU-CIP-WP-444 NOOOI4-82-K-0168 F/G 9/2 NL 4lU iQ 111125 . 1 MICROCOPY RESOLUIION TESI CHART NAL URLAD Of SIANDARDS %4 A Isp...About 1760 - the exact date is not known - Joseph Black, a Scottish chemistry professor, made the first of the several important discoveries that have...preserved his name.5 Using data reported in a standard chemistry textbook of his time (Boerhaave’s) and obtained from an experiment performed at

  2. The discovery of columnar jointing on Mars

    Science.gov (United States)

    Milazzo, M.P.; Keszthelyi, L.P.; Jaeger, W.L.; Rosiek, M.; Mattson, S.; Verba, C.; Beyer, R.A.; Geissler, P.E.; McEwen, A.S.; ,

    2009-01-01

    We report on the discovery of columnar jointing in Marte Valles, Mars. These columnar lavas were discovered in the wall of a pristine, 16-km-diameter impact crater and exhibit the features of terrestrial columnar basalts. There are discontinuous outcrops along the entire crater wall, suggesting that the columnar rocks covered a surface area of at least 200 km2, assuming that the rocks obliterated by the impact event were similarly jointed. We also see columns in the walls of other fresh craters in the nearby volcanic plains of Elysium Planitia–Amazonis Planitia, which include Marte Vallis, and in a well-preserved crater in northeast Hellas.

  3. Big Data for cardiology: novel discovery?

    Science.gov (United States)

    Mayer-Schönberger, Viktor

    2016-03-21

    Big Data promises to change cardiology through a massive increase in the data gathered and analysed; but its impact goes beyond improving incrementally existing methods. The potential of comprehensive data sets for scientific discovery is examined, and its impact on the scientific method generally and cardiology in particular is posited, together with likely consequences for research and practice. Big Data in cardiology changes how new insights are being discovered. For it to flourish, significant modifications in the methods, structures, and institutions of the profession are necessary. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  4. Motif discovery in ranked lists of sequences

    DEFF Research Database (Denmark)

    Nielsen, Morten Muhlig; Tataru, Paula; Madsen, Tobias

    2016-01-01

    a growing need for motif analysis methods that can exploit this coupled data structure and be tailored for specific biological questions. Here, we present an exploratory motif analysis tool, Regmex (REGular expression Motif EXplorer), which offers several methods to evaluate the correlation of motifs....... These features make Regmex well suited for a range of biological sequence analysis problems related to motif discovery, exemplified by microRNA seed enrichment, but also including enrichment problems involving complex motifs and combinations of motifs. We demonstrate a number of usage scenarios that take...

  5. Advances in knowledge discovery in databases

    CERN Document Server

    Adhikari, Animesh

    2015-01-01

    This book presents recent advances in Knowledge discovery in databases (KDD) with a focus on the areas of market basket database, time-stamped databases and multiple related databases. Various interesting and intelligent algorithms are reported on data mining tasks. A large number of association measures are presented, which play significant roles in decision support applications. This book presents, discusses and contrasts new developments in mining time-stamped data, time-based data analyses, the identification of temporal patterns, the mining of multiple related databases, as well as local patterns analysis.  

  6. Toward discovery science of human brain function

    DEFF Research Database (Denmark)

    Biswal, Bharat B; Mennes, Maarten; Zuo, Xi-Nian

    2010-01-01

    Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints...... of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (... individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships...

  7. Discovery learning in math: Exercises versus problems

    Directory of Open Access Journals (Sweden)

    Barry Garelick

    2009-02-01

    Full Text Available In this article, Garelick confronts the myth perpetrated in education schools that math is incorrectly taught by teaching students to do "exercises" rather than solving "problems". The former are viewed as inauthentic experiences in which the student applies algorithms to previously learned types of problems in a mechanical type way. In fact, it is through the working of the so-called "exercises" that students can make meaningful discoveries which ultimately lead them to solving more complex problems. As it is, many of today's math programs have students reaching for the stars by standing on a two-legged stool.

  8. The discovery potential of laser polarization experiments

    International Nuclear Information System (INIS)

    Ahlers, Markus

    2008-12-01

    Currently, a number of experiments are searching for vacuum magnetic birefringence and dichroism, i.e. for dispersive and absorptive features in the propagation of polarized light along a transverse magnetic field in vacuum. In this note we calculate the Standard Model contributions to these signatures, thereby illuminating the discovery potential of such experiments in the search for new physics. We discuss the three main sources for a Standard Model contribution to a dichroism signal: photon splitting, neutrino pair production and production of gravitons. (orig.)

  9. The discovery potential of laser polarization experiments

    Energy Technology Data Exchange (ETDEWEB)

    Ahlers, Markus [Oxford Univ. (United Kingdom). Rudolf Peierls Centre for Theoretical Physics; Jaeckel, Joerg [Durham Univ. (United Kingdom). Inst. for Particle Physics and Phenomenology; Ringwald, Andreas [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)

    2008-12-15

    Currently, a number of experiments are searching for vacuum magnetic birefringence and dichroism, i.e. for dispersive and absorptive features in the propagation of polarized light along a transverse magnetic field in vacuum. In this note we calculate the Standard Model contributions to these signatures, thereby illuminating the discovery potential of such experiments in the search for new physics. We discuss the three main sources for a Standard Model contribution to a dichroism signal: photon splitting, neutrino pair production and production of gravitons. (orig.)

  10. Discovery Mondays: Much ado about nothing: vacuums

    CERN Multimedia

    2004-01-01

    Most people seem to agree that an empty space has nothing in it. But what about the physicists? "Wait a minute!", they will tell you, at the Microcosm's next Discovery Monday on 5th April, for they know that even interstellar space is not as empty as it might seem... Come and discover the technological advances made at CERN and their everyday applications. Take a step into the world of the vacuum... The event will take place in the Microcosm on 5th April, from 7.30 p.m. to 9.00 p.m. Entrance is free.

  11. Minireview: Targeting GPCR Activated ERK Pathways for Drug Discovery.

    Science.gov (United States)

    Eishingdrelo, Haifeng; Kongsamut, Sathapana

    2013-01-01

    It has become clear in recent years that multiple signal transduction pathways are employed upon GPCR activation. One of the major cellular effectors activated by GPCRs is extracellular signal-regulated kinase (ERK). Both G-protein and β-arrestin mediated signaling pathways can lead to ERK activation. However, depending on activation pathway, the subcellular destination of activated ERK1/2 may be different. G-protein -dependent ERK activation results in the translocation of active ERK to the nucleus, whereas ERK activated via an arrestin-dependent mechanism remains largely in the cytoplasm. The subcellular location of activated ERK1/2 determines the downstream signaling cascade. Many substrates of ERK1/2 are found in the nucleus: nuclear transcription factors that participate in gene transcription, cell proliferation and differentiation. ERK1/2 substrates are also found in cytosol and other cellular organelles: they may play roles in translation, mitosis, apoptosis and cross-talk with other signaling pathways. Therefore, determining specific subcellular locations of activated ERK1/2 mediated by GPCR ligands would be important in correlating signaling pathways with cellular physiological functions. While GPCR-stimulated selective ERK pathway activation has been studied in several receptor systems, exploitation of these different signaling cascades for therapeutics has not yet been seriously pursued. Many old drug candidates were identified from screens based on G-protein signaling assays, and their activity on β-arrestin signaling pathways being mostly unknown, especially regarding their subcellular ERK pathways. With today's knowledge of complicated GPCR signaling pathways, drug discovery can no longer rely on single-pathway approaches. Since ERK activation is an important signaling pathway and associated with many physiological functions, targeting the ERK pathway, especially specific subcellular activation pathways should provide new avenues for GPCR drug

  12. 3D in vitro technology for drug discovery.

    Science.gov (United States)

    Hosseinkhani, Hossein

    2012-02-01

    Three-dimensional (3D) in vitro systems that can mimic organ and tissue structure and function in vivo, will be of great benefit for a variety of biological applications from basic biology to toxicity testing and drug discovery. There have been several attempts to generate 3D tissue models but most of these models require costly equipment, and the most serious disadvantage in them is that they are too far from the mature human organs in vivo. Because of these problems, research and development in drug discovery, toxicity testing and biotech industries are highly expensive, and involve sacrifice of countless animals and it takes several years to bring a single drug/product to the market or to find the toxicity or otherwise of chemical entities. Our group has been actively working on several alternative models by merging biomaterials science, nanotechnology and biological principles to generate 3D in vitro living organs, to be called "Human Organs-on-Chip", to mimic natural organ/tissues, in order to reduce animal testing and clinical trials. We have fabricated a novel type of mechanically and biologically bio-mimicking collagen-based hydrogel that would provide for interconnected mini-wells in which 3D cell/organ culture of human samples in a manner similar to human organs with extracellular matrix (ECM) molecules would be possible. These products mimic the physical, chemical, and biological properties of natural organs and tissues at different scales. This paper will review the outcome of our several experiments so far in this direction and the future perspectives.

