WorldWideScience

Sample records for cell cardiopoiesis discovery

  1. Accelerated discovery via a whole-cell model.

    Science.gov (United States)

    Sanghvi, Jayodita C; Regot, Sergi; Carrasco, Silvia; Karr, Jonathan R; Gutschow, Miriam V; Bolival, Benjamin; Covert, Markus W

    2013-12-01

    To test the promise of whole-cell modeling to facilitate scientific inquiry, we compared growth rates simulated in a whole-cell model with experimental measurements for all viable single-gene disruption Mycoplasma genitalium strains. Discrepancies between simulations and experiments led to predictions about kinetic parameters of specific enzymes that we subsequently validated. These findings represent, to our knowledge, the first application of whole-cell modeling to accelerate biological discovery. PMID:24185838

  2. Sciatica leading to the discovery of a renal cell carcinoma

    OpenAIRE

    Amine Lakmichi, Mohamed; Jarir, Redouane; Kabour, Jamal; Dahami, Zakaria; Said Moudouni, Mohamed; Sarf, Ismail

    2011-01-01

    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, leading to the discovery of a renal cell carcinoma. Although uncommon, renal cell carcinoma spine metastasis should be included in the differential diagnosis of bac...

  3. University-industry alliance to advance fuel cell discoveries

    OpenAIRE

    Trulove, Susan

    2004-01-01

    Virginia universities will partner with Battelle and other industry partners, Virginia's Center for Innovative Technology, and Los Alamos National Laboratory, to build upon Virginia Tech discoveries in a program called "Bridging the Gap Between New Materials, Fuel Cell Devices and Products."

  4. Cell Migration and Invasion Assays as Tools for Drug Discovery

    OpenAIRE

    Hulkower, Keren I.; Herber, Renee L.

    2011-01-01

    Cell migration and invasion are processes that offer rich targets for intervention in key physiologic and pathologic phenomena such as wound healing and cancer metastasis. With the advent of high-throughput and high content imaging systems, there has been a movement towards the use of physiologically relevant cell-based assays earlier in the testing paradigm. This allows more effective identification of lead compounds and recognition of undesirable effects sooner in the drug discovery screeni...

  5. Antibody Discovery via Multiplexed Single Cell Characterization

    OpenAIRE

    Harriman, William D.; Collarini, Ellen J.; Sperinde, Gizette V.; Strandh, Magnus; Fatholahi, Marjan M.; Dutta, April; Lee, Yunji; Mettler, Shelley E.; Keyt, Bruce A.; Ellsworth, Stote L.; Kauvar, Lawrence M.

    2008-01-01

    The secreted immunoglobulin footprint of single hybridoma cells, containing ~10 fg of antibody purified in situ, has been probed for 9 properties concurrently by use of detection labels comprising 280 nm combinatorially colored fluorescent latex beads functionalized with proteins. Specificity of each individual hybridoma cell’s product has thereby been assessed in a primary screen. Varying the density of antigen on beads to modulate the avidity of the interaction between bead and secreted ant...

  6. Cell Migration and Invasion Assays as Tools for Drug Discovery

    Directory of Open Access Journals (Sweden)

    Keren I. Hulkower

    2011-03-01

    Full Text Available Cell migration and invasion are processes that offer rich targets for intervention in key physiologic and pathologic phenomena such as wound healing and cancer metastasis. With the advent of high-throughput and high content imaging systems, there has been a movement towards the use of physiologically relevant cell-based assays earlier in the testing paradigm. This allows more effective identification of lead compounds and recognition of undesirable effects sooner in the drug discovery screening process. This article will review the effective use of several principle formats for studying cell motility: scratch assays, transmembrane assays, microfluidic devices and cell exclusion zone assays.

  7. 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

  8. Discovery of the cancer stem cell related determinants of radioresistance

    International Nuclear Information System (INIS)

    Tumors are known to be heterogeneous containing a dynamic mixture of phenotypically and functionally different tumor cells. The two concepts attempting to explain the origin of intratumor heterogeneity are the cancer stem cell hypothesis and the clonal evolution model. The stochastic model argues that tumors are biologically homogenous and all cancer cells within the tumor have equal ability to propagate the tumor growth depending on continuing mutations and selective pressure. By contrast, the stem cells model suggests that cancer heterogeneity is due to the hierarchy that originates from a small population of cancer stem cells (CSCs) which are biologically distinct from the bulk tumor and possesses self-renewal, tumorigenic and multilineage potential. Although these two hypotheses have been discussed for a long time as mutually exclusive explanations of tumor heterogeneity, they are easily reconciled serving as a driving force of cancer evolution and diversity. Recent discovery of the cancer cell plasticity and heterogeneity makes the CSC population a moving target that could be hard to track and eradicate. Understanding the signaling mechanisms regulating CSCs during the course of cancer treatment can be indispensable for the optimization of current treatment strategies

  9. Kicking off adaptive immunity: the discovery of dendritic cells

    OpenAIRE

    Katsnelson, Alla

    2006-01-01

    In 1973, Ralph Steinman and Zanvil Cohn discovered an unusual looking population of cells with an unprecedented ability to activate naive T cells. Dubbed “dendritic cells,” these cells are now known as the primary instigators of adaptive immunity.

  10. Potential Approaches and Recent Advances in Biomarker Discovery in Clear-Cell Renal Cell Carcinoma

    Science.gov (United States)

    Majer, Weronika; Kluzek, Katarzyna; Bluyssen, Hans; Wesoły, Joanna

    2015-01-01

    The early diagnosis and monitoring of clear-cell Renal Cell Carcinoma (ccRCC), which is the most common renal malignancy, remains challenging. The late diagnosis and lack of tools that can be used to assess the progression of the disease and metastasis significantly influence the chance of survival of ccRCC patients. Molecular biomarkers have been shown to aid the diagnosis and disease monitoring for other cancers, but such markers are not currently available for ccRCC. Recently, plasma and serum circulating nucleic acids, nucleic acids present in urine, and plasma and urine proteins gained interest in the field of cancer biomarker discovery. Here, we describe the applicability of plasma and urine nucleic acids as cancer biomarkers with a particular focus on DNA, small RNA, and protein markers for ccRCC. PMID:26516358

  11. Discovery of Human sORF-Encoded Polypeptides (SEPs) in Cell Lines and Tissue

    OpenAIRE

    Ma, Jiao; Ward, Carl C.; Jungreis, Irwin; Slavoff, Sarah A.; Schwaid, Adam G.; Neveu, John; Budnik, Bogdan A.; Kellis, Manolis; Saghatelian, Alan

    2014-01-01

    The existence of nonannotated protein-coding human short open reading frames (sORFs) has been revealed through the direct detection of their sORF-encoded polypeptide (SEP) products. The discovery of novel SEPs increases the size of the genome and the proteome and provides insights into the molecular biology of mammalian cells, such as the prevalent usage of non-AUG start codons. Through modifications of the existing SEP-discovery workflow, we discover an additional 195 SEPs in K562 cells and ...

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

    Directory of Open Access Journals (Sweden)

    Alan Mackay-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

  13. Pluripotent stem cells in disease modelling and drug discovery.

    Science.gov (United States)

    Avior, Yishai; Sagi, Ido; Benvenisty, Nissim

    2016-03-01

    Experimental modelling of human disorders enables the definition of the cellular and molecular mechanisms underlying diseases and the development of therapies for treating them. The availability of human pluripotent stem cells (PSCs), which are capable of self-renewal and have the potential to differentiate into virtually any cell type, can now help to overcome the limitations of animal models for certain disorders. The ability to model human diseases using cultured PSCs has revolutionized the ways in which we study monogenic, complex and epigenetic disorders, as well as early- and late-onset diseases. Several strategies are used to generate such disease models using either embryonic stem cells (ES cells) or patient-specific induced PSCs (iPSCs), creating new possibilities for the establishment of models and their use in drug screening. PMID:26818440

  14. Accelerated discovery via a whole-cell model

    OpenAIRE

    Sanghvi, Jayodita C.; Regot, Sergi; Carrasco, Silvia; Karr, Jonathan R.; Miriam V Gutschow; Bolival, Benjamin; Covert, Markus W

    2013-01-01

    Whole-cell modeling promises to facilitate scientific inquiry by prioritizing future experiments based on existing datasets. To test this promise, we compared simulated growth rates with new measurements for all viable single-gene disruption strains in Mycoplasma genitalium. The discrepancies between simulations and experiments led to novel model predictions about specific kinetic parameters that we subsequently validated. These findings represent the first application of whole-cell modeling ...

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

    OpenAIRE

    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

    Global lncRNA discovery reveals novel erythroid-specific lncRNAs that are dynamically expressed and targeted by GATA1, TAL1, and KLF1.Multiple types of lncRNAs promote red cell maturation by regulating neighboring loci, including DLEU2 and a novel Band 3 enhancer lncRNA.

  16. 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).

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

    OpenAIRE

    Kitambi SS; Chandrasekar G

    2011-01-01

    Satish Srinivas Kitambi1, Gayathri Chandrasekar21Department of Medical Biochemistry and Biophysics; 2Department of Biosciences, Karolinska Institutet, Stockholm, SwedenAbstract: The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficac...

  18. 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.

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

    Directory of Open Access Journals (Sweden)

    Kitambi SS

    2011-09-01

    Full Text Available Satish Srinivas Kitambi1, Gayathri Chandrasekar21Department of Medical Biochemistry and Biophysics; 2Department of Biosciences, Karolinska Institutet, Stockholm, SwedenAbstract: The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficacy studies using stem cells offers a reliable platform for the drug discovery process. Advances made in the generation of induced pluripotent stem cells from normal or diseased tissue serves as a platform to perform drug screens aimed at developing cell-based therapies against conditions like Parkinson's disease and diabetes. This review discusses the application of stem cells and cancer stem cells in drug screening and their role in complementing, reducing, and replacing animal testing. In addition to this, target identification and major advances in the field of personalized medicine using induced pluripotent cells are also discussed.Keywords: therapeutics, stem cells, cancer stem cells, screening models, drug development, high throughput screening

  20. Induced Pluripotent Stem Cells: From Product-Focused Disease Modeling to Process-Focused Disease Discovery

    Science.gov (United States)

    Campbell, Katherine A.; Terzic, Andre; Nelson, Timothy J.

    2016-01-01

    Summary Induced pluripotent stem (iPS) cell technology offers an unprecedented opportunity to study patient-specific disease. This biotechnology platform enables recapitulation of individualized disease signatures in a dish through differentiation of patient-derived iPS cells. Beyond disease modeling, the in vitro process of differentiation toward genuine patient tissue offers a blueprint to inform disease etiology and molecular pathogenesis. Here, we highlight recent advances in patient-specific cardiac disease modeling and outline the future promise of iPS cell-based disease discovery applications. PMID:26439809

  1. Advancing drug discovery for neuropsychiatric disorders using patient-specific stem cell models.

    Science.gov (United States)

    Haggarty, Stephen J; Silva, M Catarina; Cross, Alan; Brandon, Nicholas J; Perlis, Roy H

    2016-06-01

    Compelling clinical, social, and economic reasons exist to innovate in the process of drug discovery for neuropsychiatric disorders. The use of patient-specific, induced pluripotent stem cells (iPSCs) now affords the ability to generate neuronal cell-based models that recapitulate key aspects of human disease. In the context of neuropsychiatric disorders, where access to physiologically active and relevant cell types of the central nervous system for research is extremely limiting, iPSC-derived in vitro culture of human neurons and glial cells is transformative. Potential applications relevant to early stage drug discovery, include support of quantitative biochemistry, functional genomics, proteomics, and perhaps most notably, high-throughput and high-content chemical screening. While many phenotypes in human iPSC-derived culture systems may prove adaptable to screening formats, addressing the question of which in vitro phenotypes are ultimately relevant to disease pathophysiology and therefore more likely to yield effective pharmacological agents that are disease-modifying treatments requires careful consideration. Here, we review recent examples of studies of neuropsychiatric disorders using human stem cell models where cellular phenotypes linked to disease and functional assays have been reported. We also highlight technical advances using genome-editing technologies in iPSCs to support drug discovery efforts, including the interpretation of the functional significance of rare genetic variants of unknown significance and for the purpose of creating cell type- and pathway-selective functional reporter assays. Additionally, we evaluate the potential of in vitro stem cell models to investigate early events of disease pathogenesis, in an effort to understand the underlying molecular mechanism, including the basis of selective cell-type vulnerability, and the potential to create new cell-based diagnostics to aid in the classification of patients and subsequent

  2. Discovery of T cell antigens by high-throughput screening of synthetic minigene libraries.

    Directory of Open Access Journals (Sweden)

    Brian D Hondowicz

    Full Text Available The identification of novel T cell antigens is central to basic and translational research in autoimmunity, tumor immunology, transplant immunology, and vaccine design for infectious disease. However, current methods for T cell antigen discovery are low throughput, and fail to explore a wide range of potential antigen-receptor interactions. To overcome these limitations, we developed a method in which programmable microarrays are used to cost-effectively synthesize complex libraries of thousands of minigenes that collectively encode the content of hundreds of candidate protein targets. Minigene-derived mRNA are transfected into autologous antigen presenting cells and used to challenge complex populations of purified peripheral blood CD8+ T cells in multiplex, parallel ELISPOT assays. In this proof-of-concept study, we apply synthetic minigene screening to identify two novel pancreatic islet autoantigens targeted in a patient with Type I Diabetes. To our knowledge, this is the first successful screen of a highly complex, synthetic minigene library for identification of a T cell antigen. In principle, responses against the full protein complement of any tissue or pathogen can be assayed by this approach, suggesting that further optimization of synthetic libraries holds promise for high throughput antigen discovery.

  3. The neural crest and neural crest cells: discovery and significance for theories of embryonic organization

    Indian Academy of Sciences (India)

    Brian K Hall

    2008-12-01

    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. In this sense, the neural crest is a morphological term akin to head fold or limb bud. This region of the dorsal neural tube consists of neural crest cells, a special population(s) of cell, that give rise to an astonishing number of cell types and to an equally astonishing number of tissues and organs. Neural crest cell contributions may be direct — providing cells — or indirect — providing a necessary, often inductive, environment in which other cells develop. The enormous range of cell types produced provides an important source of evidence of the neural crest as a germ layer, bringing the number of germ layers to four — ectoderm, endoderm, mesoderm, and neural crest. In this paper I provide a brief overview of the major phases of investigation into the neural crest and the major players involved, discuss how the origin of the neural crest relates to the origin of the nervous system in vertebrate embryos, discuss the impact on the germ-layer theory of the discovery of the neural crest and of secondary neurulation, and present evidence of the neural crest as the fourth germ layer. A companion paper (Hall, Evol. Biol. 2008) deals with the evolutionary origins of the neural crest and neural crest cells.

  4. 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.

  5. 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....

  6. Induced pluripotent stem cells, new tools for drug discovery and new hope for stem cell therapies

    OpenAIRE

    Shi, Yanhong

    2009-01-01

    Somatic cell nuclear transfer or therapeutic cloning has provided great hope for stem cell-based therapies. However therapeutic cloning has been experiencing both ethical and technical difficulties. Recent breakthrough studies using a combination of four factors to reprogram human somatic cells into pluripotent stem cells without using embryos or eggs led to an important revolution in stem cell research. Comparative analysis of human induced pluripotent stem cells and human embryonic stem cel...

  7. 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. PMID:24636868

  8. 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.

  9. Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer | Office of Cancer Genomics

    Science.gov (United States)

    Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets. Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding.

  10. Stem cell signaling as a target for novel drug discovery: recent progress in the WNT and Hedgehog pathways

    Institute of Scientific and Technical Information of China (English)

    Songzhu Michael AN; Qiang Peter DING; Ling-song LI

    2013-01-01

    One of the most exciting fields in biomedical research over the past few years is stem cell biology,and therapeutic application of stem cells to replace the diseased or damaged tissues is also an active area in development.Although stem cell therapy has a number of technical challenges and regulatory hurdles to overcome,the use of stem cells as tools in drug discovery supported by mature technologies and established regulatory paths is expected to generate more immediate returns.In particular,the targeting of stem cell signaling pathways is opening up a new avenue for drug discovery.Aberrations in these pathways result in various diseases,including cancer,fibrosis and degenerative diseases.A number of drug targets in stem cell signaling pathways have been identified.Among them,WNT and Hedgehog are two most important signaling pathways,which are the focus of this review.A hedgehog pathway inhibitor,vismodegib (Erivedge),has recently been approved by the US FDA for the treatment of skin cancer,while several drug candidates for the WNT pathway are entering clinical trials.We have discovered that the stem cell signaling pathways respond to traditional Chinese medicines.Substances isolated from herbal medicine may act specifically on components of stem cell signaling pathways with high affinities.As many of these events can be explained through molecular interactions,these phenomena suggest that discovery of stem cell-targeting drugs from natural products may prove to be highly successful.

  11. Complex Minigene Library Vaccination for Discovery of Pre-Erythrocytic Plasmodium T Cell Antigens

    Science.gov (United States)

    Stone, Brad C.; Kas, Arnold; Billman, Zachary P.; Fuller, Deborah H.; Fuller, James T.; Shendure, Jay; Murphy, Sean C.

    2016-01-01

    Development of a subunit vaccine targeting liver-stage Plasmodium parasites requires the identification of antigens capable of inducing protective T cell responses. However, traditional methods of antigen identification are incapable of evaluating T cell responses against large numbers of proteins expressed by these parasites. This bottleneck has limited development of subunit vaccines against Plasmodium and other complex intracellular pathogens. To address this bottleneck, we are developing a synthetic minigene technology for multi-antigen DNA vaccines. In an initial test of this approach, pools of long (150 bp) antigen-encoding oligonucleotides were synthesized and recombined into vectors by ligation-independent cloning to produce two DNA minigene library vaccines. Each vaccine encoded peptides derived from 36 (vaccine 1) and 53 (vaccine 2) secreted or transmembrane pre-erythrocytic P. yoelii proteins. BALB/cj mice were vaccinated three times with a single vaccine by biolistic particle delivery (gene gun) and screened for interferon-γ-producing T cell responses by ELISPOT. Library vaccination induced responses against four novel antigens. Naïve mice exposed to radiation-attenuated sporozoites mounted a response against only one of the four novel targets (PyMDH, malate dehydrogenase). The response to PyMDH could not be recalled by additional homologous sporozoite immunizations but could be partially recalled by heterologous cross-species sporozoite exposure. Vaccination against the dominant PyMDH epitope by DNA priming and recombinant Listeria boosting did not protect against sporozoite challenge. Improvements in library design and delivery, combined with methods promoting an increase in screening sensitivity, may enable complex minigene screening to serve as a high-throughput system for discovery of novel T cell antigens. PMID:27070430

  12. 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.

  13. Live cell discovery of microbial vitamin transport and enzyme-cofactor interactions by chemoproteomics

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-02-01

    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.

  14. 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 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 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...... stem cell favourable environment. We propose that this model system could play a role in testing of new drugs targeting tumor stem cells....

  15. Drug Repositioning Discovery for Early- and Late-Stage Non-Small-Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Chien-Hung Huang

    2014-01-01

    Full Text Available Drug repositioning is a popular approach in the pharmaceutical industry for identifying potential new uses for existing drugs and accelerating the development time. Non-small-cell lung cancer (NSCLC is one of the leading causes of death worldwide. To reduce the biological heterogeneity effects among different individuals, both normal and cancer tissues were taken from the same patient, hence allowing pairwise testing. By comparing early- and late-stage cancer patients, we can identify stage-specific NSCLC genes. Differentially expressed genes are clustered separately to form up- and downregulated communities that are used as queries to perform enrichment analysis. The results suggest that pathways for early- and late-stage cancers are different. Sets of up- and downregulated genes were submitted to the cMap web resource to identify potential drugs. To achieve high confidence drug prediction, multiple microarray experimental results were merged by performing meta-analysis. The results of a few drug findings are supported by MTT assay or clonogenic assay data. In conclusion, we have been able to assess the potential existing drugs to identify novel anticancer drugs, which may be helpful in drug repositioning discovery for NSCLC.

  16. Towards an Appropriate Beamforming Scheme for Initial Cell Discovery in mmW 5G Cellular Networks

    OpenAIRE

    Abbas, Waqas bin; Zorzi, Michele

    2016-01-01

    Beamforming is an essential requirement to combat high pathloss and to improve signal-to-noise ratio during initial cell discovery in future millimeter wave cellular networks. The choice of an appropriate beamforming is directly coupled with its energy consumption. The energy consumption is even of more concern at a battery limited mobile station (MS). In this work, we provide an energy consumption based comparison of different beamforming schemes while considering both a low power and a high...

  17. A phenotypic drug discovery study on thienodiazepine derivatives as inhibitors of T cell proliferation induced by CD28 co-stimulation leads to the discovery of a first bromodomain inhibitor.

    Science.gov (United States)

    Endo, Junichi; Hikawa, Hidemasa; Hamada, Maiko; Ishibuchi, Seigo; Fujie, Naoto; Sugiyama, Naoki; Tanaka, Minoru; Kobayashi, Haruhito; Sugahara, Kunio; Oshita, Koichi; Iwata, Kazunori; Ooike, Shinsuke; Murata, Meguru; Sumichika, Hiroshi; Chiba, Kenji; Adachi, Kunitomo

    2016-03-01

    A phenotypic screening of thienodiazepines derived from a hit compound found through a binding assay targeting co-stimulatory molecules on T cells and antigen presenting cells successfully led to the discovery of a thienotriazolodiazepine compound (7f) possessing potent immunosuppressive activity. A chemical biology approach has succeeded in revealing that 7f is a first inhibitor of epigenetic bromodomain-containing proteins. 7f is expected to become an anti-cancer agent as well as an immunosuppressive agent. PMID:26869194

  18. Toward the Development of a Virus-Cell-Based Assay for the Discovery of Novel Compounds against Human Immunodeficiency Virus Type 1

    OpenAIRE

    Adelson, Martin E.; Pacchia, Annmarie L.; Kaul, Malvika; Rando, Robert F.; Ron, Yacov; Peltz, Stuart W.; Dougherty, Joseph P.

    2003-01-01

    The emergence of human immunodeficiency virus type 1 (HIV-1) strains resistant to highly active antiretroviral therapy necessitates continued drug discovery for the treatment of HIV-1 infection. Most current drug discovery strategies focus upon a single aspect of HIV-1 replication. A virus-cell-based assay, which can be adapted to high-throughput screening, would allow the screening of multiple targets simultaneously. HIV-1-based vector systems mimic the HIV-1 life cycle without yielding repl...

  19. Synthetic time series resembling human (HeLa) cell-cycle gene expression data and application to gene regulatory network discovery

    OpenAIRE

    Tam, GHF; Hung, YS; Chang, C.

    2013-01-01

    Evaluation of gene regulatory network (GRN) discovery methods relies heavily on synthetic time series. However, synthetic data generated by traditional method deviate a lot from real data, making such evaluation questionable. Guiding by decaying sinusoids, we propose a new method that generates synthetic data resembling human (HeLa) cell-cycle gene expression data. Using the new synthetic data, a simple comparison between four GRN discovery methods reveals that Granger causality (GC) methods ...

  20. Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design

    Energy Technology Data Exchange (ETDEWEB)

    Friberg, Anders [Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Vigil, Dominico [Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Zhao, Bin [Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Daniels, R. Nathan [Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Burke, Jason P. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Garcia-Barrantes, Pedro M. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Camper, DeMarco [Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Chauder, Brian A. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Lee, Taekyu [Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Olejniczak, Edward T. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Fesik, Stephen W. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States)

    2012-12-17

    Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified two chemically distinct hit series that bind to different sites on Mcl-1. Members of the two fragment classes were merged together to produce lead compounds that bind to Mcl-1 with a dissociation constant of <100 nM with selectivity for Mcl-1 over Bcl-xL and Bcl-2. Structures of merged compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition of small-molecule ligands binding Mcl-1. The compounds represent starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers.

  1. Human Stem Cells for Modeling Heart Disease and for Drug Discovery

    Science.gov (United States)

    Matsa, Elena; Burridge, Paul W.; Wu, Joseph C.