  13. Discovery of a proteolytic flagellin family in diverse bacterial phyla that assembles enzymatically active flagella

    OpenAIRE

    Eckhard, Ulrich; Bandukwala, Hina; Mansfield, Michael J.; Marino, Giada; Cheng, Jiujun; Wallace, Iain; Holyoak, Todd; Charles, Trevor C.; Austin, John; Overall, Christopher M.; Doxey, Andrew C.

    2017-01-01

    Bacterial flagella are cell locomotion and occasional adhesion organelles composed primarily of the polymeric protein flagellin, but to date have not been associated with any enzymatic function. Here, we report the bioinformatics-driven discovery of a class of enzymatic flagellins that assemble to form proteolytically active flagella. Originating by a metallopeptidase insertion into the central flagellin hypervariable region, this flagellin family has expanded to at least 74 bacterial species...

  14. Discovery Monday - Behind the plug: communication networks

    CERN Multimedia

    2004-01-01

    Ever wondered what happens to your email when you click "send"? And when you make a phone call, how does your voice travel down the wire? Find out more about communication networks and their applications at the next Discovery Monday in Microcosm on 1 March. At CERN, networks are used for a multitude of reasons. Mobile phones, for example, are used in the laboratory's underground areas. Optical fibre cabling ensures that CERN's computers are connected to the rest of the world. But how do optical fibres work and what does the future have in store? CERN's experiments also need networks. Particle detectors are made of many layers, each relays complex information to a computer analysis centre which reconstitutes the passage of the particles resulting from collisions. Many billions of bytes are transmitted every second from a multitude of sources, to many computers.  No single computer can handle such a huge flow of information. The next Discovery Monday is your chance to find out how this works.  Participate i...

  15. X-Ray Astronomy Discovery Experiments, III*

    Science.gov (United States)

    Fisher, P. C.

    2011-04-01

    The first paper established the existence of concurrent discovery experiments by Riccardo Giacconi and myself at the start of x-ray astronomy.footnotetextR. Giacconi et al., Phys. Rev. Lett. 9, 439 (1962).^,footnotetextP. C. Fisher et al., Quasars and High Energy Astronomy including Proceedings of the 2^nd Texas Symposium on Relativistic Astrophysics 15 - 19 December 1964 (K. N. Douglas et. al., eds.) Gordon and Breach Science Publishers, New York, p. 253 (1969).^,footnotetextP. C. Fisher, BAPS 53 No. 2, 165 (2008). Paper II footnotetextP.C. Fisher, http://www.aps.org/units/fhp/index.cfm plus FHP link to April 2009 presentation H14.00006. described some acts by some individuals/institutions over four decades that may have caused the illusion that I had not made a discovery. Some additional data about this illusion, and the first possible measurement of x-ray emission from a black hole, will be presented. This paper's primary goal is for the American Physical Society to have Giacconi comment on several questions of a historical nature. [4pt] *Work supported by NASA contracts NAS5-1174 and NASw-909, the Lockheed Independent Research Program, and Ruffner Associates.

  16. Discovery Mondays - The detectors: tracking particles

    CERN Document Server

    2005-01-01

    View of a module from the LHCb vertex detector, which will be presented at the next Discovery Monday. How do you observe the invisible? In order to deepen still further our knowledge of the infinitely small, physicists accelerate beams of particles at close to the speed of light, then generate collisions between them at extraordinary energies, giving birth to showers of new particles. What are these particles? In order to find out, physicists transform themselves into detectives with the help of the detectors. Located around the collision area, these exceptional machines are made up of various layers, each of which detects and measures specific properties of the particles that travel through them. Powerful computers then reconstruct their trajectory and record their charge, mass and energy in order to build up a kind of particle ID card. At the next Discovery Monday you will be able to find out about the different methods used at CERN to detect particles. A cloud chamber will provide live images of the trac...

  17. Discovery Mondays - The detectors: tracking particles

    CERN Document Server

    2005-01-01

    View of a module from the LHCb vertex detector, which will be presented at the next Discovery Monday. How do you observe the invisible? In order to deepen still further our knowledge of the infinitely small, physicists accelerate beams of particles and generate collisions between them at extraordinary energies. The collisions give birth to showers of new particles. What are they? In order to find out, physicists slip into the role of detectives thanks to the detectors. At the next Discovery Monday you will find out about the different methods used at CERN to detect particles. A cloud chamber will allow you to see the tracks of cosmic particles live. You will also be given the chance to see real modules for the ATLAS and for the LHCb experiments. Strange materials will be on hand, such as crystals that are heavier than iron and yet as transparent as glass... Come to the Microcosm and become a top detective yourself! This event will take place in French. Join us at the Microcosm (Reception Building 33, M...

  18. FastMotif: spectral sequence motif discovery.

    Science.gov (United States)

    Colombo, Nicoló; Vlassis, Nikos

    2015-08-15

    Sequence discovery tools play a central role in several fields of computational biology. In the framework of Transcription Factor binding studies, most of the existing motif finding algorithms are computationally demanding, and they may not be able to support the increasingly large datasets produced by modern high-throughput sequencing technologies. We present FastMotif, a new motif discovery algorithm that is built on a recent machine learning technique referred to as Method of Moments. Based on spectral decompositions, our method is robust to model misspecifications and is not prone to locally optimal solutions. We obtain an algorithm that is extremely fast and designed for the analysis of big sequencing data. On HT-Selex data, FastMotif extracts motif profiles that match those computed by various state-of-the-art algorithms, but one order of magnitude faster. We provide a theoretical and numerical analysis of the algorithm's robustness and discuss its sensitivity with respect to the free parameters. The Matlab code of FastMotif is available from http://lcsb-portal.uni.lu/bioinformatics. vlassis@adobe.com Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  19. First discovery of Holocene cryptotephra in Amazonia.

    Science.gov (United States)

    Watson, Elizabeth J; Swindles, Graeme T; Savov, Ivan P; Bacon, Karen L

    2015-10-23

    The use of volcanic ash layers for dating and correlation (tephrochronology) is widely applied in the study of past environmental changes. We describe the first cryptotephra (non-visible volcanic ash horizon) to be identified in the Amazon basin, which is tentatively attributed to a source in the Ecuadorian Eastern Cordillera (0-1°S, 78-79°W), some 500-600 km away from our field site in the Peruvian Amazon. Our discovery 1) indicates that the Amazon basin has been subject to volcanic ash fallout during the recent past; 2) highlights the opportunities for using cryptotephras to date palaeoenvironmental records in the Amazon basin and 3) indicates that cryptotephra layers are preserved in a dynamic Amazonian peatland, suggesting that similar layers are likely to be present in other peat sequences that are important for palaeoenvironmental reconstruction. The discovery of cryptotephra in an Amazonian peatland provides a baseline for further investigation of Amazonian tephrochronology and the potential impacts of volcanism on vegetation.

  20. Centenary of the discovery of superconductivity

    CERN Multimedia

    Anaïs Vernède

    2011-01-01

    To mark the centenary of the discovery of the phenomenon of superconductivity, MANEP and the University of Geneva are organising open days at the PhysiScope between 8 and 15 April 2011. On 13 April CERN will make a contribution to the series of events with a lecture on superconductivity followed by a demonstration of the phenomenon at the Globe   Historic graph showing the superconducting transition of mercury, measured in Leiden in 1911 by H. Kamerlingh Onnes. On 8 April 2011 it will be a hundred years since the discovery of superconductivity by the Dutch physicist Kamerlingh Onnes. To mark the occasion, the University of Geneva and MANEP are organising a week-long interactive workshop at the PhysiScope. “The purpose of this initiative is to introduce the general public to this spectacular phenomenon by giving them an opportunity to take part in entertaining experiments”, explains Adriana Aleman, Head of Communications of the University of Geneva. As its contribution to the e...

  1. Business Model Discovery by Technology Entrepreneurs

    Directory of Open Access Journals (Sweden)

    Steven Muegge

    2012-04-01

    Full Text Available Value creation and value capture are central to technology entrepreneurship. The ways in which a particular firm creates and captures value are the foundation of that firm's business model, which is an explanation of how the business delivers value to a set of customers at attractive profits. Despite the deep conceptual link between business models and technology entrepreneurship, little is known about the processes by which technology entrepreneurs produce successful business models. This article makes three contributions to partially address this knowledge gap. First, it argues that business model discovery by technology entrepreneurs can be, and often should be, disciplined by both intention and structure. Second, it provides a tool for disciplined business model discovery that includes an actionable process and a worksheet for describing a business model in a form that is both concise and explicit. Third, it shares preliminary results and lessons learned from six technology entrepreneurs applying a disciplined process to strengthen or reinvent the business models of their own nascent technology businesses.

  2. New genetic discoveries and primary immune deficiencies.

    Science.gov (United States)

    Hernandez-Trujillo, Vivian

    2014-04-01

    The field of immunology has undergone recent discoveries of genetic causes for many primary immunodeficiency diseases (PIDD). The ever-expanding knowledge has led to increased understanding behind the pathophysiology of these diseases. Since these diseases are rare, the patients are frequently misdiagnosed early in the presentation of their illnesses. The identification of new genes has increased our opportunities for recognizing and making the diagnosis in patients with PIDD before they succumb to infections that may result secondary to their PIDD. Some mutations lead to a variety of presentations of severe combined immunodeficiency (SCID). The myriad and ever-growing genetic mutations which lead to SCID phenotypes have been identified in recent years. Other mutations associated with some genetic syndromes have associated immunodeficiency and are important for making the diagnosis of primary immunodeficiency in patients with some syndromes, who may otherwise be missed within the larger context of their syndromes. A variety of mutations also lead to increased susceptibility to infections due to particular organisms. These patterns of infections due to specific organisms are important keys in properly identifying the part of the immune system which is affected in these patients. This review will discuss recent genetic discoveries that enhance our understanding of these complex diseases.

  3. Scientists Like Me: Faces of Discovery

    Science.gov (United States)

    Enevoldsen, A. A. G.; Culp, S.; Trinh, A.

    2010-08-01

    During the International Year of Astronomy, Pacific Science Center is hosting a photography exhibit: Scientists Like Me: Faces of Discovery. The exhibit contains photographs of real, current astronomers and scientists working in astronomy and aerospace-related fields from many races, genders, cultural affiliations and walks of life. The photographs were taken and posters designed by Alyssa Trinh and Sarah Culp, high school interns in Discovery Corps, Pacific Science Center's youth development program. The direct contact between the scientists and the interns helps the intended audience of teachers and families personally connect with scientists. The finished posters from this exhibit are available online (http://pacificsciencecenter.org/scientists) for teachers to use in their classrooms, in addition to being displayed at Pacific Science Center and becoming part of Pacific Science Center's permanent art rotation. The objective of this project was to fill a need for representative photographs of scientists in the world community. It also met two of the goals of International Year of Astronomy: to provide a modern image of science and scientists, and to improve the gender-balanced representation of scientists at all levels and promote greater involvement by all people in scientific and engineering careers. We would like to build on the success of this project and create an annual summer internship, with different interns, focusing on creating posters for different fields of science.

  4. Feedback-Driven Dynamic Invariant Discovery

    Science.gov (United States)

    Zhang, Lingming; Yang, Guowei; Rungta, Neha S.; Person, Suzette; Khurshid, Sarfraz

    2014-01-01

    Program invariants can help software developers identify program properties that must be preserved as the software evolves, however, formulating correct invariants can be challenging. In this work, we introduce iDiscovery, a technique which leverages symbolic execution to improve the quality of dynamically discovered invariants computed by Daikon. Candidate invariants generated by Daikon are synthesized into assertions and instrumented onto the program. The instrumented code is executed symbolically to generate new test cases that are fed back to Daikon to help further re ne the set of candidate invariants. This feedback loop is executed until a x-point is reached. To mitigate the cost of symbolic execution, we present optimizations to prune the symbolic state space and to reduce the complexity of the generated path conditions. We also leverage recent advances in constraint solution reuse techniques to avoid computing results for the same constraints across iterations. Experimental results show that iDiscovery converges to a set of higher quality invariants compared to the initial set of candidate invariants in a small number of iterations.

  5. Discovery potential for supersymmetry in CMS

    CERN Document Server

    Abdullin, Salavat; Charles, François; Denegri, Daniel; Dydak, U; Dzelalija, Mile; Genchev, Vladimir; Graham, Douglas Jonathon; Iashvili, Ia; Kharchilava, Avto; Kinnunen, Ritva; Kunori, Shuichi; Mazumdar, Kajari; Racca, Chantal; Rurua, Lali; Stepanov, Nikita; Womersley, J

    2002-01-01

    This work summarizes and puts in an overall perspective studies done within CMS concerning the discovery potential for squarks and gluinos, sleptons, charginos and neutralinos, SUSY dark matter, lightest Higgs, sparticle mass determination methods and the detector design optimisation in view of SUSY searches. It represents the status of our understanding of these subjects as of Summer 1997. As a benchmark model we used the minimal supergravity-inspired super- symmetric standard model (mSUGRA) with a stable LSP. Discovery of SUSY at the LHC should be relatively straightforward. It may occur through the observation of a large excesses of events in missing E_T + jets, or with one or more isolated leptons. An excess of trilepton events or of isolated dileptons with E_T^miss, exhibiting a characteristic signature in the l^+l^- invariant mass distribution could also be the first manifestation of SUSY production. Squark and gluino production may represent a copious source of Higgs bosons through cascade decays. The ...

  6. Discovery Mondays: crystals and particles for medicine

    CERN Document Server

    2003-01-01

    Question: what are as heavy as lead, as clear as glass, and appear as tiny specks in a doctor's scanner but large as life in a physicist's detector? Answer: the crystals you will be able to observe in all their facets on 1 September at the start of a new season of Discovery Mondays at Microcosm. Come along and meet the CERN physicists who use crystals not only in their detectors but also in the latest generation of scanners. Four workshops will be organised, each devoted to a different medical imaging technique. The first workshop will be run by a physicist from the Crystal Clear collaboration, who will present her collaboration's special breed of crystals, which emit light when they are traversed by high-energy particles, and explain to you these crystals' role in Positron Emission Tomographs. The second workshop will focus on an imaging technique known as the Compton Camera, also based on scintillating crystals. Crystals worth looking at and admiring. Come to the next Discovery Monday to find out how they ...

  7. Optical design of the Discovery Channel Telescope

    Science.gov (United States)

    MacFarlane, Malcolm J.; Dunham, Edward W.

    2004-10-01

    The Discovery Channel Telescope (DCT) is a joint venture between Discovery Communications and Lowell Observatory. The telescope will have a 4.2-meter clear aperture, active primary mirror working at F/1.9. Two observing stations are presently planned; a Ritchey-Chretien focus some two meters behind the vertex of the primary mirror and a prime focus featuring a wide-field optical corrector (WFOC) with a two-degree field of view. The Ritchey-Chretien focus will be used for a variety of optical and near infrared imaging and spectroscopic instrumentation while the prime focus will be largely used as a survey tool to search for near-earth and Kuiper belt objects, for example. In order to take advantage of sub-arc second seeing at the DCT site, a stringent set of requirements has been placed on the two foci. The requirements are for the full-width, half-maximum (FWHM) image of a point source to be less than 0.20 arc second at the Ritchey-Chretien focus over a 21 arc minute field and less than 0.27 arc second at prime focus in each of six filter bands including a very broad band for survey purposes. This paper describes the optical design of the field correctors at the two foci. Particular attention is paid to the WFOC. This state of the art device poses a number of optical challenges which are discussed here, as well as mechanical challenges which are discussed elsewhere.

  8. Epigenetics and cancer: implications for drug discovery and safety assessment

    International Nuclear Information System (INIS)

    Moggs, Jonathan G.; Goodman, Jay I.; Trosko, James E.; Roberts, Ruth A.

    2004-01-01

    It is necessary to determine whether chemicals or drugs have the potential to pose a threat to human health. Research conducted over the last two decades has led to the paradigm that chemicals can cause cancer either by damaging DNA or by altering cellular growth, probably via receptor-mediated changes in gene expression. However, recent evidence suggests that gene expression can be altered markedly via several diverse epigenetic mechanisms that can lead to permanent or reversible changes in cellular behavior. Key molecular events underlying these mechanisms include the alteration of DNA methylation and chromatin, and changes in the function of cell surface molecules. Thus, for example, DNA methyltransferase enzymes together with chromatin-associated proteins such as histone modifying enzymes and remodelling factors can modify the genetic code and contribute to the establishment and maintenance of altered epigenetic states. This is relevant to many types of toxicity including but not limited to cancer. In this paper, we describe the potential for interplay between genetic alteration and epigenetic changes in cell growth regulation and discuss the implications for drug discovery and safety assessment

  9. Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors.

    Science.gov (United States)

    McIver, Andrew L; Zhang, Weihe; Liu, Qingyang; Jiang, Xinpeng; Stashko, Michael A; Nichols, James; Miley, Michael J; Norris-Drouin, Jacqueline; Machius, Mischa; DeRyckere, Deborah; Wood, Edgar; Graham, Douglas K; Earp, H Shelton; Kireev, Dmitri; Frye, Stephen V; Wang, Xiaodong

    2017-02-03

    Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK. Through structure-activity relationship (SAR) studies, analogue 11 [UNC2541; (S)-7-amino-N-(4-fluorobenzyl)-8-oxo-2,9,16-triaza-1(2,4)-pyrimidinacyclohexadecaphane-1-carboxamide] was identified as a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Inositol Polyphosphate Kinases, Fungal Virulence and Drug Discovery.