    2014-01-01

    A major research focus in the field of cardiovascular medicine is the prospect of using stem cells and progenitor cells for cardiac regeneration. With the advent of induced pluripotent stem cell (iPSC) technology, major efforts are also underway to use iPSCs to model heart disease, to screen for new drugs, and to test candidate drugs for cardiotoxicity. Here, we discuss recent advances in the exciting fields of stem cells and cardiovascular disease. PMID:24898747

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

    OpenAIRE

    Kawser Hossain, Mohammed; Abdal Dayem, Ahmed; Han, Jihae; Kumar Saha, Subbroto; Yang, Gwang-Mo; Choi, Hye Yeon; Cho, Ssang-Goo

    2016-01-01

    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 fro...

  3. 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.

  4. 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…

  5. Human embryonic stem cells as a model for cardiac gene discovery : from chip to chap

    NARCIS (Netherlands)

    Beqqali, A.

    2008-01-01

    Here we described the use of human embryonic stem cells (hESCs) as a model to obtain insights into commitment to the mesoderm and endoderm lineages and the early steps in human cardiac cell differentiation by means of whole-genome temporal expression profiling. Furthermore, we used it as an approach

  6. Methods for discovery and characterization of cell subsets in high dimensional mass cytometry data.

    Science.gov (United States)

    Diggins, Kirsten E; Ferrell, P Brent; Irish, Jonathan M

    2015-07-01

    The flood of high-dimensional data resulting from mass cytometry experiments that measure more than 40 features of individual cells has stimulated creation of new single cell computational biology tools. These tools draw on advances in the field of machine learning to capture multi-parametric relationships and reveal cells that are easily overlooked in traditional analysis. Here, we introduce a workflow for high dimensional mass cytometry data that emphasizes unsupervised approaches and visualizes data in both single cell and population level views. This workflow includes three central components that are common across mass cytometry analysis approaches: (1) distinguishing initial populations, (2) revealing cell subsets, and (3) characterizing subset features. In the implementation described here, viSNE, SPADE, and heatmaps were used sequentially to comprehensively characterize and compare healthy and malignant human tissue samples. The use of multiple methods helps provide a comprehensive view of results, and the largely unsupervised workflow facilitates automation and helps researchers avoid missing cell populations with unusual or unexpected phenotypes. Together, these methods develop a framework for future machine learning of cell identity. PMID:25979346

  7. A multi-gene transcriptional profiling approach to the discovery of cell signature markers.

    Science.gov (United States)

    Wada, Youichiro; Li, Dan; Merley, Anne; Zukauskas, Andrew; Aird, William C; Dvorak, Harold F; Shih, Shou-Ching

    2011-01-01

    A profile of transcript abundances from multiple genes constitutes a molecular signature if the expression pattern is unique to one cell type. Here we measure mRNA copy numbers per cell by normalizing per million copies of 18S rRNA and identify 6 genes (TIE1, KDR, CDH5, TIE2, EFNA1 and MYO5C) out of 79 genes tested as excellent molecular signature markers for endothelial cells (ECs) in vitro. The selected genes are uniformly expressed in ECs of 4 different origins but weakly or not expressed in 4 non-EC cell lines. A multi-gene transcriptional profile of these 6 genes clearly distinguishes ECs from non-ECs in vitro. We conclude that (i) a profile of mRNA copy numbers per cell from a well-chosen multi-gene panel can act as a sensitive and accurate cell type signature marker, and (ii) the method described here can be applied to in vivo cell fingerprinting and molecular diagnosis. PMID:20972619

  8. A multi-gene transcriptional profiling approach to the discovery of cell signature markers

    OpenAIRE

    Wada, Youichiro; Li, Dan; Merley, Anne; Zukauskas, Andrew; Aird, William C.; Dvorak, Harold F.; Shih, Shou-Ching

    2010-01-01

    A profile of transcript abundances from multiple genes constitutes a molecular signature if the expression pattern is unique to one cell type. Here we measure mRNA copy numbers per cell by normalizing per million copies of 18S rRNA and identify 6 genes (TIE1, KDR, CDH5, TIE2, EFNA1 and MYO5C) out of 79 genes tested as excellent molecular signature markers for endothelial cells (ECs) in vitro. The selected genes are uniformly expressed in ECs of 4 different origins but weakly or not expressed ...

  9. Discovery of Uranium in Outer Coat of Sri Lankan Red Rain Cells

    Science.gov (United States)

    Miyake, Nori; Matsui, Takafumi; Wallis, Jamie; Wallis, Daryl H.; Samaranayake, Anil; Wickramarathne, Keerthi; Wickramasinghe, N. Chandra

    2013-03-01

    The microbial content of the red rain that fell over central Sri Lanka in November/December 2012 shows generic similarities to that of the Kerala red rain. Light microscope examination of the Sri Lankan red rain indicates that the defining red rain cells exist in the presence of other microorganisms including diatoms. We report the results of a preliminary TEM study of the red rain cells that shows them to have outer cell walls unusually rich in uranium, and a nuclear region with a strong deficit or absence of phosphorus.

  10. Neural stem cells isolated from amyloid precursor protein-mutated mice for drug discovery

    OpenAIRE

    2013-01-01

    AIM: To develop an in vitro model based on neural stem cells derived from transgenic animals, to be used in the study of pathological mechanisms of Alzheimer’s disease and for testing new molecules.

  11. Synovial fluid and synovial membrane mesenchymal stem cells: latest discoveries and therapeutic perspectives

    OpenAIRE

    de Sousa, Eduardo Branco; Casado, Priscila Ladeira; Neto, Vivaldo Moura; Duarte, Maria Eugenia Leite; Aguiar, Diego Pinheiro

    2014-01-01

    Mesenchymal stem cells (MSCs) have the ability to differentiate into osteoblasts, chondroblasts, adipocytes, and even myoblasts. Most studies have focused on finding MSCs in different parts of the body for medical treatment. Every joint structure, including bone, joint fat, articular cartilage, and synovium, potentially contains resident MSCs. Recently, a progenitor cell population has been found in synovial fluid and showed similarities with both bone marrow and synovial membrane MSCs. Synov...

  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. Induced Pluripotent Stem Cells: From Product-Focused Disease Modeling to Process-Focused Disease Discovery

    OpenAIRE

    Campbell, Katherine A; Terzic, Andre; Nelson, Timothy J

    2015-01-01

    Induced pluripotent stem (iPS) cell technology offers an unprecedented opportunity to study patient-specific disease. This biotechnology platform enables recapitulation of individualized disease signatures in a dish through differentiation of patient-derived iPS cells. Beyond disease modeling, the in vitro process of differentiation toward genuine patient tissue offers a blueprint to inform disease etiology and molecular pathogenesis. Here, we highlight recent advances in patient-specific car...

  14. Discovery of New Cargo Proteins that enter Cells through Clathrin-Independent Endocytosis

    OpenAIRE

    Eyster, Craig A.; Higginson, Jason D.; Huebner, Robert; Porat-Shliom, Natalie; Weigert, Roberto; Wu, Wells W.; Shen, Rong-Fong; Donaldson, Julie G.

    2009-01-01

    Clathrin-independent endocytosis (CIE) allows internalization of plasma membrane proteins lacking clathrin-targeting sequences, such as the major histocompatibility complex Class I protein (MHCI), into cells. After internalization, vesicles containing MHCI fuse with transferrin-containing endosomes generated from clathrin-dependent endocytosis. In HeLa cells, MHCI is subsequently routed to late endosomes or recycled back out to the plasma membrane (PM) in distinctive tubular carriers. Arf6 is...

  15. Stem Cell Hydrogel, Jump-Starting Zika Drug Discovery, and Engineering RNA Recognition.

    Science.gov (United States)

    Kostic, Milka

    2016-08-18

    Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature that impressed them with creativity and potential for follow up work. Our August 2016 selection includes a description of hydrogels with self-tunable stiffness that are used to profile lipid metabolites during stems cell differentiation, a look at whether we can find a drug repurposing solution to Zika virus infection, and an engineered RNA recognition motif (RRM). PMID:27541191

  16. Recent developments in cell-based assays and stem cell technologies for Botulinum neurotoxin research and drug discovery

    OpenAIRE

    Kiris, Erkan; Kota, Krishna P.; James C. Burnett; Soloveva, Veronica; Kane, Christopher D.; Bavari, Sina

    2014-01-01

    Botulinum neurotoxins (BoNTs) are exceptionally potent inhibitors of neurotransmission, causing muscle paralysis and respiratory failure associated with the disease botulism. Currently, no drugs are available to counter intracellular BoNT poisoning. To develop effective medical treatments, cell-based assays provide a valuable system to identify novel inhibitors in a time- and cost-efficient manner. Consequently, cell-based systems including immortalized cells, primary neurons, and stem-cell d...

  17. Discovery of molecular associations among aging, stem cells, and cancer based on gene expression profiling

    Institute of Scientific and Technical Information of China (English)

    Xiaosheng Wang

    2013-01-01

    The emergence of a huge volume of "omics" data enables a computational approach to the investigation of the biology of cancer.The cancer informatics approach is a useful supplement to the traditional experimental approach.I reviewed several reports that used a bioinformatics approach to analyze the associations among aging,stem cells,and cancer by microarray gene expression profiling.The high expression of aging-or human embryonic stem cell-related molecules in cancer suggests that certain important mechanisms are commonly underlying aging,stem cells,and cancer.These mechanisms are involved in cell cycle regulation,metabolic process,DNA damage response,apoptosis,p53 signaling pathway,immune/inflammatory response,and other processes,suggesting that cancer is a developmental and evolutional disease that is strongly related to aging.Moreover,these mechanisms demonstrate that the initiation,proliferation,and metastasis of cancer are associated with the deregulation of stem cells.These findings provide insights into the biology of cancer.Certainly,the findings that are obtained by the informatics approach should be justified by experimental validation.This review also noted that next-generation sequencing data provide enriched sources for cancer informatics study.

  18. Left behind? Drug discovery in extensive-stage small-cell lung cancer.

    Science.gov (United States)

    Riess, Jonathan W; Lara, Primo N

    2014-03-01

    Systemic therapy and subsequent survival for patients with extensive-stage small-cell lung cancer (SCLC) are poor and have remained unchanged in the past quarter century. To improve outcomes in these patients, a new drug development paradigm must be adopted that moves away from empiricism and instead focuses on tumor biology and heterogeneity as a means to increase target and drug class diversity. By incorporating tools that have led to new diagnostic and treatment options in non-small-cell lung cancer, there could be hope yet for the future of SCLC therapeutics. PMID:24529447

  19. Peptidomic discovery of short open reading frame-encoded peptides in human cells

    OpenAIRE

    Slavoff, Sarah A.; Mitchell, Andrew J.; Schwaid, Adam G.; Cabili, Moran N; Ma, Jiao; Levin, Joshua Z.; Karger, Amir; Budnik, Bogdan A.; Rinn, John L; Saghatelian, Alan

    2012-01-01

    The amount of the transcriptome that is translated into polypeptides is of fundamental importance. We developed a peptidomic strategy to detect short ORF (sORF)-encoded polypeptides (SEPs) in human cells. We identified 90 SEPs, 86 of which are novel, the largest number of human SEPs ever reported. SEP abundances range from 10-1000 molecules per cell, identical to known proteins. SEPs arise from sORFs in non-coding RNAs as well as multi-cistronic mRNAs, and many SEPs initiate with non-AUG star...

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

    DEFF Research Database (Denmark)

    Vieira Campos, Diana Alexandra; Freitas, Daniela; Gomes, Joana; Magalhães, Ana; Steentoft, Catharina; Gomes, Catarina; Vester-Christensen, Malene B; Ferreira, José Alexandre; Afonso, Luis P; Santos, Lúcio L; de Sousa, João Pinto; Mandel, Ulla; Clausen, Henrik; Vakhrushev, Sergey Y; Reis, Celso A

    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...

  1. A cell-free framework for rapid biosynthetic pathway prototyping and enzyme discovery.

    Science.gov (United States)

    Karim, Ashty S; Jewett, Michael C

    2016-07-01

    Speeding up design-build-test (DBT) cycles is a fundamental challenge facing biochemical engineering. To address this challenge, we report a new cell-free protein synthesis driven metabolic engineering (CFPS-ME) framework for rapid biosynthetic pathway prototyping. In our framework, cell-free cocktails for synthesizing target small molecules are assembled in a mix-and-match fashion from crude cell lysates either containing selectively enriched pathway enzymes from heterologous overexpression or directly producing pathway enzymes in lysates by CFPS. As a model, we apply our approach to n-butanol biosynthesis showing that Escherichia coli lysates support a highly active 17-step CoA-dependent n-butanol pathway in vitro. The elevated degree of flexibility in the cell-free environment allows us to manipulate physiochemical conditions, access enzymatic nodes, discover new enzymes, and prototype enzyme sets with linear DNA templates to study pathway performance. We anticipate that CFPS-ME will facilitate efforts to define, manipulate, and understand metabolic pathways for accelerated DBT cycles without the need to reengineer organisms. PMID:26996382

  2. Motif discovery in promoters of genes co-localized and co-expressed during myeloid cells differentiation

    Science.gov (United States)

    Coppe, Alessandro; Ferrari, Francesco; Bisognin, Andrea; Danieli, Gian Antonio; Ferrari, Sergio; Bicciato, Silvio; Bortoluzzi, Stefania

    2009-01-01

    Genes co-expressed may be under similar promoter-based and/or position-based regulation. Although data on expression, position and function of human genes are available, their true integration still represents a challenge for computational biology, hampering the identification of regulatory mechanisms. We carried out an integrative analysis of genomic position, functional annotation and promoters of genes expressed in myeloid cells. Promoter analysis was conducted by a novel multi-step method for discovering putative regulatory elements, i.e. over-represented motifs, in a selected set of promoters, as compared with a background model. The combination of transcriptional, structural and functional data allowed the identification of sets of promoters pertaining to groups of genes co-expressed and co-localized in regions of the human genome. The application of motif discovery to 26 groups of genes co-expressed in myeloid cells differentiation and co-localized in the genome showed that there are more over-represented motifs in promoters of co-expressed and co-localized genes than in promoters of simply co-expressed genes (CEG). Motifs, which are similar to the binding sequences of known transcription factors, non-uniformly distributed along promoter sequences and/or occurring in highly co-expressed subset of genes were identified. Co-expressed and co-localized gene sets were grouped in two co-expressed genomic meta-regions, putatively representing functional domains of a high-level expression regulation. PMID:19059999

  3. Recent developments in cell-based assays and stem cell technologies for botulinum neurotoxin research and drug discovery.

    Science.gov (United States)

    Kiris, Erkan; Kota, Krishna P; Burnett, James C; Soloveva, Veronica; Kane, Christopher D; Bavari, Sina

    2014-03-01

    Botulinum neurotoxins (BoNTs) are exceptionally potent inhibitors of neurotransmission, causing muscle paralysis and respiratory failure associated with the disease botulism. Currently, no drugs are available to counter intracellular BoNT poisoning. To develop effective medical treatments, cell-based assays provide a valuable system to identify novel inhibitors in a time- and cost-efficient manner. Consequently, cell-based systems including immortalized cells, primary neurons and stem cell-derived neurons have been established. Stem cell-derived neurons are highly sensitive to BoNT intoxication and represent an ideal model to study the biological effects of BoNTs. Robust immunoassays are used to quantify BoNT activity and play a central role during inhibitor screening. In this review, we examine recent progress in physiologically relevant cell-based assays and high-throughput screening approaches for the identification of both direct and indirect BoNT inhibitors. PMID:24450833

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

    OpenAIRE

    Deshmukh, Rahul S.; Kovács, Krisztián A; Dinnyés, András

    2012-01-01

    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 th...

  5. Drug discovery toward successful cell transplantation therapy for Parkinson’s disease using human pluripotent stem cells

    OpenAIRE

    Nishimura, Kaneyasu; Takahashi, Jun

    2016-01-01

    Cell transplantation therapy using human pluripotent stem cell (PSC)–derived midbrain dopaminergic (mDA) neurons is soon expected to be available for patients with Parkinson’s disease (PD). Highly efficient and reproducible protocols for the induction of mDA neurons for clinical application have already been reported, and the therapeutic potential and safety of these cells have been studied in parkinsonian animal models as preclinical trials. However, a new strategy that improves the survival...

  6. Higgs Discovery

    DEFF Research Database (Denmark)

    Sannino, Francesco

    2013-01-01

    via first principle lattice simulations with encouraging results. The new findings show that the recent naive claims made about new strong dynamics at the electroweak scale being disfavoured by the discovery of a not-so-heavy composite Higgs are unwarranted. I will then introduce the more speculative......I discuss the impact of the discovery of a Higgs-like state on composite dynamics starting by critically examining the reasons in favour of either an elementary or composite nature of this state. Accepting the standard model interpretation I re-address the standard model vacuum stability within a...... has been challenged by the discovery of a not-so-heavy Higgs-like state. I will therefore review the recent discovery \\cite{Foadi:2012bb} that the standard model top-induced radiative corrections naturally reduce the intrinsic non-perturbative mass of the composite Higgs state towards the desired...

  7. Volatility Discovery

    DEFF Research Database (Denmark)

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

    There is a large literature that investigates how homogenous securities traded on different markets incorporate new information (price discovery analysis). We extend this concept to the stochastic volatility process and investigate how markets contribute to the efficient stochastic volatility whi...

  8. 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.

  9. The AMD3100 story: the path to the discovery of a stem cell mobilizer (Mozobil)

    OpenAIRE

    De Clercq, Erik

    2009-01-01

    Abstract AMD3100 was found to inhibit HIV-1 and HIV-2 within the 1?10nM concentration range while not being toxic to the host cells at concentrations up to 500?M, thus achieving a selectivity index of approximately 100,000. The target of action was initially thought to be the viral envelope glycoprotein gp120. It appeared only to be the indirect target. The direct target of action turned out to be the co-receptor CXCR4 used by T-lymphotropic HIV strains (now referred to as X4 strai...

  10. A cell-based fluorescent glucose transporter assay for SGLT2 inhibitor discovery

    OpenAIRE

    Yi Huan; Linyi Li; Quan Liu; Shuainan Liu; Zhufang Shen

    2013-01-01

    The sodium/glucose cotransporter 2 (SGLT2) is responsible for the majority of glucose reabsorption in the kidney, and currently, SGLT2 inhibitors are considered as promising hypoglycemic agents for the treatment of type 2 diabetes mellitus. By constructing CHO cell lines that stably express the human SGLT2 transmembrane protein, along with a fluorescent glucose transporter assay that uses 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]2-deoxyglucose (2-NBDG) as a glucose analog, we have develo...

  11. 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.

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

    International Nuclear Information System (INIS)

    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, nm 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)

  13. Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell

    Science.gov (United States)

    Chattopadhyay, Anasuya; O’Connor, Cornelius J.; Zhang, Fengzhi; Galvagnion, Celine; Galloway, Warren R. J. D.; Tan, Yaw Sing; Stokes, Jamie E.; Rahman, Taufiq; Verma, Chandra; Spring, David R.; Itzhaki, Laura S.

    2016-04-01

    Gankyrin is an ankyrin-repeat oncoprotein whose overexpression has been implicated in the development of many cancer types. Elevated gankyrin levels are linked to aberrant cellular events including enhanced degradation of tumour suppressor protein p53, and inhibition of gankyrin activity has therefore been identified as an attractive anticancer strategy. Gankyrin interacts with several partner proteins, and a number of these protein-protein interactions (PPIs) are of relevance to cancer. Thus, molecules that bind the PPI interface of gankyrin and interrupt these interactions are of considerable interest. Herein, we report the discovery of a small molecule termed cjoc42 that is capable of binding to gankyrin. Cell-based experiments demonstrate that cjoc42 can inhibit gankyrin activity in a dose-dependent manner: cjoc42 prevents the decrease in p53 protein levels normally associated with high amounts of gankyrin, and it restores p53-dependent transcription and sensitivity to DNA damage. The results represent the first evidence that gankyrin is a “druggable” target with small molecules.

  14. Combined blood/tissue analysis for cancer biomarker discovery: application to renal cell carcinoma.

    Science.gov (United States)

    Johann, Donald J; Wei, Bih-Rong; Prieto, DaRue A; Chan, King C; Ye, Xiaying; Valera, Vladimir A; Simpson, R Mark; Rudnick, Paul A; Xiao, Zhen; Issaq, Haleem J; Linehan, W Marston; Stein, Stephen E; Veenstra, Timothy D; Blonder, Josip

    2010-03-01

    A method that relies on subtractive tissue-directed shot-gun proteomics to identify tumor proteins in the blood of a patient newly diagnosed with cancer is described. To avoid analytical and statistical biases caused by physiologic variability of protein expression in the human population, this method was applied on clinical specimens obtained from a single patient diagnosed with nonmetastatic renal cell carcinoma (RCC). The proteomes extracted from tumor, normal adjacent tissue and preoperative plasma were analyzed using 2D-liquid chromatography-mass spectrometry (LC-MS). The lists of identified proteins were filtered to discover proteins that (i) were found in the tumor but not normal tissue, (ii) were identified in matching plasma, and (iii) whose spectral count was higher in tumor tissue than plasma. These filtering criteria resulted in identification of eight tumor proteins in the blood. Subsequent Western-blot analysis confirmed the presence of cadherin-5, cadherin-11, DEAD-box protein-23, and pyruvate kinase in the blood of the patient in the study as well as in the blood of four other patients diagnosed with RCC. These results demonstrate the utility of a combined blood/tissue analysis strategy that permits the detection of tumor proteins in the blood of a patient diagnosed with RCC. PMID:20121140

  15. Discovery of ERBB3 inhibitors for non-small cell lung cancer (NSCLC) via virtual screening.

    Science.gov (United States)

    Guo, Rong; Zhang, Yuan; Li, Xiao; Song, Xinrui; Li, Da; Zhao, Yong

    2016-06-01

    As a member of the epidermal growth factor receptor family (EGFR) of receptor tyrosine kinases, ERBB3 plays an important role in mediating cellular growth and differentiation. Recent research works identified that CD74-NRG1 fusions lead to overexpression of the EGF-like domain of NRG1, and thus activate ERBB3 and PI3K-AKT signaling pathways. The fusion was detected in lung adenocarcinomas, and served as an important oncogenic factor for ERBB3 driven cancers. A sequential virtual screening strategy has been applied to ERBB3 crystal structure using databases of natural products and Chinese traditional medicine compounds, and led to identification of a group of small molecular compounds potentially capable of blocking ERBB3. Six small molecular compounds were selected for in vitro analysis. Five of these molecules significantly inhibited the growth of A549 cells. Among them, compound VS1 is the most promising one with IC50 values of 269.75 μM, comparing to the positive control of nimustine hydrochloride with IC50 values of 264.14 μM. With good specificity and predicted ADMET results, our results support the feasibility by using a pharmacophore of the compound VS1 for designing and optimization of ERBB3 inhibitors. PMID:27188722

  16. Discovery of TUG-770

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Hansen, Steffen V F; 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...

  17. Beyond Discovery

    DEFF Research Database (Denmark)

    Korsgaard, Steffen; Sassmannshausen, Sean Patrick

    2015-01-01

    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 their...... central concepts and conceptualization of the entrepreneurial function. On this basis we discuss three central themes that cut across the four alternatives: process, uncertainty, and agency. These themes provide new foci for entrepreneurship research and can help to generate new research questions and...

  18. 5,10b-Ethanophenanthridine amaryllidaceae alkaloids inspire the discovery of novel bicyclic ring systems with activity against drug resistant cancer cells.