    Science.gov (United States)

    Li, Cecilia; Lev, Sophie; Saiardi, Adolfo; Desmarini, Desmarini; Sorrell, Tania C; Djordjevic, Julianne T

    2016-09-06

    Opportunistic fungi are a major cause of morbidity and mortality world-wide, particularly in immunocompromised individuals. Developing new treatments to combat invasive fungal disease is challenging given that fungal and mammalian host cells are eukaryotic, with similar organization and physiology. Even therapies targeting unique fungal cell features have limitations and drug resistance is emerging. New approaches to the development of antifungal drugs are therefore needed urgently. Cryptococcus neoformans , the commonest cause of fungal meningitis worldwide, is an accepted model for studying fungal pathogenicity and driving drug discovery. We recently characterized a phospholipase C (Plc1)-dependent pathway in C. neoformans comprising of sequentially-acting inositol polyphosphate kinases (IPK), which are involved in synthesizing inositol polyphosphates (IP). We also showed that the pathway is essential for fungal cellular function and pathogenicity. The IP products of the pathway are structurally diverse, each consisting of an inositol ring, with phosphate (P) and pyrophosphate (PP) groups covalently attached at different positions. This review focuses on (1) the characterization of the Plc1/IPK pathway in C. neoformans ; (2) the identification of PP-IP₅ (IP₇) as the most crucial IP species for fungal fitness and virulence in a mouse model of fungal infection; and (3) why IPK enzymes represent suitable candidates for drug development.

  11. Inositol Polyphosphate Kinases, Fungal Virulence and Drug Discovery

    Directory of Open Access Journals (Sweden)

    Cecilia Li

    2016-09-01

    Full Text Available Opportunistic fungi are a major cause of morbidity and mortality world-wide, particularly in immunocompromised individuals. Developing new treatments to combat invasive fungal disease is challenging given that fungal and mammalian host cells are eukaryotic, with similar organization and physiology. Even therapies targeting unique fungal cell features have limitations and drug resistance is emerging. New approaches to the development of antifungal drugs are therefore needed urgently. Cryptococcus neoformans, the commonest cause of fungal meningitis worldwide, is an accepted model for studying fungal pathogenicity and driving drug discovery. We recently characterized a phospholipase C (Plc1-dependent pathway in C. neoformans comprising of sequentially-acting inositol polyphosphate kinases (IPK, which are involved in synthesizing inositol polyphosphates (IP. We also showed that the pathway is essential for fungal cellular function and pathogenicity. The IP products of the pathway are structurally diverse, each consisting of an inositol ring, with phosphate (P and pyrophosphate (PP groups covalently attached at different positions. This review focuses on (1 the characterization of the Plc1/IPK pathway in C. neoformans; (2 the identification of PP-IP5 (IP7 as the most crucial IP species for fungal fitness and virulence in a mouse model of fungal infection; and (3 why IPK enzymes represent suitable candidates for drug development.

  12. Discovery of Empirical Components by Information Theory

    Science.gov (United States)

    2016-08-10

    multi-level cells with 2 (SLC), 4 (MLC) or 8 ( TLC ) levels per cell. MLCs are usually preferred because they are more mature than TLCs and provide...longer retain information. The number of Program/Erase (P/E) cycles that a cell can tolerate depends on the type of the cell used (SLC, MLC or TLC ...HPCA 2013), pp. 222-233, Shenzhen, China , February 2013 2. M. Wang, W. Xu and R. Calderbank, Compressed sensing with corrupted participants

  13. The Proteomics Big Challenge for Biomarkers and New Drug-Targets Discovery

    Science.gov (United States)

    Savino, Rocco; Paduano, Sergio; Preianò, Mariaimmacolata; Terracciano, Rosa

    2012-01-01

    In the modern process of drug discovery, clinical, functional and chemical proteomics can converge and integrate synergies. Functional proteomics explores and elucidates the components of pathways and their interactions which, when deregulated, lead to a disease condition. This knowledge allows the design of strategies to target multiple pathways with combinations of pathway-specific drugs, which might increase chances of success and reduce the occurrence of drug resistance. Chemical proteomics, by analyzing the drug interactome, strongly contributes to accelerate the process of new druggable targets discovery. In the research area of clinical proteomics, proteome and peptidome mass spectrometry-profiling of human bodily fluid (plasma, serum, urine and so on), as well as of tissue and of cells, represents a promising tool for novel biomarker and eventually new druggable targets discovery. In the present review we provide a survey of current strategies of functional, chemical and clinical proteomics. Major issues will be presented for proteomic technologies used for the discovery of biomarkers for early disease diagnosis and identification of new drug targets. PMID:23203042

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

    Science.gov (United States)

    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.

  15. Providing data science support for systems pharmacology and its implications to drug discovery.

    Science.gov (United States)

    Hart, Thomas; Xie, Lei

    2016-01-01

    The conventional one-drug-one-target-one-disease drug discovery process has been less successful in tracking multi-genic, multi-faceted complex diseases. Systems pharmacology has emerged as a new discipline to tackle the current challenges in drug discovery. The goal of systems pharmacology is to transform huge, heterogeneous, and dynamic biological and clinical data into interpretable and actionable mechanistic models for decision making in drug discovery and patient treatment. Thus, big data technology and data science will play an essential role in systems pharmacology. This paper critically reviews the impact of three fundamental concepts of data science on systems pharmacology: similarity inference, overfitting avoidance, and disentangling causality from correlation. The authors then discuss recent advances and future directions in applying the three concepts of data science to drug discovery, with a focus on proteome-wide context-specific quantitative drug target deconvolution and personalized adverse drug reaction prediction. Data science will facilitate reducing the complexity of systems pharmacology modeling, detecting hidden correlations between complex data sets, and distinguishing causation from correlation. The power of data science can only be fully realized when integrated with mechanism-based multi-scale modeling that explicitly takes into account the hierarchical organization of biological systems from nucleic acid to proteins, to molecular interaction networks, to cells, to tissues, to patients, and to populations.

  16. Space Shuttle Discovery waits in VAB for rollout

    Science.gov (United States)

    2001-01-01

    KENNEDY SPACE CENTER, Fla. -- Viewed from below, Space Shuttle Discovery nearly hides the orange external tank behind it. The twin solid rocket boosters can be seen on either side. Discovery waits in the Vehicle Assembly Building for rollout to Launch Pad 39A. Inclement weather has been a prime factor delaying the rollout. Discovery is scheduled for launch no earlier than Aug. 5 on mission STS-105, carrying the Expedition Three crew that will replace Expedition Two on the International Space Station.

  17. Chance, creativity, and the discovery of the nerve growth factor.

    Science.gov (United States)

    de Romo, Ana Cecilia Rodríguez

    2007-01-01

    This essay analyzes the history of the Nerve Growth Factor (NGF) discovery, relating some of the principles of the theory of scientific creativity to the cognitive and personal qualities of the scientists that participated in the discovery, particularly Rita Levi-Montalcini and Viktor Hamburger. The discovery of NGF is especially attractive for the history of science as it involves chance, luck, creativity, and some extraordinary scientists.

  18. Understanding Self-healing in Service-Discovery Systems

    Science.gov (United States)

    2002-11-01

    service manager (SM) and service user (SU). Figure 1 shows a two-party architecture deployed in a six-component topology: one SM and five SUs. A...sufficient number of SCMs. Upon cessation of aggressive discovery, a component Service Manager Service User Service Cache Manager Aggressive-Discovery... Manager UPnP Multicast Group Unicast Links Figure 2. Three-party service-discovery architecture with five service users (SUs), a service manager (SM), a

  19. How Will We React to the Discovery of Extraterrestrial Life?

    OpenAIRE

    Kwon, Jung Yul; Bercovici, Hannah L.; Cunningham, Katja; Varnum, Michael E. W.

    2018-01-01

    How will humanity react to the discovery of extraterrestrial life? Speculation on this topic abounds, but empirical research is practically non-existent. We report the results of three empirical studies assessing psychological reactions to the discovery of extraterrestrial life using the Linguistic Inquiry and Word Count (LIWC) text analysis software. We examined language use in media coverage of past discovery announcements of this nature, with a focus on extraterrestrial microbial life (Pil...

  20. Conceptual Design For Interplanetary Spaceship Discovery

    Science.gov (United States)

    Benton, Mark G.