    Science.gov (United States)

    Henry, Sean; Kidner, Ria; Reisenauer, Mary R; Magedov, Igor V; Kiss, Robert; Mathieu, Véronique; Lefranc, Florence; Dasari, Ramesh; Evidente, Antonio; Yu, Xiaojie; Ma, Xiuye; Pertsemlidis, Alexander; Cencic, Regina; Pelletier, Jerry; Cavazos, David A; Brenner, Andrew J; Aksenov, Alexander V; Rogelj, Snezna; Kornienko, Alexander; Frolova, Liliya V

    2016-09-14

    Plants of the Amaryllidaceae family produce a large variety of alkaloids and non-basic secondary metabolites, many of which are investigated for their promising anticancer activities. Of these, crinine-type alkaloids based on the 5,10b-ethanophenanthridine ring system were recently shown to be effective at inhibiting proliferation of cancer cells resistant to various pro-apoptotic stimuli and representing tumors with dismal prognoses refractory to current chemotherapy, such as glioma, melanoma, non-small-cell lung, esophageal, head and neck cancers, among others. Using this discovery as a starting point and taking advantage of a concise biomimetic route to the crinine skeleton, a collection of crinine analogues were synthetically prepared and evaluated against cancer cells. The compounds exhibited single-digit micromolar activities and retained this activity in a variety of drug-resistant cancer cell cultures. This investigation resulted in the discovery of new bicyclic ring systems with significant potential in the development of effective clinical cancer drugs capable of overcoming cancer chemotherapy resistance. PMID:27218860

  19. 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...

  20. Discovery of a gamma heavy chain disease in a patient followed-up for a lymphoplasma cell proliferative disorder.

    Science.gov (United States)

    Humeau, Camille; Monjanel, Hélène; Schellenberg, François

    2016-06-01

    Gamma-heavy chains disease is a rare disease, with very few cases described in the literature. It is characterized by the presence of a monoclonal gamma-heavy chain without associated light chain. Its prevalence and prognosis are unknown. We report here the accidental discovery of a case of gamma-heavy chain disease during a pancytopenia exploration, performed in the hospital, in a patient known since 2002 for a lymphoplasmacytic type lymphoma first localized in bone marrow. PMID:27237805

  1. Discovery of Small-Molecule Enhancers of Reactive Oxygen Species That are Nontoxic or Cause Genotype-Selective Cell Death

    OpenAIRE

    Adams, Drew J.; Boskovic, Zarko; Theriault, Jimmy R.; Wang, Alex J.; Stern, Andrew M.; Wagner, Bridget K.; Shamji, Alykhan Farid; Schreiber, Stuart L.

    2013-01-01

    Elevation of reactive oxygen species (ROS) levels has been observed in many cancer cells relative to nontransformed cells, and recent reports have suggested that small-molecule enhancers of ROS may selectively kill cancer cells in various in vitro and in vivo models. We used a high-throughput screening approach to identify several hundred small-molecule enhancers of ROS in a human osteosarcoma cell line. A minority of these compounds diminished the viability of cancer cell lines, indicating t...

  2. In Vitro Assessment of the Inflammatory Breast Cancer Cell Line SUM 149: Discovery of 2 Single Nucleotide Polymorphisms in the RNase L Gene

    Directory of Open Access Journals (Sweden)

    Brandon T. Nokes, Heather E. Cunliffe, Bonnie LaFleur, David W. Mount, Robert B. Livingston, Bernard W. Futscher, Julie E. Lang

    2013-01-01

    Full Text Available Background: Inflammatory breast cancer (IBC is a rare, highly aggressive form of breast cancer. The mechanism of IBC carcinogenesis remains unknown. We sought to evaluate potential genetic risk factors for IBC and whether or not the IBC cell lines SUM149 and SUM190 demonstrated evidence of viral infection.Methods: We performed single nucleotide polymorphism (SNP genotyping for 2 variants of the ribonuclease (RNase L gene that have been correlated with the risk of prostate cancer due to a possible viral etiology. We evaluated dose-response to treatment with interferon-alpha (IFN-α; and assayed for evidence of the putative human mammary tumor virus (HMTV, which has been implicated in IBC in SUM149 cells. A bioinformatic analysis was performed to evaluate expression of RNase L in IBC and non-IBC.Results: 2 of 2 IBC cell lines were homozygous for RNase L common missense variants 462 and 541; whereas 2 of 10 non-IBC cell lines were homozygous positive for the 462 variant (p= 0.09 and 0 of 10 non-IBC cell lines were homozygous positive for the 541 variant (p = 0.015. Our real-time polymerase chain reaction (RT-PCR and Southern blot analysis for sequences of HMTV revealed no evidence of the putative viral genome.Conclusion: We discovered 2 SNPs in the RNase L gene that were homozygously present in IBC cell lines. The 462 variant was absent in non-IBC lines. Our discovery of these SNPs present in IBC cell lines suggests a possible biomarker for risk of IBC. We found no evidence of HMTV in SUM149 cells. A query of a panel of human IBC and non-IBC samples showed no difference in RNase L expression. Further studies of the RNase L 462 and 541 variants in IBC tissues are warranted to validate our in vitro findings.

  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.

    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°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. A novel antibody discovery platform identifies anti-influenza A broadly neutralizing antibodies from human memory B cells.

    Science.gov (United States)

    Xiao, Xiaodong; Chen, Yan; Varkey, Reena; Kallewaard, Nicole; Koksal, Adem C; Zhu, Qing; Wu, Herren; Chowdhury, Partha S; Dall'Acqua, William F

    2016-07-01

    Monoclonal antibody isolation directly from circulating human B cells is a powerful tool to delineate humoral responses to pathological conditions and discover antibody therapeutics. We have developed a platform aimed at improving the efficiencies of B cell selection and V gene recovery. Here, memory B cells are activated and amplified using Epstein-Barr virus infection, co-cultured with CHO-muCD40L cells, and then assessed by functional screenings. An in vitro transcription and translation (IVTT) approach was used to analyze variable (V) genes recovered from each B cell sample and identify the relevant heavy/light chain pair(s). We achieved efficient amplification and activation of memory B cells, and eliminated the need to: 1) seed B cells at clonal level (≤1 cell/well) or perform limited dilution cloning; 2) immortalize B cells; or 3) assemble V genes into an IgG expression vector to confirm the relevant heavy/light chain pairing. Cross-reactive antibodies targeting a conserved epitope on influenza A hemagglutinin were successfully isolated from a healthy donor. In-depth analysis of the isolated antibodies suggested their potential uses as anti-influenza A antibody therapeutics and uncovered a distinct affinity maturation pathway. Importantly, our results showed that cognate heavy/light chain pairings contributed to both the expression level and binding abilities of our newly isolated VH1-69 family, influenza A neutralizing antibodies, contrasting with previous observations that light chains do not significantly contribute to the function of this group of antibodies. Our results further suggest the potential use of the IVTT as a powerful antibody developability assessment tool. PMID:27049174

  5. Discovery of a dual-targeting organometallic ruthenium complex with high activity inducing early stage apoptosis of cancer cells.

    Science.gov (United States)

    Du, Jun; Zhang, Erlong; Zhao, Yao; Zheng, Wei; Zhang, Yang; Lin, Yu; Wang, Zhaoying; Luo, Qun; Wu, Kui; Wang, Fuyi

    2015-12-01

    Ruthenium based complexes are promising antitumour candidates due to their lower toxicity and better water-solubility compared to the platinum antitumour complexes. An epidermal growth factor receptor (EGFR) has been found to be overexpressed in a large set of tumour cells. In this work, a series of organoruthenium complexes containing EGFR-inhibiting 4-anilinoquinazoline pharmacophores were synthesised and characterised. These complexes exhibited excellent inhibitory activity against EGFR and high affinity to interact with DNA via minor groove binding, featuring dual-targeting properties. In vitro screening demonstrated that the as-prepared ruthenium complexes are anti-proliferating towards a series of cancer cell lines, in particular the non-small-cell lung cancer cell line A549. Fluorescence-activated cell sorting analysis and fluorescence microscopy revealed that the most active complex 3 induced much more early-stage cell apoptosis than its cytotoxic arene ruthenium analogue and the EGFR-inhibiting 4-anilinoquinazolines, verifying the synergetic effect of the two mono-functional pharmacophores. PMID:26446567

  6. Quantitative proteomics of the Neisseria gonorrhoeae cell envelope and membrane vesicles for the discovery of potential therapeutic targets.

    Science.gov (United States)

    Zielke, Ryszard A; Wierzbicki, Igor H; Weber, Jacob V; Gafken, Philip R; Sikora, Aleksandra E

    2014-05-01

    Neisseria gonorrhoeae (GC) is a human-specific pathogen, and the agent of a sexually transmitted disease, gonorrhea. There is a critical need for new approaches to study and treat GC infections because of the growing threat of multidrug-resistant isolates and the lack of a vaccine. Despite the implied role of the GC cell envelope and membrane vesicles in colonization and infection of human tissues and cell lines, comprehensive studies have not been undertaken to elucidate their constituents. Accordingly, in pursuit of novel molecular therapeutic targets, we have applied isobaric tagging for absolute quantification coupled with liquid chromatography and mass spectrometry for proteome quantitative analyses. Mining the proteome of cell envelopes and native membrane vesicles revealed 533 and 168 common proteins, respectively, in analyzed GC strains FA1090, F62, MS11, and 1291. A total of 22 differentially abundant proteins were discovered including previously unknown proteins. Among those proteins that displayed similar abundance in four GC strains, 34 were found in both cell envelopes and membrane vesicles fractions. Focusing on one of them, a homolog of an outer membrane protein LptD, we demonstrated that its depletion caused loss of GC viability. In addition, we selected for initial characterization six predicted outer membrane proteins with unknown function, which were identified as ubiquitous in the cell envelopes derived from examined GC isolates. These studies entitled a construction of deletion mutants and analyses of their resistance to different chemical probes. Loss of NGO1985, in particular, resulted in dramatically decreased GC viability upon treatment with detergents, polymyxin B, and chloramphenicol, suggesting that this protein functions in the maintenance of the cell envelope permeability barrier. Together, these findings underscore the concept that the cell envelope and membrane vesicles contain crucial, yet under-explored determinants of GC

  7. PHASTpep: Analysis Software for Discovery of Cell-Selective Peptides via Phage Display and Next-Generation Sequencing

    Science.gov (United States)

    Dasa, Siva Sai Krishna; Kelly, Kimberly A.

    2016-01-01

    Next-generation sequencing has enhanced the phage display process, allowing for the quantification of millions of sequences resulting from the biopanning process. In response, many valuable analysis programs focused on specificity and finding targeted motifs or consensus sequences were developed. For targeted drug delivery and molecular imaging, it is also necessary to find peptides that are selective—targeting only the cell type or tissue of interest. We present a new analysis strategy and accompanying software, PHage Analysis for Selective Targeted PEPtides (PHASTpep), which identifies highly specific and selective peptides. Using this process, we discovered and validated, both in vitro and in vivo in mice, two sequences (HTTIPKV and APPIMSV) targeted to pancreatic cancer-associated fibroblasts that escaped identification using previously existing software. Our selectivity analysis makes it possible to discover peptides that target a specific cell type and avoid other cell types, enhancing clinical translatability by circumventing complications with systemic use. PMID:27186887

  8. 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

    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...... the LPMOs that are present in current commercial cellulase mixtures in part is due to hitherto undetected LPMO activities on recalcitrant hemicellulose structures....

  9. 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; Kildgaard, Sara; Frisvad, Jens Christian; Gotfredsen, Charlotte Held; Seiffert, Martina; Larsen, Thomas Ostenfeld

    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-cul...

  10. High-content live cell imaging with RNA probes: advancements in high-throughput antimalarial drug discovery

    Science.gov (United States)

    Cervantes, Serena; Prudhomme, Jacques; Carter, David; Gopi, Krishna G; Li, Qian; Chang, Young-Tae; Le Roch, Karine G

    2009-01-01

    Background Malaria, a major public health issue in developing nations, is responsible for more than one million deaths a year. The most lethal species, Plasmodium falciparum, causes up to 90% of fatalities. Drug resistant strains to common therapies have emerged worldwide and recent artemisinin-based combination therapy failures hasten the need for new antimalarial drugs. Discovering novel compounds to be used as antimalarials is expedited by the use of a high-throughput screen (HTS) to detect parasite growth and proliferation. Fluorescent dyes that bind to DNA have replaced expensive traditional radioisotope incorporation for HTS growth assays, but do not give additional information regarding the parasite stage affected by the drug and a better indication of the drug's mode of action. Live cell imaging with RNA dyes, which correlates with cell growth and proliferation, has been limited by the availability of successful commercial dyes. Results After screening a library of newly synthesized stryrl dyes, we discovered three RNA binding dyes that provide morphological details of live parasites. Utilizing an inverted confocal imaging platform, live cell imaging of parasites increases parasite detection, improves the spatial and temporal resolution of the parasite under drug treatments, and can resolve morphological changes in individual cells. Conclusion This simple one-step technique is suitable for automation in a microplate format for novel antimalarial compound HTS. We have developed a new P. falciparum RNA high-content imaging growth inhibition assay that is robust with time and energy efficiency. PMID:19515257

  11. Application of Cell-Based Assay Systems for the Early Screening of Human Drug Hepatotoxicity in the Discovery Phase of Drug Development

    Directory of Open Access Journals (Sweden)

    Jalal Pourahmad

    2005-01-01

    Full Text Available While drug toxicity (especially hepatotoxicity is the most frequent reason cited for withdrawal of an approved drug, no simple solution exists to adequately predict such adverse events. Simple cytotoxicity assays in HepG2 cells are relatively insensitive to human hepatotoxic drugs in a retrospective analysis of marketed pharmaceuticals. In comparison, a panel of pre-lethal mechanistic cellular assays hold the promise to deliver a more sensitiveapproach to detect endpoint-specific drug toxicities. The panel of assays covered by this review includes steatosis, cholestasis, phospholipidosis, reactive intermediates, mitochondria membrane function, oxidative stress, and drug interactions. In addition, the use of metabolically competent cells or the introduction of major human hepatocytes in these in-vitro studies allow a more complete picture of potential drug side effect. Since inter-individual therapeutic index (TI may differ from patient to patient, the rational use of one or more of these cellular assay and targeted in-vivo exposure data may allow pharmaceutical scientists to select drugcandidates with a higher TI potential in the drug discovery phase.

  12. Nod2-Nodosome in a Cell-Free System: Implications in Pathogenesis and Drug Discovery for Blau Syndrome and Early-Onset Sarcoidosis

    Directory of Open Access Journals (Sweden)

    Tomoyuki Iwasaki

    2016-01-01

    Full Text Available Nucleotide-binding oligomerization domain-containing protein (Nod 2 is an intracellular pattern recognition receptor, which recognizes muramyl dipeptide (N-Acetylmuramyl-L-Alanyl-D-Isoglutamine: MDP, a bacterial peptidoglycan component, and makes a NF-κB-activating complex called nodosome with adaptor protein RICK (RIP2/RIPK2. Nod2 mutants are associated with the autoinflammatory diseases, Blau syndrome (BS/early-onset sarcoidosis (EOS. For drug discovery of BS/EOS, we tried to develop Nod2-nodosome in a cell-free system. FLAG-tagged RICK, biotinylated-Nod2, and BS/EOS-associated Nod2 mutants were synthesized, and proximity signals between FLAG-tagged and biotinylated proteins were detected by amplified luminescent proximity homogeneous assay (ALPHA. Upon incubation with MDP, the ALPHA signal of interaction between Nod2-WT and RICK was increased in a dose-dependent manner. The ALPHA signal of interaction between RICK and the BS/EOS-associated Nod2 mutants was more significantly increased than Nod2-WT. Notably, the ALPHA signal between Nod2-WT and RICK was increased upon incubation with MDP, but not when incubated with the same concentrations, L-alanine, D-isoglutamic acid, or the MDP-D-isoform. Thus, we successfully developed Nod2-nodosome in a cell-free system reflecting its function in vivo, and it can be useful for screening Nod2-nodosome-targeted therapeutic molecules for BS/EOS and granulomatous inflammatory diseases.

  13. 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

  14. Discovery and optimization of new benzofuran derivatives against p53-independent malignant cancer cells through inhibition of HIF-1 pathway.

    Science.gov (United States)

    Yang, Ying-Rui; Wei, Jin-Lian; Mo, Xiao-Fei; Yuan, Zhen-Wei; Wang, Jia-Lin; Zhang, Chao; Xie, Yi-Yue; You, Qi-Dong; Sun, Hao-Peng

    2016-06-01

    p53-independent malignant cancer is still severe health problem of human beings. HIF-1 pathway is believed to play an important role in the survival and developing progress of such cancers. In the present study, with the aim to inhibit the proliferation of p53-independent malignant cells, we disclose the optimization of 6a, the starting compound which is discovered in the screening of in-house compound collection. The structure-activity relationship (SAR) is summarized. The most potent derivative 8d, inhibits the proliferation of both p53-null and p53-mutated cells through inhibition of HIF-1 pathway. Our findings here provide a new chemotype in designing potent anticancer agent especially against those p53-independent malignant tumors. PMID:27101893

  15. 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. PMID:25128456

  16. Motif discovery in promoters of genes co-localized and co-expressed during myeloid cells differentiation

    OpenAIRE

    Coppe, Alessandro; Ferrari, Francesco; Bisognin, Andrea; Danieli, Gian Antonio; Ferrari, Sergio; Bicciato, Silvio; Bortoluzzi, Stefania

    2008-01-01

    Genes co-expressed may be under similar promoter-based and/or position-based regulation. Although data on expression, position and function of human genes are available, their true integration still represents a challenge for computational biology, hampering the identification of regulatory mechanisms. We carried out an integrative analysis of genomic position, functional annotation and promoters of genes expressed in myeloid cells. Promoter analysis was conducted by a novel multi-step method...

  17. Human Biomarker Discovery and Predictive Models for Disease Progression for Idiopathic Pneumonia Syndrome Following Allogeneic Stem Cell Transplantation*

    OpenAIRE

    Schlatzer, Daniela M.; Dazard, Jean-Eudes; Ewing, Rob M.; Ilchenko, Serguei; Tomcheko, Sara E.; Eid, Saada; Ho, Vincent; Yanik, Greg; Chance, Mark R.; Cooke, Kenneth R.

    2012-01-01

    Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative therapy for many malignant and nonmalignant conditions. Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication that limits successful outcomes. Preclinical models suggest that IPS represents an immune mediated attack on the lung involving elements of both the adaptive and the innate immune system. However, the etiology of IPS in humans is less well understood. To explore the disease pathway and uncov...

  18. 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.

  19. Histological observation of germ cell development and discovery of spermatophores in ovoviviparous black rockfish ( Sebastes schlegeli Hilgendorf) in reproductive season

    Science.gov (United States)

    Feng, Junrong; Liu, Liming; Jiang, Haibin; Wang, Maojian; Du, Rongbin

    2014-10-01

    Black rockfish ( Sebastes schlegeli) is an important species for culture; however, its reproductive characteristics have not been fully documented. In this study, we investigated the morphology and developmental process of germ cells in this ovoviviparous rockfish in reproductive season (October 2011-November 2012) with histological methods. We found that the gonad of mature fish showed notable seasonal changes in developmental characteristics and morphological structure. The sperm cells matured during a period lasting from October to December, significantly earlier than the oocytes did. A large number of spermatozoa and other cells occurred in testis at different developmental stages. Vitellogenesis in oocytes began in October, and gestation appeared in April next year. Spermatophores were discovered for the first time in Sebastes, which assembled in testis, main sperm duct, oviduct and genital tract, as well as ovarian cavity in October and April. These organs may serve either as production or hiding places for spermatophores and spermatozoa which were stored and transported in form of spermatophores. Testicular degeneration started from the distal part of testis in April, with spermatophores assembled in degenerating testis and waiting for transportation. The copulation probably lasted for a long period, during which the spermatozoa were discharged in batches as spermatophores. These spermatophores were coated with sticky materials secreted from the interstitial areas of testis and the main sperm duct, then transported into ovary.

  20. 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.

  1. Discovery of new selective cytotoxic agents against Bcl-2 expressing cancer cells using ligand-based modeling.

    Science.gov (United States)

    Aboalhaija, Nour H; Zihlif, Malek A; Taha, Mutasem O

    2016-04-25

    Bcl-2 is an anti-apoptotic protein involved in cancer resistance to cytotoxic therapies making it an interesting target for inhibitors design. Towards this end, we implemented an elaborated ligand-based computational workflow that combines exhaustive pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis to explore the structural features required for potent Bcl-2 inhibitors employing 98 known Bcl-2 inhibitors. Genetic function algorithm (GFA) coupled with k nearest neighbor (kNN) or multiple linear regression (MLR) analyses were employed to generate predictive QSAR models based on optimal combinations of pharmacophores and physicochemical descriptors. The optimal QSAR-selected pharmacophore models were validated by receiver operating characteristic (ROC) curve analysis and by comparison with crystallographic structures of known inhibitors co-crystallized within Bcl-2 binding pocket. Optimal QSAR models and their associated pharmacophore hypotheses were validated by identification and experimental evaluation of new selective cytotoxic compounds against Bcl-2 expressing cancer cells. The hits were retrieved from the National Cancer Institute (NCI) structural database. Several potent hits were captured. The most potent hits illustrated IC50 values of 4.2 and 2.60 μM against MDA-MB-231 cancer cell-line. PMID:26954606

  2. The Discovery and Validation of Biomarkers for the Diagnosis of Esophageal Squamous Dysplasia and Squamous Cell Carcinoma.

    Science.gov (United States)

    Couch, George; Redman, James E; Wernisch, Lorenz; Newton, Richard; Malhotra, Shalini; Dawsey, Sanford M; Lao-Sirieix, Pierre; Fitzgerald, Rebecca C

    2016-07-01

    The 5-year survival rate of esophageal cancer is less than 10% in developing countries, where more than 90% of these cancers are esophageal squamous cell carcinomas (ESCC). Endoscopic screening is undertaken in high incidence areas. Biomarker analysis could reduce the subjectivity associated with histologic assessment of dysplasia and thus improve diagnostic accuracy. The aims of this study were therefore to identify biomarkers for esophageal squamous dysplasia and carcinoma. A publicly available dataset was used to identify genes with differential expression in ESCC compared with normal esophagus. Each gene was ranked by a support vector machine separation score. Expression profiles were examined, before validation by qPCR and IHC. We found that 800 genes were overexpressed in ESCC compared with normal esophagus (P < 10(-5)). Of the top 50 genes, 33 were expressed in ESCC epithelium and not in normal esophagus epithelium or stroma using the Protein Atlas website. These were taken to qPCR validation, and 20 genes were significantly overexpressed in ESCC compared with normal esophagus (P < 0.05). TNFAIP3 and CHN1 showed differential expression with IHC. TNFAIP3 expression increased gradually through normal esophagus, mild, moderate and severe dysplasia, and SCC (P < 0.0001). CHN1 staining was rarely present in the top third of normal esophagus epithelium and extended progressively towards the surface in mild, moderate, and severe dysplasia, and SCC (P < 0.0001). Two novel promising biomarkers for ESCC were identified, TNFAIP3 and CHN1. CHN1 and TNFAIP3 may improve diagnostic accuracy of screening methods for ESCC. Cancer Prev Res; 9(7); 558-66. ©2016 AACR. PMID:27072986

  3. Computational drug discovery

    Institute of Scientific and Technical Information of China (English)

    Si-sheng OU-YANG; Jun-yan LU; Xiang-qian KONG; Zhong-jie LIANG; Cheng LUO; Hualiang JIANG

    2012-01-01

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

  4. Reliable knowledge discovery

    CERN Document Server

    Dai, Honghua; Smirnov, Evgueni

    2012-01-01

    Reliable Knowledge Discovery focuses on theory, methods, and techniques for RKDD, a new sub-field of KDD. It studies the theory and methods to assure the reliability and trustworthiness of discovered knowledge and to maintain the stability and consistency of knowledge discovery processes. RKDD has a broad spectrum of applications, especially in critical domains like medicine, finance, and military. Reliable Knowledge Discovery also presents methods and techniques for designing robust knowledge-discovery processes. Approaches to assessing the reliability of the discovered knowledge are introduc

  5. Evaluation of reverse phase protein array (RPPA)-based pathway-activation profiling in 84 non-small cell lung cancer (NSCLC) cell lines as platform for cancer proteomics and biomarker discovery.

    Science.gov (United States)

    Ummanni, Ramesh; Mannsperger, Heiko A; Sonntag, Johanna; Oswald, Marcus; Sharma, Ashwini K; König, Rainer; Korf, Ulrike

    2014-05-01

    The reverse phase protein array (RPPA) approach was employed for a quantitative analysis of 71 cancer-relevant proteins and phosphoproteins in 84 non-small cell lung cancer (NSCLC) cell lines and by monitoring the activation state of selected receptor tyrosine kinases, PI3K/AKT and MEK/ERK1/2 signaling, cell cycle control, apoptosis, and DNA damage. Additional information on NSCLC cell lines such as that of transcriptomic data, genomic aberrations, and drug sensitivity was analyzed in the context of proteomic data using supervised and non-supervised approaches for data analysis. First, the unsupervised analysis of proteomic data indicated that proteins clustering closely together reflect well-known signaling modules, e.g. PI3K/AKT- and RAS/RAF/ERK-signaling, cell cycle regulation, and apoptosis. However, mutations of EGFR, ERBB2, RAF, RAS, TP53, and PI3K were found dispersed across different signaling pathway clusters. Merely cell lines with an amplification of EGFR and/or ERBB2 clustered closely together on the proteomic, but not on the transcriptomic level. Secondly, supervised data analysis revealed that sensitivity towards anti-EGFR drugs generally correlated better with high level EGFR phosphorylation than with EGFR abundance itself. High level phosphorylation of RB and high abundance of AURKA were identified as candidates that can potentially predict sensitivity towards the aurora kinase inhibitor VX680. Examples shown demonstrate that the RPPA approach presents a useful platform for targeted proteomics with high potential for biomarker discovery. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. PMID:24361481

  6. Decades of Discovery

    Science.gov (United States)

    2011-06-01

    For the past two-and-a-half decades, the Office of Science at the U.S. Department of Energy has been at the forefront of scientific discovery. Over 100 important discoveries supported by the Office of Science are represented in this document.

  7. 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...

  8. Higgs Discovery Movie

    CERN Multimedia

    2014-01-01

    The ATLAS & CMS Experiments Celebrate the 2nd Anniversary of the Discovery of the Higgs boson. Here, are some images of the path from LHC startup to Nobel Prize, featuring a musical composition by Roger Zare, performed by the Donald Sinta Quartet, called “LHC”. Happy Discovery Day!

  9. "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…

  10. Worldwide Discoveries Help People Everywhere

    Science.gov (United States)

    ... Home Current Issue Past Issues Special Section Worldwide Discoveries Help People Everywhere Past Issues / Spring 2008 Table ... shows examples of discoveries and their impact. Diseases Discoveries The Benefits for All Americans Huntington's Disease Venezuela— ...

  11. Drug discovery in ovarian cancer.

    Science.gov (United States)

    Chase, Dana M; Mathur, Nidhee; Tewari, Krishnansu S

    2010-11-01

    Drug discovery in the ovarian cancer arena has led to the activation of several important clinical trials. Many biologic agents have come down the pipeline and are being studied in phase II trials for recurrent disease. These agents include antivascular compounds that disrupt angiogenesis through a variety of mechanisms (e.g., prevention of ligand-binding to the vascular endothelial growth factor receptor-2 (VEGF-R2), high-affinity VEGF blockade, oral inhibitors of tyrosine kinases stimulated by VEGF, inhibition of alpha5beta1 integrin, neutralization of angioproteins, etc.). Other novel drugs include oral platinum compounds as well as those that antagonize the tumor proliferation genes in the Hedgehog pathway, and that target folic acid receptors which are expressed by ovarian cancer cells. In addition, studies are underway with oral agents that inhibit the tyrosine kinase activity associated with two oncogenes (epidermal growth factor receptor (EGFR) and HER-2/neu). Finally, emerging technologies in clinical trials include nanotechnology to enhance delivery of chemotherapy to ovarian tumors, drug resistance/sensitivity assays to guide therapy, and agents that mobilize and induce proliferation of hematopoetic progenitor cells to aid in red blood cell, white blood cell, and platelet recovery following chemotherapy. The relevant patents in drug discovery of ovarian cancer are discussed. PMID:20524931

  12. 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.

  13. Toxins and drug discovery.

    Science.gov (United States)

    Harvey, Alan L

    2014-12-15

    Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine. Drug discovery and development is an inherently risky business, and the main causes of failure during development programmes are outlined in order to highlight steps that might be taken to increase the chances of success with toxin-based drug discovery. These include having a clear focus on unmet therapeutic needs, concentrating on targets that are well-validated in terms of their relevance to the disease in question, making use of phenotypic screening rather than molecular-based assays, and working with development partners with the resources required for the long and expensive development process. PMID:25448391

  14. Leadership and Discovery

    CERN Document Server

    Goethals, George R

    2009-01-01

    This book, a collection of essays from scholars across disciplines, explores leadership of discovery, probing the guided and collaborative exploration and interpretation of the experience of our inner thoughts and feelings, and of our external worlds

  15. 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)

  16. Discovery Driven Growth

    DEFF Research Database (Denmark)

    Bukh, Per Nikolaj

    2009-01-01

    Anmeldelse af Discovery Driven Growh : A breakthrough process to reduce risk and seize opportunity, af Rita G. McGrath & Ian C. MacMillan, Boston: Harvard Business Press. Udgivelsesdato: 14 august......Anmeldelse af Discovery Driven Growh : A breakthrough process to reduce risk and seize opportunity, af Rita G. McGrath & Ian C. MacMillan, Boston: Harvard Business Press. Udgivelsesdato: 14 august...

  17. Higgs Discovery before LHC?

    OpenAIRE

    Chiarelli, Giorgio; Collaboration, for the CDF; The D0 Collaboration

    2001-01-01

    The proposed Run IIb of the Tevatron Collider will provide 15 fb-1 worth of ppbar data at c.o.m energy of 2 TeV per experiment by year 2007. We review the plans of the Tevatron accelerator complex upgrade and the plans for the upgrades of the experiments to match this challenge. Perspectives for the discovery of an Higgs particle are reviewed and the concrete possibility of a 5 sigmas discovery for a low mass Higgs are discussed.

  18. A Decade of Discovery

    Energy Technology Data Exchange (ETDEWEB)

    None

    2008-01-01

    This book provides a fascinating account of some of the most significant scientific discoveries and technological innovations coming out of the U.S. Department of Energy’s National Laboratories. This remarkable book illustrates how the men and women of the National Laboratories are keeping us on the cutting edge. Though few Americans are familiar with the scope and scale of the work conducted at these National Laboratories, their research is literally changing our lives and bettering our planet. The book describes the scientific discoveries and technological advancements "in recognition of the men and women working in DOE's seventeen national laboratories across the country." Through highly vivid and accessible stories, this book details recent breakthroughs in three critical areas: 1) Energy and Environment, 2) National Security and 3) Life and Physical Science. The book illustrates how this government-funded research has resulted in more energy-efficient buildings; new, cleaner alternative fuels that reduce greenhouse gas emissions; safer, more efficient, nuclear power plants; improved responses to disease outbreaks; more secure and streamlined airport security; more effective treatments for cancer and other diseases; and astonishing discoveries that are altering our understanding of the universe and enabling scientific breakthroughs in fields such as nanotechnology and particle physics. Specifically, it contains 37 stories. A Decade of Discovery is truly a recent history of discovery - and a fascinating look at what the next decade holds.

  19. Evaluating ten discoveries

    Energy Technology Data Exchange (ETDEWEB)

    1973-02-01

    Mexico's state company, Pemex, announces 10 significant oil and gas discoveries in the states of Tamaulipas and Chiapas. Most promising finds are a new oil province in S. Mexico and a deeper pool strike at the offshore Arenque field. The latter seems to point to the existence of an attractive reefal trend extending on shore toward the State of Nuevo Leon.

  20. Systematic Analysis of Cell Cycle Effects of Common Drugs Leads to the Discovery of a Suppressive Interaction between Gemfibrozil and Fluoxetine

    OpenAIRE

    Hoose, Scott A.; Duran, Camille; Malik, Indranil; Eslamfam, Shabnam; Samantha C Shasserre; Downing, S. Sabina; Evelyn M Hoover; Dowd, Katherine E.; Smith, Roger; Polymenis, Michael

    2012-01-01

    Screening chemical libraries to identify compounds that affect overall cell proliferation is common. However, in most cases, it is not known whether the compounds tested alter the timing of particular cell cycle transitions. Here, we evaluated an FDA-approved drug library to identify pharmaceuticals that alter cell cycle progression in yeast, using DNA content measurements by flow cytometry. This approach revealed strong cell cycle effects of several commonly used pharmaceuticals. We show tha...

  1. 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.

  2. COPD Discovery Might Improve Treatment

    Science.gov (United States)

    ... nlm.nih.gov/medlineplus/news/fullstory_158852.html COPD Discovery Might Improve Treatment Study may help pinpoint ... will progress, a discovery they believe could improve COPD treatment. Their research might help doctors determine which ...

  3. COPD Discovery Might Improve Treatment

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_158852.html COPD Discovery Might Improve Treatment Study may help pinpoint ... will progress, a discovery they believe could improve COPD treatment. Their research might help doctors determine which ...

  4. Creating A Guided- discovery Lesson

    Institute of Scientific and Technical Information of China (English)

    田枫

    2005-01-01

    In a guided - discovery lesson, students sequentially uncover layers of mathematical information one step at a time and learn new mathematics. We have identified eight critical steps necessary in developing a successful guided- discovery lesson.

  5. Discovery with FAST

    Science.gov (United States)

    Wilkinson, P.

    2016-02-01

    FAST offers "transformational" performance well-suited to finding new phenomena - one of which might be polarised spectral transients. But discoveries will only be made if "the system" provides its users with the necessary opportunities. In addition to designing in as much observational flexibility as possible, FAST should be operated with a philosophy which maximises its "human bandwidth". This band includes the astronomers of tomorrow - many of whom not have yet started school or even been born.

  6. Fateful discovery almost forgotten

    International Nuclear Information System (INIS)

    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.)

  7. Opportunistic Adaptation Knowledge Discovery

    OpenAIRE

    Badra, Fadi; Cordier, Amélie; Lieber, Jean

    2009-01-01

    The original publication is available at www.springerlink.com International audience Adaptation has long been considered as the Achilles' heel of case-based reasoning since it requires some domain-specific knowledge that is difficult to acquire. In this paper, two strategies are combined in order to reduce the knowledge engineering cost induced by the adaptation knowledge (CA) acquisition task: CA is learned from the case base by the means of knowledge discovery techniques, and the CA a...

  8. 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.

  9. The von Hippel-Lindau Gene: Turning Discovery Into Therapy

    OpenAIRE

    Clark, Peter E.; Cookson, Michael S.

    2008-01-01

    Mutations or aberrations of the von Hippel-Lindau gene are responsible for the hereditary neoplastic syndrome that bears the same name, as well as for the majority of sporadic clear cell renal cell carcinomas. The discovery of this gene and subsequent clarification of its mechanism of action have led to a series of targeted treatments for advanced kidney cancer and have dramatically changed how we manage this disease. The discovery of the VHL gene is a prime example of how discoveries at the ...

  10. Systematic analysis of cell cycle effects of common drugs leads to the discovery of a suppressive interaction between gemfibrozil and fluoxetine.

    Directory of Open Access Journals (Sweden)

    Scott A Hoose

    Full Text Available Screening chemical libraries to identify compounds that affect overall cell proliferation is common. However, in most cases, it is not known whether the compounds tested alter the timing of particular cell cycle transitions. Here, we evaluated an FDA-approved drug library to identify pharmaceuticals that alter cell cycle progression in yeast, using DNA content measurements by flow cytometry. This approach revealed strong cell cycle effects of several commonly used pharmaceuticals. We show that the antilipemic gemfibrozil delays initiation of DNA replication, while cells treated with the antidepressant fluoxetine severely delay progression through mitosis. Based on their effects on cell cycle progression, we also examined cell proliferation in the presence of both compounds. We discovered a strong suppressive interaction between gemfibrozil and fluoxetine. Combinations of interest among diverse pharmaceuticals are difficult to identify, due to the daunting number of possible combinations that must be evaluated. The novel interaction between gemfibrozil and fluoxetine suggests that identifying and combining drugs that show cell cycle effects might streamline identification of drug combinations with a pronounced impact on cell proliferation.

  11. Marking 100 years since Rudolf Höber’s discovery of the insulating envelope surrounding cells and of the beta-dispersion exhibited by tissue

    Directory of Open Access Journals (Sweden)

    Ronald Pethig

    2012-11-01

    Full Text Available Between 1910 and 1913 Rudolf Höber presented proof that the interiors of red blood cells and muscle cells contain conducting electrolytes, and that each conducting core is contained within an insulating membrane.  He did this by demonstrating, in a series of remarkable electrical experiments, that the conductivity of compacted cell samples at low frequencies (~150 Hz was about ten-times less than the value obtained at ~5 MHz.  On perforation of the membrane, the low-frequency conductivity increased to a value approaching that exhibited at MHz frequencies. Apart from representing a major milestone in the development of cell biology and electrophysiology, Höber’s work was the first description of what we now call the dielectric b-dispersion exhibited by cell suspensions and fresh tissue.

  12. Gene expression profiling of coelomic cells and discovery of immune-related genes in the earthworm, Eisenia andrei, using expressed sequence tags.

    Science.gov (United States)

    Tak, Eun Sik; Cho, Sung-Jin; Park, Soon Cheol

    2015-01-01

    The coelomic cells of the earthworm consist of leukocytes, chlorogocytes, and coelomocytes, which play an important role in innate immunity reactions. To gain insight into the expression profiles of coelomic cells of the earthworm, Eisenia andrei, we analyzed 1151 expressed sequence tags (ESTs) derived from the cDNA library of the coelomic cells. Among the 1151 ESTs analyzed, 493 ESTs (42.8%) showed a significant similarity to known genes and represented 164 unique genes, of which 93 ESTs were singletons and 71 ESTs manifested as two or more ESTs. From the 164 unique genes sequenced, we found 24 immune-related and cell defense genes. Furthermore, real-time PCR analysis showed that levels of lysenin-related proteins mRNA in coelomic cells of E. andrei were upregulated after the injection of Bacillus subtilis bacteria. This EST data-set would provide a valuable resource for future researches of earthworm immune system. PMID:25496401

  13. Discovery of cell-permeable inhibitors that target the BRCT domain of BRCA1 protein by using a small-molecule microarray.

    Science.gov (United States)

    Na, Zhenkun; Pan, Sijun; Uttamchandani, Mahesh; Yao, Shao Q

    2014-08-01

    BRCTs are phosphoserine-binding domains found in proteins involved in DNA repair, DNA damage response and cell cycle regulation. BRCA1 is a BRCT domain-containing, tumor-suppressing protein expressed in the cells of breast and other human tissues. Mutations in BRCA1 have been found in ca. 50% of hereditary breast cancers. Cell-permeable, small-molecule BRCA1 inhibitors are promising anticancer agents, but are not available currently. Herein, with the assist of microarray-based platforms, we have discovered the first cell-permeable protein-protein interaction (PPI) inhibitors against BRCA1. By targeting the (BRCT)2 domain, we showed compound 15 a and its prodrug 15 b inhibited BRCA1 activities in tumor cells, sensitized these cells to ionizing radiation-induced apoptosis, and showed synergistic inhibitory effect when used in combination with Olaparib (a small-molecule inhibitor of poly-ADP-ribose polymerase) and Etoposide (a small-molecule inhibitor of topoisomerase II). Unlike previously reported peptide-based PPI inhibitors of BRCA1, our compounds are small-molecule-like and could be directly administered to tumor cells, thus making them useful for future studies of BRCA1/PARP-related pathways in DNA damage and repair response, and in cancer therapy. PMID:24961672

  14. Interpretation of a discovery

    OpenAIRE

    Vučković Vladan

    2006-01-01

    The paper presents the development of the theory of asynchronous motors since Tesla’s discovery until the present day. The theory of steady state, as we know it today, was completed already during the first dozen of years. That was followed by a period of stagnation during a number of decades, when the theory of asynchronous motors was developed only in the framework of the general theory of electric machines, which was stimulated by the problems of the development of synchronous generators a...

  15. 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.

  16. 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. PMID:26739136

  17. 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

  18. Identification of a novel site specific endonuclease produced by Mycoplasma fermentans: discovery while characterizing DNA binding proteins in T lymphocyte cell lines.

    OpenAIRE

    Halden, N F; Wolf, J B; Leonard, W J

    1989-01-01

    We have discovered a new restriction endonuclease, MfeI, in nuclear extracts from T cells contaminated with Mycoplasma fermentans. This endonuclease was identified while studying proteins binding to the interleukin-2 receptor alpha chain gene promoter. MfeI cuts at the recognition sequence C'AATTG generating EcoRI compatible cohesive ends. Potential applications are discussed.

  19. Denton Vacuum Discovery-550 Sputterer

    Data.gov (United States)

    Federal Laboratory Consortium — Description: CORAL Name: Sputter 2 Similar to the existing 4-Gun Denton Discovery 22 Sputter system, with the following enhancements: Specifications / Capabilities:...

  20. In Vitro Assessment of the Inflammatory Breast Cancer Cell Line SUM 149: Discovery of 2 Single Nucleotide Polymorphisms in the RNase L Gene

    OpenAIRE

    Nokes, Brandon T.; Cunliffe, Heather E; LaFleur, Bonnie; Mount, David W.; Livingston, Robert B.; Bernard W Futscher; Lang, Julie E.

    2013-01-01

    Background: Inflammatory breast cancer (IBC) is a rare, highly aggressive form of breast cancer. The mechanism of IBC carcinogenesis remains unknown. We sought to evaluate potential genetic risk factors for IBC and whether or not the IBC cell lines SUM149 and SUM190 demonstrated evidence of viral infection. Methods: We performed single nucleotide polymorphism (SNP) genotyping for 2 variants of the ribonuclease (RNase) L gene that have been correlated with the risk of prostate cancer due to a ...

  1. In Vitro Assessment of the Inflammatory Breast Cancer Cell Line SUM 149: Discovery of 2 Single Nucleotide Polymorphisms in the RNase L Gene

    OpenAIRE

    Brandon T. Nokes, Heather E. Cunliffe, Bonnie LaFleur, David W. Mount, Robert B. Livingston, Bernard W. Futscher, Julie E. Lang

    2013-01-01

    Background: Inflammatory breast cancer (IBC) is a rare, highly aggressive form of breast cancer. The mechanism of IBC carcinogenesis remains unknown. We sought to evaluate potential genetic risk factors for IBC and whether or not the IBC cell lines SUM149 and SUM190 demonstrated evidence of viral infection.Methods: We performed single nucleotide polymorphism (SNP) genotyping for 2 variants of the ribonuclease (RNase) L gene that have been correlated with the risk of prostate cancer due to a p...

  2. 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)

    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)

  3. 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.

  4. Burkitt Lymphoma: beyond discoveries.

    Science.gov (United States)

    Mbulaiteye, Sam M

    2013-01-01

    First described in 1958 in Uganda, Burkitt lymphoma (BL) attracted interest worldwide following reports of its uneven geographic distribution and rapidly fatal clinical course. Both suggested infectious etiology and curability. Seminal discoveries followed in quick succession. Viral etiology - due to Epstein-Barr virus (EBV) - was confirmed. Chromosomal translocations, involving cellular MYC, a protooncogene, were discovered, shown to be a hallmark of BL, and central to the genetic basis of cancer. Cure of BL using combination chemotherapy was demonstrated. Unfortunately, civil disturbance in Africa disrupted BL research and blunted its impact on education and oncology care in Africa. Important questions went unanswered. The risk of BL due to malaria or EBV was not quantified. Efforts to answer whether BL could be prevented - by preventing malaria or early EBV infection - were abandoned. The mechanism of malaria in BL is unknown. In Africa, BL remains mostly fatal and diagnosis is still made clinically. Unprecedented advances in molecular, genomics and proteomic technologies, promising to unlock mysteries of cancers, have re-awakened interest in BL. With return of stability to Africa, the unanswered questions about BL are re-attracting global interest. This interest now includes exploiting the knowledge gained about genetics, proteomics, and bioinformatics to enable the development of targeted less toxic treatment for BL; and simpler methods to diagnose BL with high accuracy and sensitivity. The articles in the Burkitt Lymphoma (BL): Beyond Discoveries in Infectious Agents and Cancer highlight BL as priority. Authors explore etiology, pathology, pathogenesis of BL, and whether knowledge gained in the studies of BL can catalyze sustainable cancer services in one of the world's poorest served regions. PMID:24079372

  5. Discoveries of isotopes by fission

    Indian Academy of Sciences (India)

    M Thoennessen

    2015-09-01

    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.

  6. Service discovery using Bloom filters

    NARCIS (Netherlands)

    Goering, Patrick; Heijenk, Geert; Lelieveldt, B.P.F.; Haverkort, B.R.H.M.; Laat, de C.T.A.M.; Heijnsdijk, J.W.J.

    2006-01-01

    A protocol to perform service discovery in adhoc networks is introduced in this paper. Attenuated Bloom filters are used to distribute services to nodes in the neighborhood and thus enable local service discovery. The protocol has been implemented in a discrete event simulator to investigate the beh

  7. 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

  8. 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.

  9. Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Jingsong; Campobasso, Nino; Biju, Mangatt P.; Fisher, Kelly; Pan, Xiao-Qing; Cottom, Josh; Galbraith, Sarah; Ho, Thau; Zhang, Hong; Hong, Xuan; Ward, Paris; Hofmann, Glenn; Siegfried, Brett; Zappacosta, Francesca; Washio, Yoshiaki; Cao, Ping; Qu, Junya; Bertrand, Sophie; Wang, Da-Yuan; Head, Martha S.; Li, Hu; Moores, Sheri; Lai, Zhihong; Johanson, Kyung; Burton, George; Erickson-Miller, Connie; Simpson, Graham; Tummino, Peter; Copeland, Robert A.; Oliff, Allen (GSKPA)

    2014-10-02

    c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the {alpha}I helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the {alpha}I helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.

  10. Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial

    Science.gov (United States)

    Saxena, Deepti; Spino, Michael; Tricta, Fernando; Connelly, John; Cracchiolo, Bernadette M.; Hanauske, Axel-Rainer; D’Alliessi Gandolfi, Darlene; Mathews, Michael B.; Karn, Jonathan; Holland, Bart; Park, Myung Hee; Pe’ery, Tsafi; Palumbo, Paul E.; Hanauske-Abel, Hartmut M.

    2016-01-01

    Antiretrovirals suppress HIV-1 production yet spare the sites of HIV-1 production, the HIV-1 DNA-harboring cells that evade immune detection and enable viral resistance on-drug and viral rebound off-drug. Therapeutic ablation of pathogenic cells markedly improves the outcome of many diseases. We extend this strategy to HIV-1 infection. Using drug-based lead discovery, we report the concentration threshold-dependent antiretroviral action of the medicinal chelator deferiprone and validate preclinical findings by a proof-of-concept double-blind trial. In isolate-infected primary cultures, supra-threshold concentrations during deferiprone monotherapy caused decline of HIV-1 RNA and HIV-1 DNA; did not allow viral breakthrough for up to 35 days on-drug, indicating resiliency against viral resistance; and prevented, for at least 87 days off-drug, viral rebound. Displaying a steep dose-effect curve, deferiprone produced infection-independent deficiency of hydroxylated hypusyl-eIF5A. However, unhydroxylated deoxyhypusyl-eIF5A accumulated particularly in HIV-infected cells; they preferentially underwent apoptotic DNA fragmentation. Since the threshold, ascertained at about 150 μM, is achievable in deferiprone-treated patients, we proceeded from cell culture directly to an exploratory trial. HIV-1 RNA was measured after 7 days on-drug and after 28 and 56 days off-drug. Subjects who attained supra-threshold concentrations in serum and completed the protocol of 17 oral doses, experienced a zidovudine-like decline of HIV-1 RNA on-drug that was maintained off-drug without statistically significant rebound for 8 weeks, over 670 times the drug’s half-life and thus clearance from circulation. The uniform deferiprone threshold is in agreement with mapping of, and crystallographic 3D-data on, the active site of deoxyhypusyl hydroxylase (DOHH), the eIF5A-hydroxylating enzyme. We propose that deficiency of hypusine-containing eIF5A impedes the translation of mRNAs encoding proline

  11. Discovery and Formulation

    Science.gov (United States)

    Clark, Don; Rodger, Caroline

    The uses of Raman spectroscopy in active pharmaceutical ingredient (API) discovery, development and release cover a wide variety of sample types and applications. However, the technique does not have a high prominence in the pharmaceutical industry despite being recognised by regulatory authorities as a suitable methodology for the analysis and release of pharmaceutical API and products. One reason is that other analytical techniques are well established and changing to Raman methods is cost prohibitive considering return on investments (ROI). In addition the technique is often regarded as being one for "experts" and not one for main stream applications. As a consequence Raman spectroscopy is frequently the 2nd or 3rd technique of choice for a specific application. However, due to its unique sampling attributes (e.g. micro and macro measurements direct from the sample, through glass, from well plates or in the presence of water) and selectivity, applications of this technology are found throughout the life cycles of pharmaceutical products. It can therefore be considered to be a spectroscopic common denominator. This chapter highlights a number of routine, specialised and niche Raman spectroscopy applications which have been used in the development of new medicines while detailing some of the limitations of these approaches.