    2006-01-01

    With the recently revived national interest in Lunar and Mars missions, this design study was undertaken by the author in an attempt to satisfy the long-term space exploration vision of human travel ``to the Moon, Mars, and beyond'' with a single design or family of vehicles. This paper describes a conceptual design for an interplanetary spaceship of the not-to-distant future. It is a design that is outwardly similar to the spaceship Discovery depicted in the novel ``2001 - A Space Odyssey'' and film of the same name. Like its namesake, this spaceship could one day transport a human expedition to explore the moons of Jupiter. This spaceship Discovery is a real engineering design that is capable of being implemented using technologies that are currently at or near the state-of-the-art. The ship's main propulsion and electrical power are provided by bi-modal nuclear thermal rocket engines. Configurations are presented to satisfy four basic Design Reference Missions: (1) a high-energy mission to Jupiter's moon Callisto, (2) a high-energy mission to Mars, (3) a low-energy mission to Mars, and (4) a high-energy mission to the Moon. The spaceship design includes dual, strap-on boosters to enable the high-energy Mars and Jupiter missions. Three conceptual lander designs are presented: (1) Two types of Mars landers that utilize atmospheric and propulsive braking, and (2) a lander for Callisto or Earth's Moon that utilizes only propulsive braking. Spaceship Discovery offers many advantages for human exploration of the Solar System: (1) Nuclear propulsion enables propulsive capture and escape maneuvers at Earth and target planets, eliminating risky aero-capture maneuvers. (2) Strap-on boosters provide robust propulsive energy, enabling flexibility in mission planning, shorter transit times, expanded launch windows, and free-return abort trajectories from Mars. (3) A backup abort propulsion system enables crew aborts at multiple points in the mission. (4) Clustered NTR

  1. Comparison of Alternative Mesenchymal Stem Cell Sources for Cell Banking and Musculoskeletal Advanced Therapies

    NARCIS (Netherlands)

    Cavallo, Carola; Cuomo, Carmela; Fantini, Sara; Ricci, Francesca; Tazzari, Pier Luigi; Lucarelli, Enrico; Donati, Davide; Facchini, Andrea; Lisignoli, Gina; Fornasari, Pier Maria; Grigolo, Brunella; Moroni, Lorenzo

    2011-01-01

    With the continuous discovery of new alternative sources containing mesenchymal stem cells (MSCs), regenerative medicine therapies may find tailored applications in the clinics. Although these cells have been demonstrated to express specific mesenchymal markers and are able to differentiate into

  2. Rita Levi-Montalcini: the discovery of nerve growth factor and modern neurobiology.

    Science.gov (United States)

    Aloe, Luigi

    2004-07-01

    The remarkable accomplishments in developmental neurobiology within the past 60 years have depended on two things: (i) a succession of original histochemical and immunohistochemical methodologies for identifying pathways in the nervous system with increasing precision and sensitivity, and (ii) the discovery of growth factors for neurons. Growth factors are naturally occurring, essential biological mediators that promote cell growth, differentiation, survival and function in specific nerve cell populations. The discovery of nerve growth factor (NGF) by Rita Levi-Montalcini in the 1950s represents an important milestone in the processes that led to modern cell biology. NGF was the first growth factor identified, for its action on the morphological differentiation of neural-crest-derived nerve cells. Later, its effect on neuronal cells of the peripheral and central nervous systems, and on several non-neuronal cells was also determined. Thus, Levi-Montalcini's work on NGF represents, as acknowledged by the Nobel Prize Assembly in its press release of 13 October 1986, "a fascinating example of how a skilled observer can create a concept out of apparent chaos".

  3. News Shocks in Open Economies: Evidence from Giant Oil Discoveries

    OpenAIRE

    Rabah Arezki; Valerie A. Ramey; Liugang Sheng

    2015-01-01

    This paper explores the effect of news shocks on the current account and other macroeconomic variables using worldwide giant oil discoveries as a directly observable measure of news shocks about future output - the delay between a discovery and production is on average 4 to 6 years. We first present a two-sector small open economy model in order to predict the responses of macroeconomic aggregates to news of an oil discovery. We then estimate the effects of giant oil discoveries on a large pa...

  4. Sentiment Knowledge Discovery in Twitter Streaming Data

    Science.gov (United States)

    Bifet, Albert; Frank, Eibe

    Micro-blogs are a challenging new source of information for data mining techniques. Twitter is a micro-blogging service built to discover what is happening at any moment in time, anywhere in the world. Twitter messages are short, and generated constantly, and well suited for knowledge discovery using data stream mining. We briefly discuss the challenges that Twitter data streams pose, focusing on classification problems, and then consider these streams for opinion mining and sentiment analysis. To deal with streaming unbalanced classes, we propose a sliding window Kappa statistic for evaluation in time-changing data streams. Using this statistic we perform a study on Twitter data using learning algorithms for data streams.

  5. Gideon Mantell and the Discovery of Dinosaurs

    Science.gov (United States)

    Dean, Dennis R.

    1999-01-01

    Gideon Mantell and the Discovery of Dinosaurs is a scholarly yet accessible biography--the first in a generation--of a pioneering dinosaur hunter and scholar. Gideon Mantell discovered the Iguanodon (a famous tale set right in this book) and several other dinosaur species, spent over twenty-five years restoring Iguanodon fossils, and helped establish the idea of an Age of Reptiles that ended with their extinction at the conclusion of the Mesozoic Era. He had significant interaction with such well-known figures as James Parkinson, Georges Cuvier, Charles Lyell, Roderick Murchison, Charles Darwin, and Richard Owen. Dennis Dean, a well-known scholar of geology and the Victorian era, here places Mantell's career in its cultural context, employing original research in archives throughout the world, including the previously unexamined Mantell family papers in New Zealand.

  6. Computational functional group mapping for drug discovery.

    Science.gov (United States)

    Guvench, Olgun

    2016-12-01

    Computational functional group mapping (cFGM) is emerging as a high-impact complement to existing widely used experimental and computational structure-based drug discovery methods. cFGM provides comprehensive atomic-resolution 3D maps of the affinity of functional groups that can constitute drug-like molecules for a given target, typically a protein. These 3D maps can be intuitively and interactively visualized by medicinal chemists to rapidly design synthetically accessible ligands. Given that the maps can inform selection of functional groups for affinity, specificity, and pharmacokinetic properties, they are of utility for both the optimization of existing drug candidates and creating novel ones. Here, I review recent advances in cFGM with emphasis on the unique information content in the approach that offers the potential of broadly facilitating structure-based ligand design. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Translational paradigms in pharmacology and drug discovery.

    Science.gov (United States)

    Mullane, Kevin; Winquist, Raymond J; Williams, Michael

    2014-01-01

    The translational sciences represent the core element in enabling and utilizing the output from the biomedical sciences and to improving drug discovery metrics by reducing the attrition rate as compounds move from preclinical research to clinical proof of concept. Key to understanding the basis of disease causality and to developing therapeutics is an ability to accurately diagnose the disease and to identify and develop safe and effective therapeutics for its treatment. The former requires validated biomarkers and the latter, qualified targets. Progress has been hampered by semantic issues, specifically those that define the end product, and by scientific issues that include data reliability, an overt reductionistic cultural focus and a lack of hierarchically integrated data gathering and systematic analysis. A necessary framework for these activities is represented by the discipline of pharmacology, efforts and training in which require recognition and revitalization. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Biomarker Gene Signature Discovery Integrating Network Knowledge

    Directory of Open Access Journals (Sweden)

    Holger Fröhlich

    2012-02-01

    Full Text Available Discovery of prognostic and diagnostic biomarker gene signatures for diseases, such as cancer, is seen as a major step towards a better personalized medicine. During the last decade various methods, mainly coming from the machine learning or statistical domain, have been proposed for that purpose. However, one important obstacle for making gene signatures a standard tool in clinical diagnosis is the typical low reproducibility of these signatures combined with the difficulty to achieve a clear biological interpretation. For that purpose in the last years there has been a growing interest in approaches that try to integrate information from molecular interaction networks. Here we review the current state of research in this field by giving an overview about so-far proposed approaches.

  9. Discovery of columnar jointing on Mars

    Science.gov (United States)

    Milazzo, M.P.; Keszthelyi, L.P.; Jaeger, W.L.; Rosiek, M.; Mattson, S.; Verba, C.; Beyer, R.A.; Geissler, P.E.; McEwen, A.S.

    2009-01-01

    We report on the discovery of columnar jointing in Marte Valles, Mars. These columnar lavas were discovered in the wall of a pristine, 16-km-diameter impact crater and exhibit the features of terrestrial columnar basalts. There are discontinuous outcrops along the entire crater wall, suggesting that the columnar rocks covered a surface area of at least 200 km2, assuming that the rocks obliterated by the impact event were similarly jointed. We also see columns in the walls of other fresh craters in the nearby volcanic plains of Elysium Planitia-Amazonis Planitia, which include Marte Vallis, and in a well-preserved crater in northeast Hellas. ?? 2009 The Geological Society of America.