  12. Discovery of neptunium

    International Nuclear Information System (INIS)

    This paper reports that a number of distinguished scientist, all knowledgeable about the periodic table, irradiated uranium with neutrons during 1934-1938. They observed a number of beta-emitting activities that seemed to be from transuranium elements. discovery of fission and of neptunium was delayed because they assumed that elements 93 and 94 would have chemical properties similar to those of rhenium and osmium, respectively. After fission was finally demonstrated, as new search for element 93 was initiated by McMillan, who showed that when thin films of uranium are exposed to neutrons, high-energy fission products leave the film; 23-min and 2.3-day activities remain. The 23-min activity was known to be an isotope of uranium. In May 1940 Abelson produced conclusive evidence that the 2.3 day activity was from the transuranium element 93. In a reduce state, element 93 coprecipitates with rare earth fluorides. In an oxidized state, the fluoride no longer coprecipitates. Behavior of element 93 was found to resemble that of uranium

  13. 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...

  14. Knowledge Discovery in Spatial Data

    CERN Document Server

    Leung, Yee

    2009-01-01

    This book deals with knowledge discovery and data mining in spatial and temporal data, seeking to present novel methods that can be employed to discover spatial structures and processes in complex data. Spatial knowledge discovery is examined through the tasks of clustering, classification, association/relationship, and process. Among the covered topics are discovery of spatial structures as natural clusters, identification of separation surfaces and extraction of classification rules from statistical and algorithmic perspectives, detecting local and global aspects of non-stationarity of spati

  15. 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. PMID:27491648

  16. INTELLIGENT TECHNOLOGIES FOR KNOWLEDGE DISCOVERY

    Directory of Open Access Journals (Sweden)

    ADRIAN COJOCARIU

    2012-11-01

    Full Text Available Knowledge, as intellectual capital, has become the main resource of anorganization, and the process of knowledge discovery, acquisition and storage is a very important one. Knowledge discovery can be easily realized through Data Mining, a Machine Learning technique, which allows the discovery of useful knowledge from a large amount of data, this knowledge supporting the decision process. A proper knowledge management of the discovered knowledge is able to improve the organization’s results and will lead to increasing the intellectualcapital, the result being a more efficient management.

  17. Cyberinfrastructure for Atmospheric Discovery

    Science.gov (United States)

    Wilhelmson, R.; Moore, C. W.

    2004-12-01

    Each year across the United States, floods, tornadoes, hail, strong winds, lightning, hurricanes, and winter storms cause hundreds of deaths, routinely disrupt transportation and commerce, and result in billions of dollars in annual economic losses . MEAD and LEAD are two recent efforts aimed at developing the cyberinfrastructure for studying and forecasting these events through collection, integration, and analysis of observational data coupled with numerical simulation, data mining, and visualization. MEAD (Modeling Environment for Atmospheric Discovery) has been funded for two years as an NCSA (National Center for Supercomputing Applications) Alliance Expedition. The goal of this expedition has been the development/adaptation of cyberinfrastructure that will enable research simulations, datamining, machine learning and visualization of hurricanes and storms utilizing the high performance computing environments including the TeraGrid. Portal grid and web infrastructure are being tested that will enable launching of hundreds of individual WRF (Weather Research and Forecasting) simulations. In a similar way, multiple Regional Ocean Modeling System (ROMS) or WRF/ROMS simulations can be carried out. Metadata and the resulting large volumes of data will then be made available for further study and for educational purposes using analysis, mining, and visualization services. Initial coupling of the ROMS and WRF codes has been completed and parallel I/O is being implemented for these models. Management of these activities (services) are being enabled through Grid workflow technologies (e.g. OGCE). LEAD (Linked Environments for Atmospheric Discovery) is a recently funded 5-year, large NSF ITR grant that involves 9 institutions who are developing a comprehensive national cyberinfrastructure in mesoscale meteorology, particularly one that can interoperate with others being developed. LEAD is addressing the fundamental information technology (IT) research challenges needed

  18. Serendipity: Accidental Discoveries in Science

    Science.gov (United States)

    Roberts, Royston M.

    1989-06-01

    Many of the things discovered by accident are important in our everyday lives: Teflon, Velcro, nylon, x-rays, penicillin, safety glass, sugar substitutes, and polyethylene and other plastics. And we owe a debt to accident for some of our deepest scientific knowledge, including Newton's theory of gravitation, the Big Bang theory of Creation, and the discovery of DNA. Even the Rosetta Stone, the Dead Sea Scrolls, and the ruins of Pompeii came to light through chance. This book tells the fascinating stories of these and other discoveries and reveals how the inquisitive human mind turns accident into discovery. Written for the layman, yet scientifically accurate, this illuminating collection of anecdotes portrays invention and discovery as quintessentially human acts, due in part to curiosity, perserverance, and luck.

  19. Discovery of the Mercury Isotopes

    CERN Document Server

    Meierfrankenfeld, D

    2009-01-01

    Forty mercury isotopes have so far been observed; the discovery of these isotopes is discussed. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.

  20. Taxonomy Enabled Discovery (TED) Project

    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...

  1. Discovery of the Einsteinium Isotopes

    OpenAIRE

    Bury, A.; Fritsch, A; Ginepro, J. Q.; Heim, M; Schuh, A.; Shore, A.; Thoennessen, M.

    2009-01-01

    Seventeen einsteinium isotopes have so far been observed; the discovery of these isotopes is discussed. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.

  2. Discovery of the Titanium Isotopes

    OpenAIRE

    Meierfrankenfeld, D.; Thoennessen, M.

    2009-01-01

    Twentyfive titanium isotopes have so far been observed; the discovery of these isotopes is discussed. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.

  3. Discovery of the Scandium Isotopes

    CERN Document Server

    Meierfrankenfeld, D

    2010-01-01

    Twenty-three scandium isotopes have so far been observed; the discovery of these isotopes is discussed. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.

  4. Discovery of the Tungsten Isotopes

    OpenAIRE

    A. Fritsch; Ginepro, J. Q.; Heim, M.; Schuh, A.; SHORE, A.; Thoennessen, M

    2009-01-01

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

  5. Discovery of the Vanadium Isotopes

    OpenAIRE

    SHORE, A.; A. Fritsch; Heim, M.; Schuh, A.; Thoennessen, M

    2009-01-01

    Twenty-four vanadium isotopes have so far been observed; the discovery of these isotopes is discussed. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.

  6. Discovery of the Arsenic Isotopes

    OpenAIRE

    SHORE, A.; A. Fritsch; Heim, M.; Schuh, A.; Thoennessen, M

    2009-01-01

    Twenty-nine arsenic isotopes have so far been observed; the discovery of these isotopes is discussed. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.

  7. Discovery of the Barium Isotopes

    OpenAIRE

    SHORE, A.; A. Fritsch; Ginepro, J. Q.; Heim, M.; Schuh, A.; Thoennessen, M

    2009-01-01

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

  8. Discovery of the Silver Isotopes

    OpenAIRE

    Schuh, A.; A. Fritsch; Ginepro, J. Q.; Heim, M.; SHORE, A.; Thoennessen, M

    2009-01-01

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

  9. Discovery of the Cadmium Isotopes

    OpenAIRE

    Amos, S.; Thoennessen, M

    2009-01-01

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

  10. Discovery of the Krypton Isotopes

    OpenAIRE

    Heim, M.; A. Fritsch; Schuh, A.; SHORE, A.; Thoennessen, M

    2009-01-01

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

  11. Discovery of the Iron Isotopes

    OpenAIRE

    Schuh, A.; A. Fritsch; Heim, M.; SHORE, A.; Thoennessen, M

    2009-01-01

    Twenty-eight iron isotopes have so far been observed; the discovery of these isotopes is discussed. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.

  12. Discovery of the Gold Isotopes

    OpenAIRE

    Schuh, A.; A. Fritsch; Ginepro, J. Q.; Heim, M.; SHORE, A.; Thoennessen, M

    2009-01-01

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

  13. Discovery of the Cobalt Isotopes

    OpenAIRE

    Szymanski, T; Thoennessen, M

    2009-01-01

    Twenty-six cobalt isotopes have so far been observed; the discovery of these isotopes is discussed. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.

  14. Verbessern Discovery Systeme die Informationskompetenz?

    OpenAIRE

    Dörte Böhner

    2013-01-01

    Mit dem Auftauchen von Discovery Systemen entstand die Hoffnung, dass der Schulungsbedarf und damit der Aufwand für die Vermittlung von Informationskompetenz verringert und durch die Systeme selbst die Informationskompetenz verbessert werden kann. Dieser Beitrag beleuchtet kritisch das Zusam­menspiel von Discovery Systemen und Informationskompetenz anhand von Recherchegewohnheiten eher untrainierter Studierender. Anhand einer kurzen Gegenüberstellung der unterschiedlichen Recherche­konzepte v...

  15. A discovery solution from Ebsco

    OpenAIRE

    Martín Michavila, Mariano

    2009-01-01

    EBSCO offers complementary access tools to gain greater value from the discovery solution: a customizable, versatile knowledgebase and listing service that enhances discovery, brings more visibility to the library’s collection, get users to specific content, and makes it easier for librarians to manage e-resources. It is an effective tool for end users who may gather information by browsing (journal lists, TOC, etc.), alerting (journal alerts, RSS) or known-item searching.

  16. Verbessern Discovery Systeme die Informationskompetenz?

    Directory of Open Access Journals (Sweden)

    Dörte Böhner

    2013-09-01

    Full Text Available Mit dem Auftauchen von Discovery Systemen entstand die Hoffnung, dass der Schulungsbedarf und damit der Aufwand für die Vermittlung von Informationskompetenz verringert und durch die Systeme selbst die Informationskompetenz verbessert werden kann. Dieser Beitrag beleuchtet kritisch das Zusam­menspiel von Discovery Systemen und Informationskompetenz anhand von Recherchegewohnheiten eher untrainierter Studierender. Anhand einer kurzen Gegenüberstellung der unterschiedlichen Recherche­konzepte von Suchmaschinen und bibliothekarischen Rechercheangeboten werden Rückschlüsse auf die zu fördernden Schwerpunkte bei der Informationskompetenz gezogen und untersucht, welche Schlüsselrolle Discovery Systeme dabei spielen.The dissemination of discovery systems has raised hopes that the need for extensive teaching of information literacy might be reduced in the future. Also, their intuitive approach has been hopefully seen to enable the development of a better information literacy. This article critically focusses on the interaction of discovery systems and information literacy by analysing research behaviours of comparatively untrained students. In order to define which specific themes should be promoted by information literacy education, the author examines various research concepts of search engines as well as research offers of libraries. On this basis the key role of discovery systems will be explored.

  17. Get Involved in Planetary Discoveries through New Worlds, New Discoveries

    Science.gov (United States)

    Shupla, Christine; Shipp, S. S.; Halligan, E.; Dalton, H.; Boonstra, D.; Buxner, S.; SMD Planetary Forum, NASA

    2013-01-01

    "New Worlds, New Discoveries" is a synthesis of NASA’s 50-year exploration history which provides an integrated picture of our new understanding of our solar system. As NASA spacecraft head to and arrive at key locations in our solar system, "New Worlds, New Discoveries" provides an integrated picture of our new understanding of the solar system to educators and the general public! The site combines the amazing discoveries of past NASA planetary missions with the most recent findings of ongoing missions, and connects them to the related planetary science topics. "New Worlds, New Discoveries," which includes the "Year of the Solar System" and the ongoing celebration of the "50 Years of Exploration," includes 20 topics that share thematic solar system educational resources and activities, tied to the national science standards. This online site and ongoing event offers numerous opportunities for the science community - including researchers and education and public outreach professionals - to raise awareness, build excitement, and make connections with educators, students, and the public about planetary science. Visitors to the site will find valuable hands-on science activities, resources and educational materials, as well as the latest news, to engage audiences in planetary science topics and their related mission discoveries. The topics are tied to the big questions of planetary science: how did the Sun’s family of planets and bodies originate and how have they evolved? How did life begin and evolve on Earth, and has it evolved elsewhere in our solar system? Scientists and educators are encouraged to get involved either directly or by sharing "New Worlds, New Discoveries" and its resources with educators, by conducting presentations and events, sharing their resources and events to add to the site, and adding their own public events to the site’s event calendar! Visit to find quality resources and ideas. Connect with educators, students and the public to

  18. 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 ...

  19. 43 CFR 4.1130 - Discovery methods.

    Science.gov (United States)

    2010-10-01

    ... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Discovery methods. 4.1130 Section 4.1130... Special Rules Applicable to Surface Coal Mining Hearings and Appeals Discovery § 4.1130 Discovery methods. Parties may obtain discovery by one or more of the following methods— (a) Depositions upon...

  20. 42 CFR 405.1037 - Discovery.

    Science.gov (United States)

    2010-10-01

    ... original discovery deadline. (5) If the ALJ grants the extension request, it must impose a new discovery... 42 Public Health 2 2010-10-01 2010-10-01 false Discovery. 405.1037 Section 405.1037 Public Health... Appeals Under Original Medicare (Part A and Part B) Alj Hearings § 405.1037 Discovery. (a) General...

  1. A Mars Exploration Discovery Program

    Science.gov (United States)

    Hansen, C. J.; Paige, D. A.

    2000-07-01

    The Mars Exploration Program should consider following the Discovery Program model. In the Discovery Program a team of scientists led by a PI develop the science goals of their mission, decide what payload achieves the necessary measurements most effectively, and then choose a spacecraft with the capabilities needed to carry the payload to the desired target body. The primary constraints associated with the Discovery missions are time and money. The proposer must convince reviewers that their mission has scientific merit and is feasible. Every Announcement of Opportunity has resulted in a collection of creative ideas that fit within advertised constraints. Following this model, a "Mars Discovery Program" would issue an Announcement of Opportunity for each launch opportunity with schedule constraints dictated by the launch window and fiscal constraints in accord with the program budget. All else would be left to the proposer to choose, based on the science the team wants to accomplish, consistent with the program theme of "Life, Climate and Resources". A proposer could propose a lander, an orbiter, a fleet of SCOUT vehicles or penetrators, an airplane, a balloon mission, a large rover, a small rover, etc. depending on what made the most sense for the science investigation and payload. As in the Discovery program, overall feasibility relative to cost, schedule and technology readiness would be evaluated and be part of the selection process.

  2. 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.

  3. Does Discovery-Based Instruction Enhance Learning?

    OpenAIRE

    Alfieri, L.; Brooks, PJ; Aldrich, NJ; Tenenbaum, HR

    2011-01-01

    Discovery learning approaches to education have recently come under scrutiny (Tobias & Duffy, 2009), with many studies indicating limitations to discovery learning practices. Therefore, 2 meta-analyses were conducted using a sample of 164 studies: The 1st examined the effects of unassisted discovery learning versus explicit instruction, and the 2nd examined the effects of enhanced and/or assisted discovery versus other types of instruction (e.g., explicit, unassisted discovery). Random effect...

  4. Discovery of Novel (Imidazo[1,2-a]pyrazin-6-yl)ureas as Antiproliferative Agents Targeting P53 in Non-small Cell Lung Cancer Cell Lines.

    Science.gov (United States)

    Bazin, Marc-Antoine; Rousseau, Bénédicte; Marhadour, Sophie; Tomasoni, Christophe; Evenou, Pierre; Piessard, Sylvie; Vaisberg, Abraham J; Ruchaud, Sandrine; Bach, Stéphane; Roussakis, Christos; Marchand, Pascal

    2016-04-01

    A series of (imidazo[1,2-a]pyrazin-6-yl)ureas were synthesized through 6-aminoimidazo[1,2-a]pyrazine as a key intermediate. 1-(Imidazo[1,2-a]pyrazin-6-yl)-3-(4-methoxy - phenyl)urea displayed a cytostatic activity against a non-small cell lung cancer cell line and was chosen for further mechanistic studies. Growth kinetics highlighted a selective dose-dependent response of P53-mutant NSCLC-N6-L16 cell line and overexpression of TP53 gene induced by this compound. These pharmacological data suggest a promising reactivation of p53 mutant in NSCLC-N6-L16 cell line. PMID:27069139

  5. Towards structural web services discovery

    Institute of Scientific and Technical Information of China (English)

    CHEN Jiang-feng

    2008-01-01

    A syntactic and structural matching mechanism for service discovery was put forward, which tries to exploit the underlying semantics of web services to enhance the traditional syntactic service discovery. We commit WSDL (Web Service Description Language) as service description language. The syntactic matching mechanism is based on the textual similarity among WSDL documents using VSM (Vector Space Model). The structural information is extracted from WSDL document tree or the invocation sequence of a series of services which can be viewed as the problem of graph isomorphism. Then we combine the syntactic and structural similarity linearly to calculate the service similarity. Finally we provide a novel web services discovery framework named SG* to find the exact services meeting the users' goals based on service similarity.

  6. 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. PMID:20521217

  7. 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.

  8. Knowledge discovery from legal databases

    CERN Document Server

    Stranieri, Andrew; Schauer, Frederick

    2006-01-01

    Knowledge Discovery from Legal Databases is the first text to describe data mining techniques as they apply to law. Law students, legal academics and applied information technology specialists are guided thorough all phases of the knowledge discovery from databases process with clear explanations of numerous data mining algorithms including rule induction, neural networks and association rules. Throughout the text, assumptions that make data mining in law quite different to mining other data are made explicit.  Issues such as the selection of commonplace cases, the use of discretion as a form

  9. Clarification of Premature Discovery in Science in Terms of Higher Education and Broader Communication

    Science.gov (United States)

    Onuigbo, Wilson I. B.

    2009-01-01

    The concept of premature discovery in science entails the publication of an important idea which remains uncited for a long period. Thereafter, a deluge of citations of its substance would occur. An overlooked example concerns the discovery in 1963 of how lung cancer cells stimulate the formation of new lymph vessels in man. Subsequently called…

  10. Synthetic biology for pharmaceutical drug discovery

    Directory of Open Access Journals (Sweden)

    Trosset JY

    2015-12-01

    Full Text Available Jean-Yves Trosset,1 Pablo Carbonell2,3 1Bioinformation Research Laboratory, Sup’Biotech, Villejuif, France; 2Faculty of Life Sciences, SYNBIOCHEM Centre, Manchester Institute of Biotechnology, University of Manchester, Manchester, UK; 3Department of Experimental and Health Sciences (DCEXS, Research Programme on Biomedical Informatics (GRIB, Hospital del Mar Medical Research Institute (IMIM, Universitat Pompeu Fabra (UPF, Barcelona, Spain Abstract: 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. Keywords: metabolic engineering, plant synthetic biology, natural products, synthetic quorum sensing, drug resistance

  11. 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…

  12. Macchines per scoprire - Discovery Machines

    CERN Multimedia

    Auditorium, Rome

    2016-01-01

    During the FCC week 2016 a public event entitled “Discovery Machines: The Higgs Boson and the Search for New Physics took place on 14 April at the Auditorium in Rome. The event, brought together physicists and experts from economics to discuss intriguing questions on the origin and evolution of the Universe and the societal impact of large-scale research projects.

  13. Smartphones: A Potential Discovery Tool

    OpenAIRE

    Starkweather, Wendy; Stowers, Eva

    2009-01-01

    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.

  14. Trends in Modern Drug Discovery.

    Science.gov (United States)

    Eder, Jörg; Herrling, Paul L

    2016-01-01

    Drugs discovered by the pharmaceutical industry over the past 100 years have dramatically changed the practice of medicine and impacted on many aspects of our culture. For many years, drug discovery was a target- and mechanism-agnostic approach that was based on ethnobotanical knowledge often fueled by serendipity. With the advent of modern molecular biology methods and based on knowledge of the human genome, drug discovery has now largely changed into a hypothesis-driven target-based approach, a development which was paralleled by significant environmental changes in the pharmaceutical industry. Laboratories became increasingly computerized and automated, and geographically dispersed research sites are now more and more clustered into large centers to capture technological and biological synergies. Today, academia, the regulatory agencies, and the pharmaceutical industry all contribute to drug discovery, and, in order to translate the basic science into new medical treatments for unmet medical needs, pharmaceutical companies have to have a critical mass of excellent scientists working in many therapeutic fields, disciplines, and technologies. The imperative for the pharmaceutical industry to discover breakthrough medicines is matched by the increasing numbers of first-in-class drugs approved in recent years and reflects the impact of modern drug discovery approaches, technologies, and genomics. PMID:26330257

  15. New oil and gas discoveries

    International Nuclear Information System (INIS)

    During the period 1999-2003, new oil and gas fields generated additional reserves of nearly 11 000 bcm of natural gas and 62 Gbbl of oil and condensates, volumes very much superior to those discovered in the five previous years. Two-thirds of these discoveries were located offshore, half in deep water. (author)

  16. Discovery and development of sulforaphane as a cancer chemopreventive phytochemical

    Institute of Scientific and Technical Information of China (English)

    Yuesheng ZHANG; Li TANG

    2007-01-01

    Sulforaphane (SF) is a phytochemical that displays both anticarcinogenic and anticancer activity. SF modulates many cancer-related events, including suscep-tibility to carcinogens, cell death, cell cycle, angiogenesis, invasion and metastasis.We review its discovery and development as a cancer chemopreventive agent with the intention of encouraging further research on this important compound and facilitating the identification and development of new phytochemicals for cancer prevention.

  17. From bench to patient: model systems in drug discovery.

    Science.gov (United States)

    Breyer, Matthew D; Look, A Thomas; Cifra, Alessandra

    2015-10-01

    Model systems, including laboratory animals, microorganisms, and cell- and tissue-based systems, are central to the discovery and development of new and better drugs for the treatment of human disease. In this issue, Disease Models & Mechanisms launches a Special Collection that illustrates the contribution of model systems to drug discovery and optimisation across multiple disease areas. This collection includes reviews, Editorials, interviews with leading scientists with a foot in both academia and industry, and original research articles reporting new and important insights into disease therapeutics. This Editorial provides a summary of the collection's current contents, highlighting the impact of multiple model systems in moving new discoveries from the laboratory bench to the patients' bedsides. PMID:26438689

  18. From bench to patient: model systems in drug discovery

    Directory of Open Access Journals (Sweden)

    Matthew D. Breyer

    2015-10-01

    Full Text Available Model systems, including laboratory animals, microorganisms, and cell- and tissue-based systems, are central to the discovery and development of new and better drugs for the treatment of human disease. In this issue, Disease Models & Mechanisms launches a Special Collection that illustrates the contribution of model systems to drug discovery and optimisation across multiple disease areas. This collection includes reviews, Editorials, interviews with leading scientists with a foot in both academia and industry, and original research articles reporting new and important insights into disease therapeutics. This Editorial provides a summary of the collection's current contents, highlighting the impact of multiple model systems in moving new discoveries from the laboratory bench to the patients' bedsides.

  19. [GWAS of Rheumatoid Arthritis and Drug Discovery].

    Science.gov (United States)

    Ohmura, Koichiro

    2015-04-01

    We have conducted genome-wide association studies (GWAS) for rheumatoid arthritis (RA). We previously found that myelin basic protein (MBP) is associated with RA. One of the MBP isoforms (Golli-MBP) is expressed not only in nerve cells, but also in hematopoietic cells, and may negatively regulate T-cell receptor signaling. We expanded the GWAS level by collaborating with laboratories in Japan and then throughout the world. Meta-analysis of GWAS data resulted in the identification of -100 genomic loci associated with RA development. The -100 genomic loci contain -400 candidate genes, and it is not easy to find out which genes actually play important roles in RA. By incorporating available public databases, we succeeded in narrowing down the susceptibility genes from 377 to 98. We also showed that regulatory T cells are associated with RA based on the combination of the histone methylation database and our mega-GWAS results. Protein-protein interaction and drug discovery databases gave us information that some of the drugs have already been developed as therapeutic medicines for RA, and some of them were used for diseases other than RA. These drugs may be used for RA in the near future (drug repurposing). The combination of biological databases and GWAS results may be a novel method to identify new therapeutic targets. PMID:26536782

  20. 29 CFR 18.13 - Discovery methods.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 1 2010-07-01 2010-07-01 true Discovery methods. 18.13 Section 18.13 Labor Office of the... ADMINISTRATIVE LAW JUDGES General § 18.13 Discovery methods. Parties may obtain discovery by one or more of the following methods: Depositions upon oral examination or written questions; written...

  1. Does Discovery-Based Instruction Enhance Learning?

    Science.gov (United States)

    Alfieri, Louis; Brooks, Patricia J.; Aldrich, Naomi J.; Tenenbaum, Harriet R.

    2011-01-01

    Discovery learning approaches to education have recently come under scrutiny (Tobias & Duffy, 2009), with many studies indicating limitations to discovery learning practices. Therefore, 2 meta-analyses were conducted using a sample of 164 studies: The 1st examined the effects of unassisted discovery learning versus explicit instruction, and the…

  2. Materials discovery via CALYPSO methodology

    International Nuclear Information System (INIS)

    The structure prediction at the atomic level is emerging as a state-of-the-art approach to accelerate the functionality-driven discovery of materials. By combining the global swarm optimization algorithm with first-principles thermodynamic calculations, it exploits the power of current supercomputer architectures to robustly predict the ground state and metastable structures of materials with only the given knowledge of chemical composition. In this Review, we provide an overview of the basic theory and main features of our as-developed CALYPSO structure prediction method, as well as its versatile applications to design of a broad range of materials including those of three-dimensional bulks, two-dimensional reconstructed surfaces and layers, and isolated clusters/nanoparticles or molecules with a variety of functional properties. The current challenges faced by structure prediction for materials discovery and future developments of CALYPSO to overcome them are also discussed. (topical review)

  3. 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.

  4. Discovery of Renal Tuberculosis in a Partial Nephrectomy Specimen Done for Renal Tumor

    OpenAIRE

    Ahmed Saadi; Haroun Ayed; Abderrazak Bouzouita; Walid Kerkeni; Mohamed Cherif; Riadh M. Ben Slama; Amine Derouiche; Mohamed Chebil

    2015-01-01

    The association of renal cancer and renal tuberculosis is uncommon. While the incidental discovery of renal cell carcinoma in a tuberculous kidney is a classical finding, the discovery of tuberculous lesions after nephrectomy for cancer is exceptional. We report the case of a female patient aged 60 who had a partial nephrectomy for a 5 cm exophytic kidney tumor. Pathological examination concluded that renal clear cell carcinoma associated with follicular caseo tuberculosis.

  5. Discovery of Renal Tuberculosis in a Partial Nephrectomy Specimen Done for Renal Tumor

    Directory of Open Access Journals (Sweden)

    Ahmed Saadi

    2015-05-01

    Full Text Available The association of renal cancer and renal tuberculosis is uncommon. While the incidental discovery of renal cell carcinoma in a tuberculous kidney is a classical finding, the discovery of tuberculous lesions after nephrectomy for cancer is exceptional. We report the case of a female patient aged 60 who had a partial nephrectomy for a 5 cm exophytic kidney tumor. Pathological examination concluded that renal clear cell carcinoma associated with follicular caseo tuberculosis.

  6. Materials Discovery: Informatic Strategies for Optical Materials

    Energy Technology Data Exchange (ETDEWEB)

    Ferris, Kim F.; Webb-Robertson, Bobbie-Jo M.; Jones, Dumont M.

    2007-01-15

    Information-based materials discovery offers a structured method to evolve materials signatures based upon their physical properties, and to direct searches using performance-based criteria. In this current paper, we focus on the crystal structure aspects of an optical material and construct an information-based model to determine the proclivity of a particular AB composition to exhibit multiple crystal system behavior. Exploratory data methods used both supervised (support-vector machines) and unsupervised (disorder-reduction and principal-component) classification methods for structural signature development; revealing complementary valid signatures. Examination of the relative contributions of the materials chemistry descriptors within these signatures indicates a strong role for Mendeleev number chemistry which must be balanced against the cationic/anionic radius ratio and electronegativity differences of constituents within the unit cell.

  7. Metagenomic small molecule discovery methods

    OpenAIRE

    Charlop-Powers, Zachary; Milshteyn, Aleksandr; Brady, Sean F

    2014-01-01

    Metagenomic approaches to natural product discovery provide the means of harvesting bioactive small molecules synthesized by environmental bacteria without the requirement of first culturing these organisms. Advances in sequencing technologies and general metagenomic methods are beginning to provide the tools necessary to unlock the unexplored biosynthetic potential encoded by the genomes of uncultured environmental bacteria. Here, we highlight recent advances in sequence- and functional- bas...

  8. Five Years of GWAS Discovery

    OpenAIRE

    Visscher, Peter M.; Brown, Matthew A.; McCarthy, Mark I.; Yang, Jian

    2012-01-01

    The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs). These studies were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders. We start by giving a...

  9. Gas reserves, discoveries and production

    International Nuclear Information System (INIS)

    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)

  10. Freud's great voyage of discovery.

    Science.gov (United States)

    Brenner, Charles

    2007-01-01

    The author discusses some of Freud's most significant contributions: the psychoanalytic method, called free association by Freud; the discovery that symptoms have a meaning and that every symptom is a compromise formation; the interpretation of dreams; psychic determinism; the central role of infantile sexuality; and sublimation. Included is a brief review of the views of some noteworthy analysts, all of whom agree in ignoring the importance of infantile sexuality and/or in minimizing its importance. PMID:17294822

  11. Gas reserves, discoveries and production

    Energy Technology Data Exchange (ETDEWEB)

    Saniere, A

    2006-07-01

    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)

  12. Towards Discovery of Subgraph Bisociations

    OpenAIRE

    Nagel, Uwe; Thiel, Kilian; Kötter, Tobias; Piatek, Dawid; Berthold, Michael R

    2012-01-01

    The discovery of surprising relations in large, heterogeneous information repositories is gaining increasing importance in real world data analysis. If these repositories come from diverse origins, forming different domains, domain bridging associations between otherwise weakly connected domains can provide insights into the data that are not accomplished by aggregative approaches. In this paper, we propose a first formalization for the detection of such potentially interesting, domaincrossin...

  13. Molecular Networks in Drug Discovery

    OpenAIRE

    Morrow, John Kenneth; Tian, Longzhang; Zhang, Shuxing

    2010-01-01

    Despite the dramatic increase of global spending on drug discovery and development, the approval rate for new drugs is declining, due chiefly to toxicity and undesirable side effects. Simultaneously, the growth of available biomedical data in the post-genomic era has provided fresh insight into the nature of redundant and compensatory drug-target pathways. This stagnation in drug approval can be overcome by the novel concept of polypharmacology, which is built on the fundamental concept that ...

  14. Computational Methods in Drug Discovery

    OpenAIRE

    Sliwoski, Gregory; Kothiwale, Sandeepkumar; Meiler, Jens; Edward W. Lowe

    2014-01-01

    Computer-aided drug discovery/design methods have played a major role in the development of therapeutically important small molecules for over three decades. These methods are broadly classified as either structure-based or ligand-based methods. Structure-based methods are in principle analogous to high-throughput screening in that both target and ligand structure information is imperative. Structure-based approaches include ligand docking, pharmacophore, and ligand design methods. The articl...

  15. 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.

  16. Unsupervised Discovery of Subspace Trends.

    Science.gov (United States)

    Xu, Yan; Qiu, Peng; Roysam, Badrinath

    2015-10-01

    This paper presents unsupervised algorithms for discovering previously unknown subspace trends in high-dimensional data sets without the benefit of prior information. A subspace trend is a sustained pattern of gradual/progressive changes within an unknown subset of feature dimensions. A fundamental challenge to subspace trend discovery is the presence of irrelevant data dimensions, noise, outliers, and confusion from multiple subspace trends driven by independent factors that are mixed in with each other. These factors can obscure the trends in conventional dimension reduction & projection based data visualizations. To overcome these limitations, we propose a novel graph-theoretic neighborhood similarity measure for detecting concordant progressive changes across data dimensions. Using this measure, we present an unsupervised algorithm for trend-relevant feature selection, subspace trend discovery, quantification of trend strength, and validation. Our method successfully identified verifiable subspace trends in diverse synthetic and real-world biomedical datasets. Visualizations derived from the selected trend-relevant features revealed biologically meaningful hidden subspace trend(s) that were obscured by irrelevant features and noise. Although our examples are drawn from the biological domain, the proposed algorithm is broadly applicable to exploratory analysis of high-dimensional data including visualization, hypothesis generation, knowledge discovery, and prediction in diverse other applications. PMID:26353189

  17. DISCOVERY

    Institute of Scientific and Technical Information of China (English)

    2013-01-01

    新产品 国际家居品牌石家庄勒泰中心店盛大开幕近日,国际时尚家饰家用品牌HOLA特力和乐石家庄首店盛大开幕,正式入驻位于中山路核心商圈的勒泰购物中心。HOLA将以优质精品家居和贴心的服务,

  18. Method and Application of Comprehensive Knowledge Discovery

    Institute of Scientific and Technical Information of China (English)

    SHA Zongyao; BIAN Fuling

    2003-01-01

    This paper proposes the principle of comprehensive knowledge discovery. Unlike most of the current knowledge discovery methods, the comprehensive knowledge discovery considers both the spatial relations and attributes of spatial entities or objects. We introduce the theory of spatial knowledge expression system and some concepts including comprehensive knowledge discovery and spatial union information table(SUIT). In theory, SUIT records all information contained in the studied objects, but in reality, because of the complexity and varieties of spatial relations,only those factors of interest to us are selected. In order to find out the comprehensive knowledge from spatial databases, an efficient comprehensive knowledge discovery algorithm called recycled algorithm (RAR) is suggested.

  19. Decade in Review-Kidney Cancer Kidney cancer's decade—discoveries, therapies and opportunities

    OpenAIRE

    Linehan, W. Marston; Ricketts, Christopher J.

    2014-01-01

    Advances in kidney cancer have occurred over the past decade, including the discovery of mutations in chromatin remodeling genes and genomic heterogeneity in clear cell renal cell carcinoma (ccRCC), altered metabolic patterns in ccRCC and papillary renal cell carcinoma and the approval of drugs for patients with ccRCC.

  20. Guided Discovery with Socratic Questioning

    Directory of Open Access Journals (Sweden)

    M. Hakan TURKCAPAR

    2015-03-01

    Full Text Available “The Socratic method” is a way of teaching philosophical thinking and knowledge by asking questions. It was first used by in ancient times by the Greek philosopher Socrates who taught his followers by asking questions; these conversations between them are known as “Socratic dialogues”. In this methodology, no new knowledge is taught to the individual; rather, the individual is guided to remember and rediscover what was formerly known through this process. The main method used in cognitive therapy is guided discovery. There are various methods of guided discovery in cognitive therapy. The form of verbal exchange between the therapist and client which is used during the process of cognitive behavioral therapy is known as “socratic questioning”. In this method the goal is to make the client rediscover, with a series of questions, a piece of knowledge which he could otherwise know but is not presently conscious of. The Socratic Questioning consists of several steps, including: identifying the problem by listening to the client and making reflections, finding alternatives by examining and evaluating, reidentification by using the newly rediscovered information and questioning the old distorted belief, and reaching a new conclusion and applying it. Question types used during these procedures are: questions for collecting information, questions revealing meanings, questions revealing beliefs, questions about behaviours during similar past experiences, analytic questions and analytic synthesis questions. In order to make the patient feel understood, it is important to be empathetic and summarize the problem during the interview. In this text, steps of Socratic Questioning-Guided Discovery will be reviewed with sample dialogues provided for each step.

  1. Discovery of a Makemakean Moon

    Science.gov (United States)

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

    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.

  2. Discovery of Uniformly Expanding Universe

    OpenAIRE

    Cahill R. T.; Rothall D.

    2012-01-01

    Saul Perlmutter and the Brian Schmidt – Adam Riess teams reported that their Friedmann-model GR-based analysis of their supernovae magnitude-redshift data re- vealed a new phenomenon of “dark energy” which, it is claimed, forms 73% of the energy / matter density of the present-epoch universe, and which is linked to the further claim of an accelerating expansion of the universe. In 2011 Perlmutter, Schmidt and Riess received the Nobel Prize in Physics “for the discovery of...

  3. Antibody informatics for drug discovery

    DEFF Research Database (Denmark)

    Shirai, Hiroki; Prades, Catherine; Vita, Randi;

    2014-01-01

    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...... (iii) antibody numbering and IMGT. Here, we review “antibody informatics,” which may integrate the above three fields so that bridging the gaps between industrial needs and academic solutions can be accelerated. This article is part of a Special Issue entitled: Recent advances in molecular engineering...

  4. Discovery of a Makemakean Moon

    CERN Document Server

    Parker, Alex H; 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 April 27, 2015 at 7.80$\\pm$0.04 magnitudes fainter than Makemake. 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 semi-major axis $\\gtrsim$21,000 km. We find that the properties of Makemake's moon suggest that the majority ...

  5. The discovery of uranium fission

    International Nuclear Information System (INIS)

    Uranium was discovered 200 years ago. Its radioactive character was first demonstrated in 1896 and two years later radium was extracted from uranium minerals. In 1911 studies with alpha rays from radioactive decay led to the unexpected discovery of the atomic nucleus. Exposure of beryllium to alpha rays yielded neutrons, first detected in 1932. Starting in 1934, neutron irradiation of uranium produced radioactive substances erroneously attributed to transuranium elements but with confusing properties. Painstaking experiments by chemists left no doubt on 17 December 1938 that barium was produced by these irradiations: the neutrons had split some uranium nuclei. The physics of the fission process was understood two weeks later; after a few months, neutron multiplication was found to be probable. This review deals with the eminent scientists involved, their successes, errors and disappointments, and the unexpected insights which occurred on the paths and detours of scientific research. It is, therefore, instructive also to discuss how fission was not discovered. The momentous discovery must be considered inevitable; the great tragedy was that Germany started World War II just at the time when the possibility of nuclear chain reactions and bombs became known. The consequences and anxieties that remain after 50 years of nuclear fission demand that mankind act with reason and conscience to maintain peace. (author)

  6. Tools for GPCR drug discovery

    Institute of Scientific and Technical Information of China (English)

    Ru ZHANG; Xin XIE

    2012-01-01

    G-protein-coupled receptors (GPCRs) mediate many important physiological functions and are considered as one of the most successful therapeutic targets for a broad spectrum of diseases.The design and implementation of high-throughput GPCR assays that allow the cost-effective screening of large compound libraries to identify novel drug candidates are critical in early drug discovery.Early functional GPCR assays depend primarily on the measurement of G-protein-mediated 2nd messenger generation.Taking advantage of the continuously deepening understanding of GPCR signal transduction,many G-protein-independent pathways are utilized to detect the activity of GPCRs,and may provide additional information on functional selectivity of candidate compounds.With the combination of automated imaging systems and label-free detection systems,such assays are now suitable for high-throughput screening (HTS).In this review,we summarize the most widely used GPCR assays and recent advances in HTS technologies for GPCR drug discovery.

  7. The discovery of radioactivity: the centenary

    International Nuclear Information System (INIS)

    In the last decade of the nineteenth century, a number of fundamental discoveries of outstanding importance were made unexpectedly which marked the beginning of a new era in physics. A cascade of spectacular discoveries began with the announcement of the discovery of x-rays by Roentgen followed by the discoveries, in quick succession, of radioactivity by Becquerel, of Zeeman effect, of electron by J.J. Thomson, and of polonium and radium by the Curies. Both x-rays and radioactivity have wide applications in scientific, medical and industrial fields and have made outstanding contribution to the advancement of human knowledge and welfare. Radioactivity is well known and no other discovery in the field of physics or chemistry has had a more profound effect on our fundamental knowledge of nature. Present article, on the occasion of the centenary of the discovery of radioactivity, makes an attempt to describe some glimpses of the history of radioactivity. (author). 59 refs

  8. Forms of Discovery for Design Knowledge

    OpenAIRE

    Fischer, Christian; Gregor, Shirley; Aier, Stephan

    2012-01-01

    The article at hand analyses an often disregarded aspect of design science research that is how design knowledge is actually built or, more precisely, how new design knowledge is discovered. In the article we distinguish abductive and inductive forms of discovery. We describe how inductive and abductive discoveries are dealt with in traditional science and how these two forms of discovery have been discussed in Information Systems Design Science Research literature. By means of a case study w...

  9. Indexer Based Dynamic Web Services Discovery

    OpenAIRE

    Saba Bashir,; Farhan Hassan Khan; M. Younus Javed; Aihab Khan; Malik Sikandar Hayat Khiyal

    2010-01-01

    Recent advancement in web services plays an important role in business to business and business to consumer interaction. Discovery mechanism is not only used to find a suitable service but also provides collaboration between service providers and consumers by using standard protocols. A static web service discovery mechanism is not only time consuming but requires continuous human interaction. This paper proposed an efficient dynamic web services discovery mechanism that can locate relevant a...

  10. Using rule learning for subgroup discovery

    OpenAIRE

    Kavšek, Branko

    2004-01-01

    This dissertation investigates how to adapt standard classification rule learning approaches to subgroup discovery. The goal of subgroup discovery is to find rules describing subsets of a selected population that are sufficiently large and statistically unusual in terms of class distribution. The dissertation presents a subgroup discovery algorithm, CN2-SD, developed by modifying parts of the CN2 classification rule learner: its covering algorithm, search heuristic, pr...

  11. MODIS: an audio motif discovery software

    OpenAIRE

    Catanese, Laurence; Souviraà-Labastie, Nathan; Qu, Bingqing; Campion, Sébastien; Gravier, Guillaume; Vincent, Emmanuel; Bimbot, Frédéric

    2013-01-01

    International audience MODIS is a free speech and audio motif discovery software developed at IRISA Rennes. Motif discovery is the task of discovering and collecting occurrences of repeating patterns in the absence of prior knowledge, or training material. MODIS is based on a generic approach to mine repeating audio sequences, with tolerance to motif variability. The algorithm implementation allows to process large audio streams at a reasonable speed where motif discovery often requires hu...

  12. Price Discovery in the Chinese Gold Market

    OpenAIRE

    Jin, Muzhao; Li, Youwei; Wang, Jianxin; Yang, Yung Chiang

    2016-01-01

    This study conducts price discovery analysis in the Chinese gold market. Our result indicates that the price discovery in Chinese gold market occurs predominantly in the futures market. The result is robust to the different measures of price discovery, namely information share, component share, and information leadership share. Partitioning the daily trades into three trading sessions, we find that the dominance of the futures market occurs in all trading sessions. We further investigate the ...

  13. Computational Approaches for the Discovery of Human Proteasome Inhibitors: An Overview.

    Science.gov (United States)

    Guedes, Romina A; Serra, Patrícia; Salvador, Jorge A R; Guedes, Rita C

    2016-01-01

    Proteasome emerged as an important target in recent pharmacological research due to its pivotal role in degrading proteins in the cytoplasm and nucleus of eukaryotic cells, regulating a wide variety of cellular pathways, including cell growth and proliferation, apoptosis, DNA repair, transcription, immune response, and signaling processes. The last two decades witnessed intensive efforts to discover 20S proteasome inhibitors with significant chemical diversity and efficacy. To date, the US FDA approved to market three proteasome inhibitors: bortezomib, carfilzomib, and ixazomib. However new, safer and more efficient drugs are still required. Computer-aided drug discovery has long being used in drug discovery campaigns targeting the human proteasome. The aim of this review is to illustrate selected in silico methods like homology modeling, molecular docking, pharmacophore modeling, virtual screening, and combined methods that have been used in proteasome inhibitors discovery. Applications of these methods to proteasome inhibitors discovery will also be presented and discussed to raise improvements in this particular field. PMID:27438821

  14. Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development.

    Science.gov (United States)

    Axten, Jeffrey M; Romeril, Stuart P; Shu, Arthur; Ralph, Jeffrey; Medina, Jesús R; Feng, Yanhong; Li, William Hoi Hong; Grant, Seth W; Heerding, Dirk A; Minthorn, Elisabeth; Mencken, Thomas; Gaul, Nathan; Goetz, Aaron; Stanley, Thomas; Hassell, Annie M; Gampe, Robert T; Atkins, Charity; Kumar, Rakesh

    2013-10-10

    We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development. PMID:24900593

  15. Automation of a phospho-STAT5 staining procedure for flow cytometry for application in drug discovery

    NARCIS (Netherlands)

    Malergue, Fabrice; van Agthoven, Andreas; Scifo, Caroline; Egan, Dave; Strous, Ger J

    2015-01-01

    Drug discovery often requires the screening of compound libraries on tissue cultured cells. Some major targets in drug discovery belong to signal transduction pathways, and PerFix EXPOSE* allows easy flow cytometry phospho assays. We thus investigated the possibility to further simplify and automate

  16. Data Driven Discovery in Astrophysics

    CERN Document Server

    Longo, Giuseppe; Djorgovski, George S; Cavuoti, Stefano; Donalek, Ciro

    2014-01-01

    We review some aspects of the current state of data-intensive astronomy, its methods, and some outstanding data analysis challenges. Astronomy is at the forefront of "big data" science, with exponentially growing data volumes and data rates, and an ever-increasing complexity, now entering the Petascale regime. Telescopes and observatories from both ground and space, covering a full range of wavelengths, feed the data via processing pipelines into dedicated archives, where they can be accessed for scientific analysis. Most of the large archives are connected through the Virtual Observatory framework, that provides interoperability standards and services, and effectively constitutes a global data grid of astronomy. Making discoveries in this overabundance of data requires applications of novel, machine learning tools. We describe some of the recent examples of such applications.

  17. Automating Spreadsheet Discovery & Risk Assessment

    CERN Document Server

    Perry, Eric

    2008-01-01

    There have been many articles and mishaps published about the risks of uncontrolled spreadsheets in today's business environment, including non-compliance, operational risk, errors, and fraud all leading to significant loss events. Spreadsheets fall into the realm of end user developed applications and are often absent the proper safeguards and controls an IT organization would enforce for enterprise applications. There is also an overall lack of software programming discipline enforced in how spreadsheets are developed. However, before an organization can apply proper controls and discipline to critical spreadsheets, an accurate and living inventory of spreadsheets across the enterprise must be created, and all critical spreadsheets must be identified. As such, this paper proposes an automated approach to the initial stages of the spreadsheet management lifecycle - discovery, inventory and risk assessment. Without the use of technology, these phases are often treated as a one-off project. By leveraging techn...

  18. Precision multidimensional assay for high-throughput microRNA drug discovery

    OpenAIRE

    Haefliger, Benjamin; Prochazka, Laura; Angelici, Bartolomeo; Benenson, Yaakov

    2016-01-01

    Development of drug discovery assays that combine high content with throughput is challenging. Information-processing gene networks can address this challenge by integrating multiple potential targets of drug candidates' activities into a small number of informative readouts, reporting simultaneously on specific and non-specific effects. Here we show a family of networks implementing this concept in a cell-based drug discovery assay for miRNA drug targets. The networks comprise multiple modul...

  19. 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.…

  20. Intraday Price Discovery in Fragmented Markets

    NARCIS (Netherlands)

    S.R. Ozturk (Sait); M. van der Wel (Michel); D.J.C. van Dijk (Dick)

    2014-01-01

    textabstractFor many assets, trading is fragmented across multiple exchanges. Price discovery measures summarize the informativeness of trading on each venue for discovering the asset’s true underlying value. We explore intraday variation in price discovery using a structural model with time-varying

  1. 2015 Update of the Discoveries of Isotopes

    CERN Document Server

    Thoennessen, M

    2016-01-01

    The 2015 update of the discovery of nuclide project is presented. Twenty new nuclides were observed for the first time in 2015. An overall review of all previous assignments was made in order to apply the discovery criteria consistently to all elements. In addition, a list of isotopes published so far only in conference proceedings or internal reports is included.