  10. Discovery Monday: How to measure success

    CERN Multimedia

    2003-01-01

    The last Discovery Monday which was carried out by the surveyors at CERN was a great success, one which they could not measure with their usual precision. The various entertaining as well as instructive experiments deserve a big "Thank you" to the SU group at the EST division. Children learn how to measure with the water level, like in Roman times.At CERN, photogrammetric techniques are used to precisely measure positions of complex ensembles like detectors. In Microcosm, photogrammetry is also invaluable to take the measure of visitors who can no longer cheat about their size. They were measured to a precision of one tenth of a millimetre and received a certificate.The alignment of accelerators is one of the big challenges for the surveyors at CERN. But even with good instruments, you need to have good eyes!

  11. Atmospheric neutrinos and discovery of neutrino oscillations.

    Science.gov (United States)

    Kajita, Takaaki

    2010-01-01

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

  12. The Most Important Discovery of Science.

    Science.gov (United States)

    Severinghaus, John W

    2016-01-01

    Oxygen has often been called the most important discovery of science. I disagree. Over five centuries, reports by six scientists told of something in air we animals all need. Three reported how to generate it. It acquired many names, finally oxygen. After 8 years of studying it, Lavoisier still couldn't understand its nature. No special date and no scientist should get credit for discovering oxygen. Henry Cavendish discovered how to make inflammable air (H2). When burned, it made water. This was called impossible because water was assumed to be an element. When Lavoisier repeated the Cavendish test on June 24, 1783, he realized it demolished two theories, phlogiston and water as an element, a Kuhnian paradigm shift that finally unlocked his great revolution of chemistry.

  13. Natural Products in the Discovery of Agrochemicals.

    Science.gov (United States)

    Loiseleur, Olivier

    2017-12-01

    Natural products have a long history of being used as, or serving as inspiration for, novel crop protection agents. Many of the discoveries in agrochemical research in the last decades have their origin in a wide range of natural products from a variety of sources. In light of the continuing need for new tools to address an ever-changing array of fungal, weed and insect pests, new agricultural practices and evolving regulatory requirements, the needs for new agrochemical tools remains as critical as ever. In that respect, nature continues to be an important source for novel chemical structures and biological mechanisms to be applied for the development of pest control agents. Here we review several of the natural products and their derivatives which contributed to shape crop protection research in past and present.

  14. Discovery Mondays - 'Eureka! Meet the inventors'

    CERN Document Server

    2006-01-01

    Fabio Sauli, the inventor of the GEM detector. Do you imagine an invention as a spontaneous brainchild emergi from the convoluted mind of some scatterbrained and dishevelled scientist? If so, you are mistaken! Join us at Microcosm for the next Discovery Monday at which inventors will be the guests of honour. There you will meet scientists who, thanks to their creativity, have made technological progress possible. By constantly rising to new scientific and technological challenges, CERN has delivered numerous innovations, particularly in the medical field. Members of the Crystal Clear collaboration and the inventor of the GEM detector will give talks about their innovations and their applications, in particular for medical purposes. You will also be able to speak to members of the Medipix collaboration, which is working on improvements to X-ray and gamma ray imaging techniques. The event will be conducted in French. Come to Microcosm, (Reception Building 33, Meyrin site), on Monday 6 February from 7.30 p...

  15. Financing drug discovery via dynamic leverage.

    Science.gov (United States)

    Montazerhodjat, Vahid; Frishkopf, John J; Lo, Andrew W

    2016-03-01

    We extend the megafund concept for funding drug discovery to enable dynamic leverage in which the portfolio of candidate therapeutic assets is predominantly financed initially by equity, and debt is introduced gradually as assets mature and begin generating cash flows. Leverage is adjusted so as to maintain an approximately constant level of default risk throughout the life of the fund. Numerical simulations show that applying dynamic leverage to a small portfolio of orphan drug candidates can boost the return on equity almost twofold compared with securitization with a static capital structure. Dynamic leverage can also add significant value to comparable all-equity-financed portfolios, enhancing the return on equity without jeopardizing debt performance or increasing risk to equity investors. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. Chemoselective enrichment for natural products discovery.

    Science.gov (United States)

    Odendaal, Antoinette Y; Trader, Darci J; Carlson, Erin E

    2011-04-01

    Natural products account for a significant proportion of modern day therapeutic agents. However, the discovery of novel compounds is hindered by the isolation process, which often relies upon extraction and chromatographic separation techniques. These methods, which are dependent upon the physicochemical properties of the compounds, have a limited ability to both purify and concentrate the minor components of a biological extract. We have devised an isolation strategy based upon an orthogonal chemical feature, namely, functional group composition. Development of a functional group-targeted method is expected to achieve exceptional resolution given the large number of distinct moieties present in natural product extracts. Here, we describe the generation of controllably reversible covalent enrichment tags for the chemoselective isolation of alcohol-containing natural products from complex mixtures.

  17. Single feature polymorphism discovery in rice.

    Directory of Open Access Journals (Sweden)

    Rajesh Kumar

    Full Text Available The discovery of nucleotide diversity captured as single feature polymorphism (SFP by using the expression array is a high-throughput and effective method in detecting genome-wide polymorphism. The efficacy of such method was tested in rice, and the results presented in the paper indicate high sensitivity in predicting SFP. The sensitivity of polymorphism detection was further demonstrated by the fact that no biasness was observed in detecting SFP with either single or multiple nucleotide polymorphisms. The high density SFP data that can be generated quite effectively by the current method has promise for high resolution genetic mapping studies, as physical location of features are well-defined on rice genome.

  18. Recent discoveries of Uruguayan Mesozoic vertebrates

    International Nuclear Information System (INIS)

    Soto, M.; Perea, D.; Rinderknetch, A.; Ubilla, M.; Da Silva, J.

    2007-01-01

    Recently, new discoveries of Uruguayan Mesozoic vertebrates have been made, as well as the reinterpretation of already known remains. Its taxonomical and biostratigraphical significance justifies this communication. Concerning the Tacuarembo Formation, on one hand a dipnoan prearticular tooth plate has been reinterpreted as belonging to Ceratodus africanus Haug 1905, a species typical of Late Jurassic-Late Cretaceous deposits of Saharan Africa. This is the second dipnoan taxon recorded in the Tacuarembo Formation, uncovering a previously unrecognized dipnoan diversity in the mid-Mesozoic of South America. On the other hand, a few theropod tooth were confidently identified at the familial level for the first time in our country. The remains include two striated premaxillary tooth crowns, the characters of which, close to Ceratosaurus Marsh 1884, allow to refer them to the family Ceratosauridae, this being the oldest South American record of the family. The striated teeth show strong affinities with those of Late Jurassic ceratosaurids from North America, Iberian Peninsula and Tanzania, which is in accordance with recent proposals about the age of the Lower Member of the Tacuarembo Formation. Concerning the Guichon Formation, we comunicate here in the most important discovery of dinosaur remains in Uruguay. It consist in spatially associated remains from several individuals, including fifty caudal vertebra and several epiphysis, metatarsals and astragali. These materials belong to a titanosaurid sauropod, the characters of which are similar to those of certain Campanian-Maastrichtian titanosaurids. Close to the bones, several eggshell fragments referable to Sphaerovum Mones 1980 - a typical Campanian-Maastrichtian oogenus- were found. This finding represents the first record of sauropod dinosaurs from the Guichon Formation, and suggests a younger age for this unit than early proposed

  19. The Process Chain for Peptidomic Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    Michael Schrader

    2006-01-01

    Full Text Available Over the last few years the interest in diagnostic markers for specific diseases has increased continuously. It is expected that they not only improve a patient's medical treatment but also contribute to accelerating the process of drug development. This demand for new biomarkers is caused by a lack of specific and sensitive diagnosis in many diseases. Moreover, diseases usually occur in different types or stages which may need different diagnostic and therapeutic measures. Their differentiation has to be considered in clinical studies as well. Therefore, it is important to translate a macroscopic pathological or physiological finding into a microscopic view of molecular processes and vice versa, though it is a difficult and tedious task. Peptides play a central role in many physiological processes and are of importance in several areas of drug research. Exploration of endogenous peptides in biologically relevant sources may directly lead to new drug substances, serve as key information on a new target and can as well result in relevant biomarker candidates. A comprehensive analysis of peptides and small proteins of a biological system corresponding to the respective genomic information (peptidomics®methods was a missing link in proteomics. A new peptidomic technology platform addressing peptides was recently presented, developed by adaptation of the striving proteomic technologies. Here, concepts of using peptidomics technologies for biomarker discovery are presented and illustrated with examples. It is discussed how the biological hypothesis and sample quality determine the result of the study. A detailed study design, appropriate choice and application of technology as well as thorough data interpretation can lead to significant results which have to be interpreted in the context of the underlying disease. The identified biomarker candidates will be characterised in validation studies before use. This approach for discovery of peptide

  20. Energy-Water Nexus Knowledge Discovery Framework

    Science.gov (United States)

    Bhaduri, B. L.; Foster, I.; Chandola, V.; Chen, B.; Sanyal, J.; Allen, M.; McManamay, R.