  2. A Discovery Chemistry Experiment on Buffers

    Science.gov (United States)

    Kulevich, Suzanne E.; Herrick, Richard S.; Mills, Kenneth V.

    2014-01-01

    The Holy Cross Chemistry Department has designed and implemented an experiment on buffers as part of our Discovery Chemistry curriculum. The pedagogical philosophy of Discovery Chemistry is to make the laboratory the focal point of learning for students in their first two years of undergraduate instruction. We first pose questions in prelaboratory…

  3. Scaling Bayesian network discovery through incremental recovery

    NARCIS (Netherlands)

    Castelo, J.R.; Siebes, A.P.J.M.

    1999-01-01

    Bayesian networks are a type of graphical models that, e.g., allow one to analyze the interaction among the variables in a database. A well-known problem with the discovery of such models from a database is the ``problem of high-dimensionality''. That is, the discovery of a network from a database w

  4. 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.

  5. 24 CFR 26.42 - Discovery.

    Science.gov (United States)

    2010-04-01

    ... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Discovery. 26.42 Section 26.42 Housing and Urban Development Office of the Secretary, Department of Housing and Urban Development HEARING... not unduly delay the proceeding. Discovery of privileged information shall not be permitted....

  6. Proteomics: a new approach for drug discovery

    Institute of Scientific and Technical Information of China (English)

    Xue-junLI; YangXIANG; Hui-kaiTIAN; BingMA; Xiao-haoYAO; Hong-meiZHANG; He-mingYU

    2004-01-01

    Proteomics is a bridge that crosses genome to drug discovery. Proteomic studies will provide possible targets for therapeutic usage and moreover increase the efficiency of the downstream of drug discovery process. By using the 2-D electrophoresis combining with MS technology, which is most preva-lent techniques of proteome, we have identified more than 20

  7. Discovery of inhibitors of bacterial histidine kinases

    NARCIS (Netherlands)

    Velikova, N.R.

    2014-01-01

    Discovery of Inhibitors of Bacterial Histidine Kinases

    Summary

    The thesis is on novel antibacterial drug discovery (http://youtu.be/NRMWOGgeysM). Using structure-based and fragment-based dru

  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 imple

  9. DISCOVERY OF EVIDENCE IN INTERNATIONAL COMMERCIAL ARBITRATION

    Directory of Open Access Journals (Sweden)

    Bakumenko, V.V.

    2016-07-01

    Full Text Available The article considers the different concepts of discovery of evidence, which exist under different legal jurisdictions, with their theoretical analysis to determine the feasibility and rationality of the application of the discovery mechanisms in the frameworks of international commercial arbitration and its fundamental principles.

  10. 49 CFR 1121.2 - Discovery.

    Science.gov (United States)

    2010-10-01

    ... procedures set forth at 49 CFR part 1114, subpart B. Discovery may begin upon the filing of the petition for exemption or petition for revocation of an exemption. In petitions to revoke an exemption, a party must... requests at the same time it files its petition to revoke. Discovery shall be completed 30 days after...

  11. Design for a Superconductor Discovery Engine (SCODEngine)

    Science.gov (United States)

    Isikaku-Ironkwe, O. Paul

    2010-03-01

    One of the grand challenges of superconductivity is achieving a paradigm shift from discovery by serendipity to discovery by design. Periodic Table-based Maps that involve electronegativity, valence electrons and atomic number that correlate with superconducting transition temperature can be used to design novel superconductors. Combining these maps with experimental databases on superconductors, databases of crystal structures and integrating material design software engine, we can re-design many known superconductor families and predict novel systems. By adding search engine technology with a ``knowledge discovery engine'', we produce a superconductor discovery engine (SCODEngine). The SCODEngine enables us to discover novel superconductors with the accelerated speed of a Google search. We have produced a primitive SCODEngine that may revolutionize novel superconductor search and discovery.

  12. 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...... introduction of new powerful HTS electrophysiological techniques is predicted to cause a revolution in ion channel drug discovery....... 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...

  13. 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. PMID:25666063

  14. Assessment of composite motif discovery methods

    Directory of Open Access Journals (Sweden)

    Johansen Jostein

    2008-02-01

    Full Text Available Abstract Background Computational discovery of regulatory elements is an important area of bioinformatics research and more than a hundred motif discovery methods have been published. Traditionally, most of these methods have addressed the problem of single motif discovery – discovering binding motifs for individual transcription factors. In higher organisms, however, transcription factors usually act in combination with nearby bound factors to induce specific regulatory behaviours. Hence, recent focus has shifted from single motifs to the discovery of sets of motifs bound by multiple cooperating transcription factors, so called composite motifs or cis-regulatory modules. Given the large number and diversity of methods available, independent assessment of methods becomes important. Although there have been several benchmark studies of single motif discovery, no similar studies have previously been conducted concerning composite motif discovery. Results We have developed a benchmarking framework for composite motif discovery and used it to evaluate the performance of eight published module discovery tools. Benchmark datasets were constructed based on real genomic sequences containing experimentally verified regulatory modules, and the module discovery programs were asked to predict both the locations of these modules and to specify the single motifs involved. To aid the programs in their search, we provided position weight matrices corresponding to the binding motifs of the transcription factors involved. In addition, selections of decoy matrices were mixed with the genuine matrices on one dataset to test the response of programs to varying levels of noise. Conclusion Although some of the methods tested tended to score somewhat better than others overall, there were still large variations between individual datasets and no single method performed consistently better than the rest in all situations. The variation in performance on individual

  15. Accelerators for Discovery Science and Security applications

    Energy Technology Data Exchange (ETDEWEB)

    Todd, A.M.M., E-mail: alan_todd@mail.aesys.net; Bluem, H.P.; Jarvis, J.D.; Park, J.H.; Rathke, J.W.; Schultheiss, T.J.

    2015-05-01

    Several Advanced Energy Systems (AES) accelerator projects that span applications in Discovery Science and Security are described. The design and performance of the IR and THz free electron laser (FEL) at the Fritz-Haber-Institut der Max-Planck-Gesellschaft in Berlin that is now an operating user facility for physical chemistry research in molecular and cluster spectroscopy as well as surface science, is highlighted. The device was designed to meet challenging specifications, including a final energy adjustable in the range of 15–50 MeV, low longitudinal emittance (<50 keV-psec) and transverse emittance (<20 π mm-mrad), at more than 200 pC bunch charge with a micropulse repetition rate of 1 GHz and a macropulse length of up to 15 μs. Secondly, we will describe an ongoing effort to develop an ultrafast electron diffraction (UED) source that is scheduled for completion in 2015 with prototype testing taking place at the Brookhaven National Laboratory (BNL) Accelerator Test Facility (ATF). This tabletop X-band system will find application in time-resolved chemical imaging and as a resource for drug–cell interaction analysis. A third active area at AES is accelerators for security applications where we will cover some top-level aspects of THz and X-ray systems that are under development and in testing for stand-off and portal detection.

  16. Accelerators for Discovery Science and Security applications

    International Nuclear Information System (INIS)

    Several Advanced Energy Systems (AES) accelerator projects that span applications in Discovery Science and Security are described. The design and performance of the IR and THz free electron laser (FEL) at the Fritz-Haber-Institut der Max-Planck-Gesellschaft in Berlin that is now an operating user facility for physical chemistry research in molecular and cluster spectroscopy as well as surface science, is highlighted. The device was designed to meet challenging specifications, including a final energy adjustable in the range of 15–50 MeV, low longitudinal emittance (<50 keV-psec) and transverse emittance (<20 π mm-mrad), at more than 200 pC bunch charge with a micropulse repetition rate of 1 GHz and a macropulse length of up to 15 μs. Secondly, we will describe an ongoing effort to develop an ultrafast electron diffraction (UED) source that is scheduled for completion in 2015 with prototype testing taking place at the Brookhaven National Laboratory (BNL) Accelerator Test Facility (ATF). This tabletop X-band system will find application in time-resolved chemical imaging and as a resource for drug–cell interaction analysis. A third active area at AES is accelerators for security applications where we will cover some top-level aspects of THz and X-ray systems that are under development and in testing for stand-off and portal detection

  17. Swift: 10 Years of Discovery

    Science.gov (United States)

    The conference Swift: 10 years of discovery was held in Roma at La Sapienza University on Dec. 2-5 2014 to celebrate 10 years of Swift successes. Thanks to a large attendance and a lively program, it provided the opportunity to review recent advances of our knowledge of the high-energy transient Universe both from the observational and theoretical sides. When Swift was launched on November 20, 2004, its prime objective was to chase Gamma-Ray Bursts and deepen our knowledge of these cosmic explosions. And so it did, unveiling the secrets of long and short GRBs. However, its multi-wavelength instrumentation and fast scheduling capabilities made it the most versatile mission ever flown. Besides GRBs, Swift has observed, and contributed to our understanding of, an impressive variety of targets including AGNs, supernovae, pulsars, microquasars, novae, variable stars, comets, and much more. Swift is continuously discovering rare and surprising events distributed over a wide range of redshifts, out to the most distant transient objects in the Universe. Such a trove of discoveries has been addressed during the conference with sessions dedicated to each class of events. Indeed, the conference in Rome was a spectacular celebration of the Swift 10th anniversary. It included sessions on all types of transient and steady sources. Top scientists from around the world gave invited and contributed talks. There was a large poster session, sumptuous lunches, news interviews and a glorious banquet with officials attending from INAF and ASI. All the presentations, as well as several conference pictures, can be found in the conference website (http://www.brera.inaf.it/Swift10/Welcome.html). These proceedings have been collected owing to the efforts of Paolo D’Avanzo who has followed each paper from submission to final acceptance. Our warmest thanks to Paolo for all his work. The Conference has been made possible by the support from La Sapienza University as well as from the ARAP

  18. Discovery of Uniformly Expanding Universe

    Directory of Open Access Journals (Sweden)

    Cahill R. T.

    2012-01-01

    Full Text Available Saul Perlmutter and the Brian Schmidt – Adam Riess teams reported that their Friedmann-model GR-based analysis of their supernovae magnitude-redshift data re- vealed a new phenomenon of “dark energy” which, it is claimed, forms 73% of the energy / matter density of the present-epoch universe, and which is linked to the further claim of an accelerating expansion of the universe. In 2011 Perlmutter, Schmidt and Riess received the Nobel Prize in Physics “for the discovery of the accelerating ex- pansion of the Universe through observations of distant supernovae”. Here it is shown that (i a generic model-independent analysis of this data reveals a uniformly expanding universe, (ii their analysis actually used Newtonian gravity, and finally (iii the data, as well as the CMB fluctuation data, does not require “dark energy” nor “dark matter”, but instead reveals the phenomenon of a dynamical space, which is absent from the Friedmann model.

  19. 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...

  20. 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.

  1. 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...

  2. 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.

  3. 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

  4. 16 CFR 1025.36 - Motions to compel discovery.

    Science.gov (United States)

    2010-01-01

    ... ADJUDICATIVE PROCEEDINGS Discovery, Compulsory Process § 1025.36 Motions to compel discovery. If a party fails... examination to the extent possible with respect to other areas of inquiry before moving to compel discovery....

  5. Investigations into Library Web-Scale Discovery Services

    OpenAIRE

    Vaughan, Jason

    2008-01-01

    Web-scale discovery services for libraries provide deep discovery to a library’s local and licensed content, and represent an evolution, perhaps a revolution, for end user information discovery as pertains to library collections.  This article frames the topic of web-scale discovery, and begins by illuminating web-scale discovery from an academic library’s perspective – that is, the internal perspective seeking widespread staff participation in the discovery conversation.  This included the c...

  6. Service Discovery – A Survey and Comparison

    Directory of Open Access Journals (Sweden)

    Bendaoud Karim Talal

    2013-07-01

    Full Text Available With the increasing number of services in the internet, companies’ intranets, and home networks: servicediscovery becomes an integral part of modern networked system. This paper provides a comprehensivesurvey of major solutions for service discovery. We cover techniques and features used in existing systems.Although a few survey articles have been published on this object, our contribution focuses on comparingand analyzing surveyed solutions according eight prime criteria, which we have defined before. Thiscomparison will be helpful to determine limits of existing discovery protocols and identify future researchopportunities in service discovery.

  7. Two Kinds of Discovery: An Ontological Account

    CERN Document Server

    Gilead, Amihud

    2014-01-01

    What can we discover? As the discussion in this paper is limited to ontological considerations, it does not deal with the discovery of new concepts. It raises the following question: What are the entities or existents that we can discover? There are two kinds of such entities: (1) actual entities, and (2) possible entities, which are pure possibilities. The paper explains why the first kind of discovery depends primarily on the second kind. The paper illustrates the discoveries of individual pure possibilities by presenting examples such as the Higgs particle, Dirac's positron, and Pauli-Fermi's neutrino.

  8. Open PHACTS: semantic interoperability for drug discovery.

    Science.gov (United States)

    Williams, Antony J; Harland, Lee; Groth, Paul; Pettifer, Stephen; Chichester, Christine; Willighagen, Egon L; Evelo, Chris T; Blomberg, Niklas; Ecker, Gerhard; Goble, Carole; Mons, Barend

    2012-11-01

    Open PHACTS is a public-private partnership between academia, publishers, small and medium sized enterprises and pharmaceutical companies. The goal of the project is to deliver and sustain an 'open pharmacological space' using and enhancing state-of-the-art semantic web standards and technologies. It is focused on practical and robust applications to solve specific questions in drug discovery research. OPS is intended to facilitate improvements in drug discovery in academia and industry and to support open innovation and in-house non-public drug discovery research. This paper lays out the challenges and how the Open PHACTS project is hoping to address these challenges technically and socially. PMID:22683805

  9. Automated Knowledge Discovery From Simulators

    Science.gov (United States)

    Burl, Michael; DeCoste, Dennis; Mazzoni, Dominic; Scharenbroich, Lucas; Enke, Brian; Merline, William

    2007-01-01

    A computational method, SimLearn, has been devised to facilitate efficient knowledge discovery from simulators. Simulators are complex computer programs used in science and engineering to model diverse phenomena such as fluid flow, gravitational interactions, coupled mechanical systems, and nuclear, chemical, and biological processes. SimLearn uses active-learning techniques to efficiently address the "landscape characterization problem." In particular, SimLearn tries to determine which regions in "input space" lead to a given output from the simulator, where "input space" refers to an abstraction of all the variables going into the simulator, e.g., initial conditions, parameters, and interaction equations. Landscape characterization can be viewed as an attempt to invert the forward mapping of the simulator and recover the inputs that produce a particular output. Given that a single simulation run can take days or weeks to complete even on a large computing cluster, SimLearn attempts to reduce costs by reducing the number of simulations needed to effect discoveries. Unlike conventional data-mining methods that are applied to static predefined datasets, SimLearn involves an iterative process in which a most informative dataset is constructed dynamically by using the simulator as an oracle. On each iteration, the algorithm models the knowledge it has gained through previous simulation trials and then chooses which simulation trials to run next. Running these trials through the simulator produces new data in the form of input-output pairs. The overall process is embodied in an algorithm that combines support vector machines (SVMs) with active learning. SVMs use learning from examples (the examples are the input-output pairs generated by running the simulator) and a principle called maximum margin to derive predictors that generalize well to new inputs. In SimLearn, the SVM plays the role of modeling the knowledge that has been gained through previous simulation trials

  10. Discovery of Interstellar Heavy Water

    Science.gov (United States)

    Butner, H. M.; Charnley, S. B.; Ceccarelli, C.; Rodgers, S. D.; Pardo, J. R.; Parise, B.; Cernicharo, J.; Davis, G. R.

    2007-04-01

    We report the discovery of doubly deuterated water (D2O, heavy water) in the interstellar medium. Using the James Clerk Maxwell Telescope and the Caltech Submillimeter Observatory 10 m telescope, we detected the 110-101 transition of para-D2O at 316.7998 GHz in both absorption and emission toward the protostellar binary system IRAS 16293-2422. Assuming that the D2O exists primarily in the warm regions where water ices have been evaporated (i.e., in a ``hot corino'' environment), we determine a total column density of N(D2O) of 1.0×1013 cm-2 and a fractional abundance of D2O/H2=1.7×10-10. The derived column density ratios for IRAS 16293-2422 are D2O/HDO=1.7×10-3 and D2O/H2O=5×10-5 for the hot corino gas. Steady state models of water ice formation, either in the gas phase or on grains, predict D2O/HDO ratios that are about 4 times larger than that derived from our observations. For water formation on grain surfaces to be a viable explanation, a larger H2O abundance than that measured in IRAS 16293-2422 is required. Alternatively, the observed D2O/HDO ratio could be indicative of gas-phase water chemistry prior to a chemical steady state being attained, such as would have occurred during the formation of this source. Future observations with the Herschel Space Observatory satellite will be important for settling this issue.

  11. Discovery of medically significant lantibiotics.

    Science.gov (United States)

    Piper, Clare; Cotter, Paul D; Ross, R Paul; Hill, Colin

    2009-03-01

    The emergence of drug-resistant pathogens such as staphylococci and enterococci in the hospital setting has long being recognized as a serious clinical problem. Staphylococcus aureus is the causative agent of many nosocomial infections from minor skin abscesses to serious, potentially life threatening diseases such as bone and soft tissue intra-surgical infections, sepsis and invasive endocarditis, while enterococci are responsible for nosocomial bacteraemia, surgical wound infections and endocarditis. The most infamous drug-resistant forms of these include MRSA (methicillin resistant S. aureus), VISA (vancomycin insensitive S. aureus), hVISA (heterogenous vancomycin insensitive S. aureus) and VRE (vancomycin resistant S. aureus). While enhanced hygiene awareness is essential to any solution, the identification of effective novel antimicrobial compounds remains a major goal in eradicating these and other infections caused by multi-drug resistant pathogens. In recent years a class of antimicrobial peptides, the Lantibiotics, have been the focus of an ever increasing level of attention. This interest has been prompted by an enhanced appreciation of the mode of action of these peptides (including, in many cases, the ability to bind lipid II) and their frequently high levels of antimicrobial activity. Here we review lantibiotic-related issues in drug discovery, outline the strategies that have been employed to identify these peptides and summarize the use of bioengineering to generate enhanced forms of these peptides as well as the application of the associated biological machinery to generate novel forms of existing pharmaceutical compounds. In so doing we highlight how some, or all, of these approaches have the potential to result in the development of clinically important drugs. PMID:19275538

  12. 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. PMID:24255854

  13. 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).

  14. The National Cancer Program: Driving Discovery

    Science.gov (United States)

    An overview of NCI’s role in driving cancer research discoveries: conducting and funding research in challenging areas and providing resources and leadership to national infrastructures for cancer research.

  15. Association Rule Discovery and Its Applications

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Data mining, i.e. , mining knowledge from large amounts of data, is a demanding field since huge amounts of data have been collected in various applications. The collected data far exceed peoples ability to analyze it. Thus, some new and efficient methods are needed to discover knowledge from large database. Association rule discovery is an important problem in knowledge discovery and data mining.The association mining task consists of identifying the frequent item sets and then forming conditional implication rule among them. In this paper, we describe and summarize recent work on association rule discovery, offer a new method to association rule mining and point out that association rule discovery can be applied in spatial data mining. It is useful to discover knowledge from remote sensing and geographical information system.``

  16. 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-independen......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......-independent approach that makes no assumptions about when positions are sampled, gives no special importance to sampling points, and naturally supports the use of approximate trajectories. The framework's algorithms exploit state-of-the-art, density-based clustering (DBScan) to identify groups. The groups are scored...

  17. Anthelmintics – From Discovery to Resistance

    Directory of Open Access Journals (Sweden)

    Adrian J. Wolstenholme

    2014-12-01

    Full Text Available The scientific meeting entitled ‘Anthelmintics: From Discovery to Resistance’ was held in San Francisco in February 2014. The themes of the meeting were drug discovery, modes of action and resistance. Both human and veterinary parasites were covered in the oral and poster presentations. The attendees were from both academic and industrial backgrounds. In the present article we introduce a number of the papers that emerged from the meeting. Several of the papers covered current drug discovery efforts underway worldwide, with some specific examples focusing on ion channels, protein kinases and cysteine proteases. These efforts included the repurposing of known drugs as well as the discovery of novel actives. Two papers described recently-developed whole-organism screening techniques. Finally, we introduce several papers looking at mechanisms and management of drug resistance in human and veterinary parasites.

  18. Priority of discovery in the life sciences.

    Science.gov (United States)

    Vale, Ronald D; Hyman, Anthony A

    2016-01-01

    The job of a scientist is to make a discovery and then communicate this new knowledge to others. For a scientist to be successful, he or she needs to be able to claim credit or priority for discoveries throughout their career. However, despite being fundamental to the reward system of science, the principles for establishing the "priority of discovery" are rarely discussed. Here we break down priority into two steps: disclosure, in which the discovery is released to the world-wide community; and validation, in which other scientists assess the accuracy, quality and importance of the work. Currently, in biology, disclosure and an initial validation are combined in a journal publication. Here, we discuss the advantages of separating these steps into disclosure via a preprint, and validation via a combination of peer review at a journal and additional evaluation by the wider scientific community. PMID:27310529

  19. 42 CFR 93.512 - Discovery.

    Science.gov (United States)

    2010-10-01

    ... Process § 93.512 Discovery. (a) Request to provide documents. A party may only request another party to...; (2) Analyses and summaries prepared in conjunction with the inquiry, investigation, ORI...

  20. SCALABLE GRID RESOURCE DISCOVERY THROUGH DISTRIBUTED SEARCH

    Directory of Open Access Journals (Sweden)

    Fouad Butt

    2011-10-01

    Full Text Available This paper proposes a simple and scalable web-based model for grid resource discovery for the Internet.The resource discovery model contains the metadata and resource finder web services. The information ofresource finder web services is kept in the repositories that are distributed in the application layer ofInternet. The resource finder web services will be discovered by sending queries to the repositories in asimilar way as the DNS protocol. The underlying technology for implementation of the two architectures ofthis model is introduced.These architectures are: Direct and Centralized Web-Based Grid Resource Discovery. The resourcediscovery time is computed after simulating each of these models in GridSim.By performing scalability tests, we found that when increasing the load on the grid with more users andresources, the cost of our model in comparison to the grid resource discovery time is marginal.

  1. Discovery announced of four new elements

    Science.gov (United States)

    Banks, Michael

    2016-02-01

    The International Union of Pure and Applied Chemistry (IUPAC) and the International Union of Pure and Applied Physics (IUPAP) have announced the discovery of four new elements: 113, 115, 117 and 118 - completing the periodic table's seventh row.

  2. 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...

  3. 43 CFR 4.826 - Discovery.

    Science.gov (United States)

    2010-10-01

    ... Special Procedural Rules Applicable to Practice and Procedure for Hearings, Decisions, and Administrative... make any order which justice requires to limit or condition discovery in order to protect a party...

  4. Arthritis Genetics Analysis Aids Drug Discovery

    Science.gov (United States)

    ... Matters NIH Research Matters January 13, 2014 Arthritis Genetics Analysis Aids Drug Discovery An international research team ... may play a role in triggering the disease. Genetic factors are also thought to play a role. ...

  5. DNA Coding Based Knowledge Discovery Algorithm

    Institute of Scientific and Technical Information of China (English)

    LI Ji-yun; GENG Zhao-feng; SHAO Shi-huang

    2002-01-01

    A novel DNA coding based knowledge discovery algorithm was proposed, an example which verified its validity was given. It is proved that this algorithm can discover new simplified rules from the original rule set efficiently.

  6. Combinatorial Discovery and Optimization of New Materials

    Institute of Scientific and Technical Information of China (English)

    Gao Chen; Zhang Xinyi; Yan Dongsheng

    2001-01-01

    The concept of the combinatorial discovery and optimization of new materials, and its background,importance, and application, as well as its current status in the world, are briefly reviewed in this paper.