    2017-12-01

    As demand for energy grows, the energy sector is experiencing increasing competition for water. With increasing population and changing environmental, socioeconomic scenarios, new technology and investment decisions must be made for optimized and sustainable energy-water resource management. This requires novel scientific insights into the complex interdependencies of energy-water infrastructures across multiple space and time scales. An integrated data driven modeling, analysis, and visualization capability is needed to understand, design, and develop efficient local and regional practices for the energy-water infrastructure components that can be guided with strategic (federal) policy decisions to ensure national energy resilience. To meet this need of the energy-water nexus (EWN) community, an Energy-Water Knowledge Discovery Framework (EWN-KDF) is being proposed to accomplish two objectives: Development of a robust data management and geovisual analytics platform that provides access to disparate and distributed physiographic, critical infrastructure, and socioeconomic data, along with emergent ad-hoc sensor data to provide a powerful toolkit of analysis algorithms and compute resources to empower user-guided data analysis and inquiries; and Demonstration of knowledge generation with selected illustrative use cases for the implications of climate variability for coupled land-water-energy systems through the application of state-of-the art data integration, analysis, and synthesis. Oak Ridge National Laboratory (ORNL), in partnership with Argonne National Laboratory (ANL) and researchers affiliated with the Center for International Earth Science Information Partnership (CIESIN) at Columbia University and State University of New York-Buffalo (SUNY), propose to develop this Energy-Water Knowledge Discovery Framework to generate new, critical insights regarding the complex dynamics of the EWN and its interactions with climate variability and change. An overarching

  1. In silico discovery of transcription regulatory elements in Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Le Roch Karine G

    2008-02-01

    Full Text Available Abstract Background With the sequence of the Plasmodium falciparum genome and several global mRNA and protein life cycle expression profiling projects now completed, elucidating the underlying networks of transcriptional control important for the progression of the parasite life cycle is highly pertinent to the development of new anti-malarials. To date, relatively little is known regarding the specific mechanisms the parasite employs to regulate gene expression at the mRNA level, with studies of the P. falciparum genome sequence having revealed few cis-regulatory elements and associated transcription factors. Although it is possible the parasite may evoke mechanisms of transcriptional control drastically different from those used by other eukaryotic organisms, the extreme AT-rich nature of P. falciparum intergenic regions (~90% AT presents significant challenges to in silico cis-regulatory element discovery. Results We have developed an algorithm called Gene Enrichment Motif Searching (GEMS that uses a hypergeometric-based scoring function and a position-weight matrix optimization routine to identify with high-confidence regulatory elements in the nucleotide-biased and repeat sequence-rich P. falciparum genome. When applied to promoter regions of genes contained within 21 co-expression gene clusters generated from P. falciparum life cycle microarray data using the semi-supervised clustering algorithm Ontology-based Pattern Identification, GEMS identified 34 putative cis-regulatory elements associated with a variety of parasite processes including sexual development, cell invasion, antigenic variation and protein biosynthesis. Among these candidates were novel motifs, as well as many of the elements for which biological experimental evidence already exists in the Plasmodium literature. To provide evidence for the biological relevance of a cell invasion-related element predicted by GEMS, reporter gene and electrophoretic mobility shift assays

  2. Anti-regulatory T cells

    DEFF Research Database (Denmark)

    Andersen, Mads Hald

    2017-01-01

    Our initial understanding of immune-regulatory cells was based on the discovery of suppressor cells that assure peripheral T-cell tolerance and promote immune homeostasis. Research has particularly focused on the importance of regulatory T cells (Tregs) for immune modulation, e.g. directing host...... responses to tumours or inhibiting autoimmunity development. However, recent studies report the discovery of self-reactive pro-inflammatory T cells—termed anti-regulatory T cells (anti-Tregs)—that target immune-suppressive cells. Thus, regulatory cells can now be defined as both cells that suppress immune...... reactions as well as effector cells that counteract the effects of suppressor cells and support immune reactions. Self-reactive anti-Tregs have been described that specifically recognize human leukocyte antigen-restricted epitopes derived from proteins that are normally expressed by regulatory immune cells...

  3. Novel Technology for Protein-Protein Interaction-based Targeted Drug Discovery

    Directory of Open Access Journals (Sweden)

    Jung Me Hwang

    2011-12-01

    Full Text Available We have developed a simple but highly efficient in-cell protein-protein interaction (PPI discovery system based on the translocation properties of protein kinase C- and its C1a domain in live cells. This system allows the visual detection of trimeric and dimeric protein interactions including cytosolic, nuclear, and/or membrane proteins with their cognate ligands. In addition, this system can be used to identify pharmacological small compounds that inhibit specific PPIs. These properties make this PPI system an attractive tool for screening drug candidates and mapping the protein interactome.

  4. Understanding mechanisms of toxicity: Insights from drug discovery research

    International Nuclear Information System (INIS)

    Houck, Keith A.; Kavlock, Robert J.

    2008-01-01

    Toxicology continues to rely heavily on use of animal testing for prediction of potential for toxicity in humans. Where mechanisms of toxicity have been elucidated, for example endocrine disruption by xenoestrogens binding to the estrogen receptor, in vitro assays have been developed as surrogate assays for toxicity prediction. This mechanistic information can be combined with other data such as exposure levels to inform a risk assessment for the chemical. However, there remains a paucity of such mechanistic assays due at least in part to lack of methods to determine specific mechanisms of toxicity for many toxicants. A means to address this deficiency lies in utilization of a vast repertoire of tools developed by the drug discovery industry for interrogating the bioactivity of chemicals. This review describes the application of high-throughput screening assays as experimental tools for profiling chemicals for potential for toxicity and understanding underlying mechanisms. The accessibility of broad panels of assays covering an array of protein families permits evaluation of chemicals for their ability to directly modulate many potential targets of toxicity. In addition, advances in cell-based screening have yielded tools capable of reporting the effects of chemicals on numerous critical cell signaling pathways and cell health parameters. Novel, more complex cellular systems are being used to model mammalian tissues and the consequences of compound treatment. Finally, high-throughput technology is being applied to model organism screens to understand mechanisms of toxicity. However, a number of formidable challenges to these methods remain to be overcome before they are widely applicable. Integration of successful approaches will contribute towards building a systems approach to toxicology that will provide mechanistic understanding of the effects of chemicals on biological systems and aid in rationale risk assessments

  5. In silico drug combination discovery for personalized cancer therapy.

    Science.gov (United States)

    Jeon, Minji; Kim, Sunkyu; Park, Sungjoon; Lee, Heewon; Kang, Jaewoo

    2018-03-19

    Drug combination therapy, which is considered as an alternative to single drug therapy, can potentially reduce resistance and toxicity, and have synergistic efficacy. As drug combination therapies are widely used in the clinic for hypertension, asthma, and AIDS, they have also been proposed for the treatment of cancer. However, it is difficult to select and experimentally evaluate effective combinations because not only is the number of cancer drug combinations extremely large but also the effectiveness of drug combinations varies depending on the genetic variation of cancer patients. A computational approach that prioritizes the best drug combinations considering the genetic information of a cancer patient is necessary to reduce the search space. We propose an in-silico method for personalized drug combination therapy discovery. We predict the synergy between two drugs and a cell line using genomic information, targets of drugs, and pharmacological information. We calculate and predict the synergy scores of 583 drug combinations for 31 cancer cell lines. For feature dimension reduction, we select the mutations or expression levels of the genes in cancer-related pathways. We also used various machine learning models. Extremely Randomized Trees (ERT), a tree-based ensemble model, achieved the best performance in the synergy score prediction regression task. The correlation coefficient between the synergy scores predicted by ERT and the actual observations is 0.738. To compare with an existing drug combination synergy classification model, we reformulate the problem as a binary classification problem by thresholding the synergy scores. ERT achieved an F1 score of 0.954 when synergy scores of 20 and -20 were used as the threshold, which is 8.7% higher than that obtained by the state-of-the-art baseline model. Moreover, the model correctly predicts the most synergistic combination, from approximately 100 candidate drug combinations, as the top choice for 15 out of the

  6. LEGO-inspired drug design: Discovery of novel fungal Plasma membrane H+-ATPase (Pma1) inhibitors from small molecule libraries: An introduction of HFSA-SBS_DOS-RD strategy in drug discovery.

    OpenAIRE

    Tung, Truong Thanh; Dao, Trong Tuan; Palmgren, Michael B.; Fuglsang, Anja T.; Christensen, Soeren B.; Nielsen, John.

    2017-01-01

    Fungal plasma membrane H+-ATPase (Pma1) has recently emerged as a potential target for the discovery of new antifungal agents. This p-type pump which localized on the surface of fungal cells plays a crucial role in many physiol. functions and processes inside the cell. Esp., by pumping proton to extracellular, this enzyme generates a transmembrane electrochem. gradient, as a consequence, fungi can uptake nutrients by secondary transport systems. Until now, only low resoln. of protein structur...

  7. Mass Spectrometry-Based Proteomics in Molecular Diagnostics: Discovery of Cancer Biomarkers Using Tissue Culture

    Science.gov (United States)

    Paul, Debasish; Kumar, Avinash; Gajbhiye, Akshada; Santra, Manas K.; Srikanth, Rapole

    2013-01-01

    Accurate diagnosis and proper monitoring of cancer patients remain a key obstacle for successful cancer treatment and prevention. Therein comes the need for biomarker discovery, which is crucial to the current oncological and other clinical practices having the potential to impact the diagnosis and prognosis. In fact, most of the biomarkers have been discovered utilizing the proteomics-based approaches. Although high-throughput mass spectrometry-based proteomic approaches like SILAC, 2D-DIGE, and iTRAQ are filling up the pitfalls of the conventional techniques, still serum proteomics importunately poses hurdle in overcoming a wide range of protein concentrations, and also the availability of patient tissue samples is a limitation for the biomarker discovery. Thus, researchers have looked for alternatives, and profiling of candidate biomarkers through tissue culture of tumor cell lines comes up as a promising option. It is a rich source of tumor cell-derived proteins, thereby, representing a wide array of potential biomarkers. Interestingly, most of the clinical biomarkers in use today (CA 125, CA 15.3, CA 19.9, and PSA) were discovered through tissue culture-based system and tissue extracts. This paper tries to emphasize the tissue culture-based discovery of candidate biomarkers through various mass spectrometry-based proteomic approaches. PMID:23586059

  8. Mass Spectrometry-Based Proteomics in Molecular Diagnostics: Discovery of Cancer Biomarkers Using Tissue Culture

    Directory of Open Access Journals (Sweden)

    Debasish Paul

    2013-01-01

    Full Text Available Accurate diagnosis and proper monitoring of cancer patients remain a key obstacle for successful cancer treatment and prevention. Therein comes the need for biomarker discovery, which is crucial to the current oncological and other clinical practices having the potential to impact the diagnosis and prognosis. In fact, most of the biomarkers have been discovered utilizing the proteomics-based approaches. Although high-throughput mass spectrometry-based proteomic approaches like SILAC, 2D-DIGE, and iTRAQ are filling up the pitfalls of the conventional techniques, still serum proteomics importunately poses hurdle in overcoming a wide range of protein concentrations, and also the availability of patient tissue samples is a limitation for the biomarker discovery. Thus, researchers have looked for alternatives, and profiling of candidate biomarkers through tissue culture of tumor cell lines comes up as a promising option. It is a rich source of tumor cell-derived proteins, thereby, representing a wide array of potential biomarkers. Interestingly, most of the clinical biomarkers in use today (CA 125, CA 15.3, CA 19.9, and PSA were discovered through tissue culture-based system and tissue extracts. This paper tries to emphasize the tissue culture-based discovery of candidate biomarkers through various mass spectrometry-based proteomic approaches.

  9. Discovery of Aryl Aminoquinazoline Pyridones as Potent, Selective, and Orally Efficacious Inhibitors of Receptor Tyrosine Kinase c-Kit

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Essa; Tasker, Andrew; White, Ryan D.; Kunz, Roxanne K.; Human, Jason; Chen, Ning; Bürli, Roland; Hungate, Randall; Novak, Perry; Itano, Andrea; Zhang, Xuxia; Yu, Violeta; Nguyen, Yen; Tudor, Yanyan; Plant, Matthew; Flynn, Shaun; Xu, Yang; Meagher, Kristin L.; Whittington, Douglas A.; Ng, Gordon Y. (Amgen)

    2008-12-09

    Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.

  10. Patterns of species discovery in the Western Ghats, a megadiversity ...

    Indian Academy of Sciences (India)

    PRAKASH KUMAR

    Ghats (Flora of Coorg, Flora of Hassan District, Flora of. Udupi, Flora of Tamil Nadu, Flora of Maharashtra, to name a few). Analysis of species discovery curves including four plant and four animal groups indicated a mixed set of patterns. For the charismatic animal species—birds and butterflies—the discovery curve was ...

  11. Evaluation and Comparison of Discovery Tools: An Update

    Directory of Open Access Journals (Sweden)

    F. William Chickering

    2014-06-01

    Full Text Available Abstract: Selection and implementation of a web scale Discovery tool by The Rider University Libraries (RUL in the 2011-2012 academic year revealed the practical complexity of the endeavor. Research into the state of adoption of Web-scale Discovery tools in North America and the evolution of product effectiveness provided a starting point. The study reported here evaluated a total of 14 major Discovery tools (3 open source and 10 proprietary. The evaluation involves a check list of 16 criteria recognized as the advanced features of a modern OPAC. Some of the features have been used in previous research on Discovery tools and the next generation catalog. The authors examined 5 to 7 library websites that deployed a Discovery tool before a determination is made as to the presence or absence of a feature for a particular Discovery tool. The purpose of the study is to evaluate and compare all the major Discovery tools. These findings will serve to update librarians on the latest development in the library user interface and assist them in their adoption of a Discovery tool.

  12. Beyond information retrieval: information discovery and multimedia information retrieval

    OpenAIRE

    Roberto Raieli

    2017-01-01

    The paper compares the current methodologies for search and discovery of information and information resources: terminological search and term-based language, own of information retrieval (IR); semantic search and information discovery, being developed mainly through the language of linked data; semiotic search and content-based language, experienced by multimedia information retrieval (MIR).MIR semiotic methodology is, then, detailed.

  13. Cancer Biomarker Discovery: Lectin-Based Strategies Targeting Glycoproteins

    Directory of Open Access Journals (Sweden)

    David Clark

    2012-01-01

    Full Text Available Biomarker discovery can identify molecular markers in various cancers that can be used for detection, screening, diagnosis, and monitoring of disease progression. Lectin-affinity is a technique that can be used for the enrichment of glycoproteins from a complex sample, facilitating the discovery of novel cancer biomarkers associated with a disease state.

  14. Genomics-Driven Natural Product Discovery in Actinomycetes.

    Science.gov (United States)

    Niu, Guoqing

    2018-03-01

    The prevalence of antimicrobial-resistant pathogens has highlighted the urgent need for new drugs. Actinomycetes have been the most prominent sources of natural products for drug discovery and development. Advances in genomics have inspired several emerging strategies to reinvigorate the field of natural product discovery, especially in actinomycete-derived natural products. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. 10 CFR 2.705 - Discovery-additional methods.

    Science.gov (United States)

    2010-01-01

    ..., or tangible thing. In a proceeding on an application for a construction permit or an operating license for a production or utilization facility, discovery begins only after the prehearing conference... importance of the issue in the proceeding, and the importance of the proposed discovery in resolving the...

  16. Scenario Educational Software: Design and Development of Discovery Learning.

    Science.gov (United States)

    Keegan, Mark

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

  17. DHO: Discovery--Stargazing from the Ground Up

    Science.gov (United States)

    O'Leary, Niall

    2013-01-01

    In 2008, the Digital Humanities Observatory was charged with creating an all-island gateway to Irish digital collections and resources. A key factor in the achievement of this goal was the development of the web application, "DHO: Discovery." This chapter will describe what "DHO: Discovery" was intended to be and to what extent…

  18. The rays of life, centennial of discovery of Radium

    International Nuclear Information System (INIS)

    Constantin, Enrique; Plazas, Maria C.

    1999-01-01

    The authors make a recount from the discovery of the rays X for William Conrad Roentgen, in November of 1.985, until our days of the main discoveries and advances in medicine, having like base the radium and their importance in the treatment of the cancer

  19. Promise Fulfilled? An EBSCO Discovery Service Usability Study

    Science.gov (United States)

    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…

  20. Too New for Textbooks: The Biotechnology Discoveries & Applications Guidebook

    Science.gov (United States)

    Loftin, Madelene; Lamb, Neil E.

    2013-01-01

    The "Biotechnology Discoveries and Applications" guidebook aims to provide teachers with an overview of the recent advances in genetics and biotechnology, allowing them to share these findings with their students. The annual guidebook introduces a wealth of modern genomic discoveries and provides teachers with tools to integrate exciting…