  7. Laminaria: a new Timor Sea [petroluem] discovery

    Energy Technology Data Exchange (ETDEWEB)

    Smith, G.C.; Tilbury, L.A.; Chatfield, A.; Senycia, P.; Thompson, N. [Woodside Offshore Petroleum Pty. Ltd., Perth, WA (Australia)

    1996-12-31

    The Laminaria-1 discovery in the southeast of AC/P8 petroleum exploration area is a major new Timor Sea oil accumulation. It is one of several significant oil discoveries made in Australia during the last decade, and when developed, being in about 350 m of water, it should be the deepest yet undertaken. This paper describes the exploration background to the discovery, its regional setting, seismic data and interpretation, and reservoir stratigraphy and characteristics. Since the discovery, a comprehensive appraisal campaign has been undertaken to delineate the accumulation, including the acquisition of a large 3D seismic survey over almost the entire AC/P8 permit, and the drilling of a further two wells and a sidetrack. The Laminaria horst is now interpreted to comprise a series of tilted fault-blocks, oriented ENE to WSW and dipping to the southeast. (author). 19 figs., 18 refs.

  8. Indexer Based Dynamic Web Services Discovery

    CERN Document Server

    Bashir, Saba; Javed, M Younus; Khan, Aihab; Khiyal, Malik Sikandar Hayat

    2010-01-01

    Recent advancement in web services plays an important role in business to business and business to consumer interaction. Discovery mechanism is not only used to find a suitable service but also provides collaboration between service providers and consumers by using standard protocols. A static web service discovery mechanism is not only time consuming but requires continuous human interaction. This paper proposed an efficient dynamic web services discovery mechanism that can locate relevant and updated web services from service registries and repositories with timestamp based on indexing value and categorization for faster and efficient discovery of service. The proposed prototype focuses on quality of service issues and introduces concept of local cache, categorization of services, indexing mechanism, CSP (Constraint Satisfaction Problem) solver, aging and usage of translator. Performance of proposed framework is evaluated by implementing the algorithm and correctness of our method is shown. The results of p...

  9. Historical Perspective: What Constitutes Discovery (of a New Virus)?

    Science.gov (United States)

    Murphy, F A

    2016-01-01

    A historic review of the discovery of new viruses leads to reminders of traditions that have evolved over 118 years. One such tradition gives credit for the discovery of a virus to the investigator(s) who not only carried out the seminal experiments but also correctly interpreted the findings (within the technological context of the day). Early on, ultrafiltration played a unique role in "proving" that an infectious agent was a virus, as did a failure to find any microscopically visible agent, failure to show replication of the agent in the absence of viable cells, thermolability of the agent, and demonstration of a specific immune response to the agent so as to rule out duplicates and close variants. More difficult was "proving" that the new virus was the etiologic agent of the disease ("proof of causation")-for good reasons this matter has been revisited several times over the years as technologies and perspectives have changed. One tradition is that the discoverers get to name their discovery, their new virus (unless some grievous convention has been broken)-the stability of these virus names has been a way to honor the discoverer(s) over the long term. Several vignettes have been chosen to illustrate several difficulties in holding to the traditions (vignettes chosen include vaccinia and variola viruses, yellow fever virus, and influenza viruses. Crimean-Congo hemorrhagic fever virus, Murray Valley encephalitis virus, human immunodeficiency virus 1, Sin Nombre virus, and Ebola virus). Each suggests lessons for the future. One way to assure that discoveries are forever linked with discoverers would be a permanent archive in one of the universal virus databases that have been constructed for other purposes. However, no current database seems ideal-perhaps members of the global community of virologists will have an ideal solution. PMID:27112283

  10. Group Evolution Discovery in Social Networks

    OpenAIRE

    Bródka, Piotr; Saganowski, Stanisław; Kazienko, Przemysław

    2013-01-01

    Group extraction and their evolution are among the topics which arouse the greatest interest in the domain of social network analysis. However, while the grouping methods in social networks are developed very dynamically, the methods of group evolution discovery and analysis are still uncharted territory on the social network analysis map. Therefore the new method for the group evolution discovery called GED is proposed in this paper. Additionally, the results of the first experiments on the ...

  11. Fission and the discovery of isotopes

    International Nuclear Information System (INIS)

    The discovery of new isotopes requires new developments in accelerator and detector technology. The new RI Beam Factory at RIKEN and the future projects FAIR at GSI and FRIB at MSU promise to expand the nuclear horizon even further. In the talk a short history of the role that fission played in the discovery of isotopes will be presented and future perspectives will be discussed

  12. Discoveries of Elements 113, 115 and 117

    International Nuclear Information System (INIS)

    Discovery of two isotopes of the new element 117 in the 249Bk + 48Ca reaction is described. A new 243Am + 48Ca experiment was carried out to firmly establish the discoveries of new elements 115 and 113. A total of thirty one decay chains of 288115 are now observed in the Am reaction. In addition, four new decay chains are assigned to 289115.

  13. Discovery of the Higgs boson and beyond

    International Nuclear Information System (INIS)

    This talk is about the Higgs mechanism, the theoretical discovery of which, was awarded the 2013 Nobel Prize. It also discusses the discovery of the Higgs boson at the large hadron collider which provided the experimental proof that made the Nobel prize possible. It covers the implications of these for the quest of unravelling the fundamental laws of nature which seem to govern both, the behavior of the ultra small (subatomic particles) and the ultra large (the cosmos)

  14. The Higgs boson discovery and measurements

    International Nuclear Information System (INIS)

    The discovery of the Higgs boson at a mass around 125 GeV by the ATLAS and CMS experiments at the LHC collider in 2012 establishes a new landscape in high-energy physics. The analysis of the full data sample collected with pp collisions at centre-of-mass energies of 7 and 8 TeV has allowed for considerable progress since the discovery. A review of the latest results is presented. (authors)

  15. Routing Discovery Algorithm Using Parallel Chase Packet

    OpenAIRE

    Amera Al-Ameri; Muneer Bani Yassein; Khamayseh, Yaser M.

    2013-01-01

    On demand routing protocols for ad hoc networks such as Ad Hoc On Demand Distance Vector (AODV) initiate a route discovery process when a route is needed by flooding the network with a route request packet. The route discovery process in such protocols depends on a simple flooding as a broadcast technique due to its simplicity. Simple flooding results in packet congestion, route request overhead and excessive collisions, namely broadcast storm problem. A number of routing techniques have been...

  16. Towards Robot Scientists for autonomous scientific discovery

    OpenAIRE

    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.

    2010-01-01

    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 ...

  17. Towards discovery-driven translational research in breast cancer

    DEFF Research Database (Denmark)

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

    2005-01-01

    , 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......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...... biology approach to fight breast cancer....

  18. Targeting membrane proteins for antibody discovery using phage display.

    Science.gov (United States)

    Jones, Martina L; Alfaleh, Mohamed A; Kumble, Sumukh; Zhang, Shuo; Osborne, Geoffrey W; Yeh, Michael; Arora, Neetika; Hou, Jeff Jia Cheng; Howard, Christopher B; Chin, David Y; Mahler, Stephen M

    2016-01-01

    A critical factor in the successful isolation of new antibodies by phage display is the presentation of a correctly folded antigen. While this is relatively simple for soluble proteins which can be purified and immobilized onto a plastic surface, membrane proteins offer significant challenges for antibody discovery. Whole cell panning allows presentation of the membrane protein in its native conformation, but is complicated by a low target antigen density, high background of irrelevant antigens and non-specific binding of phage particles to cell surfaces. The method described here uses transient transfection of alternating host cell lines and stringent washing steps to address each of these limitations. The successful isolation of antibodies from a naive scFv library is described for three membrane bound proteins; human CD83, canine CD117 and bat CD11b. PMID:27189586

  19. 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.

  20. 18 CFR 385.908 - Discovery (Rule 908).

    Science.gov (United States)

    2010-04-01

    ... conduct discovery where such discovery relates to new facts or issues raised in accordance with Rule 907(b... discovery: (1) Relates to new facts or issues raised in accordance with Rule 907(c) (new facts and issues... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Discovery (Rule...

  1. Synthesis of 5-benzyl-2-phenylpyrazolo[1,5-a]pyrazin-4,6(5H,7H)-dione derivatives and discovery of an apoptosis inducer for H322 lung cancer cells.

    Science.gov (United States)

    Lv, Hong-Shui; Kong, Xiang-Qian; Ming, Qian-Qian; Jin, Xing; Miao, Jun-Ying; Zhao, Bao-Xiang

    2012-01-15

    A series of substituted 5-benzyl-2-phenylpyrazolo[1,5-a]pyrazin-4,6(5H,7H)-dione derivatives was synthesized by one-step reaction of ethyl 3-phenyl-1H-pyrazole-5-carboxylate derivatives and N-arylalkyl-2-chloroacetamide. Structures of the compounds were determined by IR, (1)H NMR and mass spectroscopy. In addition, a representative single-crystal structure was characterized by using X-ray diffraction analysis. The compound 5j could selectively inhibit the growth of H322 lung cancer cells which contain a mutated p53 gene in a dose-dependent manner through inducing apoptosis of cells. PMID:22209459

  2. Discovery of a novel anticancer agent with both anti-topoisomerase I and II activities in hepatocellular carcinoma SK-Hep-1 cells in vitro and in vivo: Cinnamomum verum component 2-methoxycinnamaldehyde.

    Science.gov (United States)

    Perng, Daw-Shyong; Tsai, Yu-Hsin; Cherng, Jonathan; Wang, Jeng-Shing; Chou, Kuo-Shen; Shih, Chia-Wen; Cherng, Jaw-Ming

    2016-01-01

    Cinnamomum verum is used to make the spice cinnamon and has been used as a traditional Chinese herbal medicine for various applications. We evaluated the anticancer effect of 2-methoxycinnamaldehyde (2-MCA), a constituent of the bark of the plant, and its underlying molecular biomarkers associated with carcinogenesis in human hepatocellular carcinoma SK-Hep-1 cell line. The results show that 2-MCA suppressed proliferation and induced apoptosis as indicated by mitochondrial membrane potential loss, activation of caspase-3 and caspase-9, increase in the DNA content in sub-G1, and morphological characteristics of apoptosis, including blebbing of plasma membrane, nuclear condensation, fragmentation, apoptotic body formation, and long comet tail. In addition, 2-MCA also induced lysosomal vacuolation with increased volume of acidic compartments, suppressions of nuclear transcription factors NF-κB, cyclooxygenase-2, prostaglandin E2 (PGE2), and both topoisomerase I and II activities in a dose-dependent manner. Further study reveals the growth-inhibitory effect of 2-MCA was also evident in a nude mice model. Taken together, the data suggest that the growth-inhibitory effect of 2-MCA against SK-Hep-1 cells is accompanied by downregulations of NF-κB-binding activity, inflammatory responses involving cyclooxygenase-2 and PGE2, and proliferative control involving apoptosis, both topoisomerase I and II activities, together with an upregulation of lysosomal vacuolation and volume of acidic compartments. Similar effects (including all of the above-mentioned effects) were found in other tested cell lines, including human hepatocellular carcinoma Hep 3B, lung adenocarcinoma A549, squamous cell carcinoma NCI-H520, colorectal adenocarcinoma COLO 205, and T-lymphoblastic MOLT-3 (results not shown). Our data suggest that 2-MCA could be a potential agent for anticancer therapy. PMID:26792981

  3. 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

    OpenAIRE

    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 restricti...

  4. What Does Galileo's Discovery of Jupiter's Moons Tell Us about the Process of Scientific Discovery?

    Science.gov (United States)

    Lawson, Anton E.

    2002-01-01

    Given that hypothetico-deductive reasoning has played a role in other important scientific discoveries, asks the question whether it plays a role in all important scientific discoveries. Explores and rejects as viable alternatives possible alternative scientific methods such as Baconian induction and combinatorial analysis. Discusses the…

  5. Beyond discovery: A review of the critique of the discovery view of opportunities

    DEFF Research Database (Denmark)

    Korsgaard, Steffen T.

    This paper systematically reviews and synthesises the critique since 2000 of the discovery view's interpretation of entrepreneurial opportunities. The review shows that the framing of the debate as polarised between two oppositions, the discovery view versus the creation view, is oversimplified...

  6. Discovery of a novel anticancer agent with both anti-topoisomerase I and II activities in hepatocellular carcinoma SK-Hep-1 cells in vitro and in vivo: Cinnamomum verum component 2-methoxycinnamaldehyde

    Directory of Open Access Journals (Sweden)

    Perng DS

    2016-01-01

    Full Text Available Daw-Shyong Perng,1 Yu-Hsin Tsai,2 Jonathan Cherng,3 Jeng-Shing Wang,4 Kuo-Shen Chou,5 Chia-Wen Shih,6 Jaw-Ming Cherng7 1Department of Gastroenterology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan, Republic of China; 2Sierra College, Rocklin, CA, USA; 3Faculty of Medicine, Medical University of Lublin, Lublin, Poland; 4Department of Internal Medicine, Antai Tian-Sheng Memorial Hospital, Pingtung, 5Department of Family Medicine, Saint Mary’s Hospital Luodong, 6Department of Pathology, Lotung Poh-Ai Hospital, 7Department of Internal Medicine, Saint Mary’s Hospital Luodong, Yilan, Taiwan, Republic of China Abstract: Cinnamomum verum is used to make the spice cinnamon and has been used as a traditional Chinese herbal medicine for various applications. We evaluated the anticancer effect of 2-methoxycinnamaldehyde (2-MCA, a constituent of the bark of the plant, and its underlying molecular biomarkers associated with carcinogenesis in human hepatocellular carcinoma SK-Hep-1 cell line. The results show that 2-MCA suppressed proliferation and induced apoptosis as indicated by mitochondrial membrane potential loss, activation of caspase-3 and caspase-9, increase in the DNA content in sub-G1, and morphological characteristics of apoptosis, including blebbing of plasma membrane, nuclear condensation, fragmentation, apoptotic body formation, and long comet tail. In addition, 2-MCA also induced lysosomal vacuolation with increased volume of acidic compartments, suppressions of nuclear transcription factors NF-κB, cyclooxygenase-2, prostaglandin E2 (PGE2, and both topoisomerase I and II activities in a dose-dependent manner. Further study reveals the growth-inhibitory effect of 2-MCA was also evident in a nude mice model. Taken together, the data suggest that the growth-inhibitory effect of 2-MCA against SK-Hep-1 cells is accompanied by downregulations of NF-κB-binding activity, inflammatory responses involving cyclooxygenase-2 and PGE2, and

  7. Compressed Neighbor Discovery for Wireless Networks

    CERN Document Server

    Guo, Dongning; Zhang, Lei; Shen, Kai

    2010-01-01

    This paper studies neighbor discovery problem in wireless networks. A novel scheme, called compressed neighbor discovery is proposed, which assigns each node a unique signature and let nodes simultaneously transmit their signatures during the discovery period. The query node then determines, based on the superposition of the signatures, a small number of nodes as its neighbors, out of a large number of nodes in the network. This is fundamentally a sparse recovery problem. Using the proposed scheme, a single frame time suffices to achieve reliable discovery for large networks. This is in contrast to conventional schemes, where each node repeatedly transmits its identity with random delay, so that a receiver can identify each neighbor at least once without collision. Two practical, low-complexity discovery schemes are studied. The first scheme assigns sparse pseudo-random on-off signatures to the nodes, so that each node can listen to the channel during its own off-slots. Despite of half-duplex constraint, all ...

  8. 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...

  9. Facilitating Service Discovery with Semantic Overlay

    Institute of Scientific and Technical Information of China (English)

    Hai Jin; Hao Wu; Xiao-Min Ning

    2006-01-01

    Service Oriented Architecture (SOA) and Peer-to-Peer (P2P) computing share many common characteristics.It is believed that the combination of the two emerging techniques is a very promising method in promoting the web services (WS). Because the service discovery plays a key role in the integration, here a P2P-based framework to manage the knowledge of service and locating services is proposed. In this paper, the details of the principle, constructing and maintaining of service semantic overlay architecture have been described, and the way how the semantic overlay facilitates discovery of service resources is illustrated. To enable the semantic web service superiority, Service Ontology, which is considered as the service semantic model, is employed to depict service. The service discovery includes two phases: searching on the service semantic overlay; and local discovery in peer's service repository. Various solutions have been proposed to realize those two phases.Furthermore, tests are carried out to evaluate service discovery on the architecture.

  10. A new era for GPCR research: structures, biology anddrug discovery

    Institute of Scientific and Technical Information of China (English)

    H Eric XU; Rui-ping XIAO

    2012-01-01

    Cells in a living organism must communicate with each other through continuously sending and receiving messages.G-protein coupled receptors (GPCRs) are the largest family of communicating molecules at the cell surface.They transmit diverse extracellular signals,ranging from light and small chemical hormones to large peptide and protein hormones,and as such they play crucial roles in numerous physiological and pathological processes.More importantly,GPCRsare the most successful class of drug targets that are relevant to many major diseases,including cancer,heart failure,and inflammatory diseases.Over 50% of currently used drugs are targeted to GPCRs.However,these drugs target only 50-60 GPCRs,leaving the majority of human GPCRs,exceeding 800,unexplored for drug discovery.Given the prominent roles of GPCRs in biology and their successful track records as drug targets,GPCRs have become a hot frontier in basic research of life science and therapeutic discovery of translational medicines.

  11. Biophysical Discovery through the Lens of a Computational Microscope

    Science.gov (United States)

    Amaro, Rommie

    With exascale computing power on the horizon, improvements in the underlying algorithms and available structural experimental data are enabling new paradigms for chemical discovery. My work has provided key insights for the systematic incorporation of structural information resulting from state-of-the-art biophysical simulations into protocols for inhibitor and drug discovery. We have shown that many disease targets have druggable pockets that are otherwise ``hidden'' in high resolution x-ray structures, and that this is a common theme across a wide range of targets in different disease areas. We continue to push the limits of computational biophysical modeling by expanding the time and length scales accessible to molecular simulation. My sights are set on, ultimately, the development of detailed physical models of cells, as the fundamental unit of life, and two recent achievements highlight our efforts in this arena. First is the development of a molecular and Brownian dynamics multi-scale modeling framework, which allows us to investigate drug binding kinetics in addition to thermodynamics. In parallel, we have made significant progress developing new tools to extend molecular structure to cellular environments. Collectively, these achievements are enabling the investigation of the chemical and biophysical nature of cells at unprecedented scales.

  12. 喉癌 Hep -2细胞来源的 exosomes 的发现和鉴定%Discovery and isolation of exosomes derived from laryngocarcinoma Hep - 2 cells

    Institute of Scientific and Technical Information of China (English)

    吉晓滨; 梁俊毅; 刘启才; 谢景华

    2015-01-01

    Objective:To observe whether laryngocarcinoma Hep - 2 cells can secrete exosomes,and to identify exosomes morphologically. Methods:A large number of laryngocarcinoma Hep - 2 cells were cultivated,the yield of exosomes increased by hot shock,cell culture supernatant was gathered. Firstly,the culture supernatant was pretreat-ment by clarification through a 3 / 0. 8μm small filter element for deep filter to remove particles and impurities with larger diameter. Secondly,exosome isolation kit was used to isolate and extract exosomes. Cells culture supernatant 4ml was gathered,the solutions of the kit were added into the supernatant in proper sequence,then filtered by the special column,the concentrated fluid was obtained. The exosomes were observed under transmission electron microscopy. Re-sults:Exosomes could be isolated and extracted from culture supernatant of laryngocarcinoma Hep - 2 cells,and it present circular or elliptical vesicle with bilayer membrane,high density,well - distribution,and with range from 20 to 100nm of diameter. Conclusion:Exosomes can be secreted from laryngocarcinoma Hep - 2 cells was first discovered, which provide a new research to laryngocarcinoma immunotherapy.%目的:观察喉癌 Hep -2细胞可否分泌 exosomes,并从形态学角度鉴定。方法:大量培养喉癌 Hep -2细胞,热休克处理,收集培养上清。先通过3/0.8μm 深层过滤小型滤芯对上清进行预处理,去除直径较大的颗粒和杂质。采用 Exosome Isolation Kit(商品化试剂盒)收集培养上清液4ml,依次加入 Exosome Isolation Kit内试剂,通过 exosomes 提取专用过滤柱,收集浓缩液。用高倍透射电子显微镜对 exosomes 做鉴定。结果:成功从喉癌 Hep -2细胞培养上清中分离提取出 exosomes,电镜观察见 exosomes 呈圆形或椭圆形双层膜的囊泡状结构,直径约20~100nm,密度较高,分散均匀。结论:首次发现喉癌细胞自身能分泌 exosomes,为喉

  13. A Cell-Based Screening Model for Human PPARα Agonist Ligands Discovery and Its Applicability%基于人PPARα为靶标的药物筛选细胞模型的建立与应用评价

    Institute of Scientific and Technical Information of China (English)

    马晶晶; 张潜; 方宁; 万卫红; 刘祖林; 章涛

    2011-01-01

    目的 构建一种新的、具有生物活性检测能力的人过氧化物酶体增殖物激活受体α(hPPARo)配体药物筛选细胞模型.方法 采用Lipofectamine 2000将含人PPARα基因质粒phPPARα-IRES2-EGFP、含人PPRE报告质粒ptk-PPRE×3-1uc及内部对照质粒pRL-CMV共转染293T细胞,并对phPPARα-IRES2-EGFP转染效率进行流式细胞仪(FCM)分析;通过双荧光素酶报告基因法(DLR)检测不同浓度、不同时间阳性药物WY14643干预共转染细胞体系的荧光素酶表达活性;实验还换用RXRα激动剂全反式维甲酸(ATRA)干预,以评价该细胞模型反应的特异性;并用贝特类降脂药苯扎贝特、环丙贝特、氯贝丁酯对建立的药物筛选细胞模型进行应用能力评价.结果 FCM检测共转染293T细胞phPPARα-IRES2-EGFP质粒转染效率为68%;DLR检测WY14643干预该hPPARα药物筛选模型获得了理想的量—效、时—效关系结果,且该模型不能通过RXRα配体激动剂ATRA激活.苯扎贝特、环丙贝特、氯贝丁酯干预模型均呈现良好的量—效反应性,且反应强度存在差异(P<0.05).结论 成功构建了基于hPPARα为靶标的药物筛选细胞模型,为筛选具有生物活性的hPPARα配体激动剂新药提供了一种可靠的新平台.%OBJECTIVE To establish a novel cell-based model for the screening of human PPARa agonist ligands. METHODS Recombinant plasmid phPPARa-IRES2-EGFP, firefly luciferase-containing report plasmid ptk-PPRE x3-luc and renilla luciferase-containing inner control plasmid pRL-CMV were co-transfected into 293T cells using lipofectamine 2000. The transfection efficiency of phPPARot-IRES2-EGFP was measured by flow cytometry (FCM). Dual-luciferase reporter assay (DLR) was used to detect the lucifer-ase activity of co-transfected 293T cells under concentration gradient at different time points of positive drug WY14643 intervention. Furthermore, WY14643 was replaced by all-trans-retinoic acid (ATRA) , a RXRa

  14. 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.

  15. Discovery and design of nuclear fuels

    Directory of Open Access Journals (Sweden)

    Marius Stan

    2009-11-01

    Full Text Available To facilitate the discovery and design of innovative nuclear fuels, multi-scale models and simulations are used to predict irradiation effects on properties such as thermal conductivity, oxygen diffusivity, and thermal expansion. The multi-scale approach is illustrated using results on ceramic fuels, with a focus on predictions of point defect concentration, stoichiometry, and phase stability. The high performance computer simulations include coupled heat transport, diffusion, and thermal expansion, and gas bubble formation and evolution in a fuel element consisting of UO2 fuel and metallic cladding. The second part of the paper is dedicated to a discussion of an international strategy for developing advanced, innovative nuclear fuels. Four initiatives are proposed to accelerate the discovery and design of new materials: (a Create Institutes for Materials Discovery and Design, (b Create an International Knowledgebase for experimental data, models (mathematical expressions, and simulations (codes, (c Improve education and (d Set up international collaborations.

  16. Antifungal drug discovery: the process and outcomes.

    Science.gov (United States)

    Calderone, Richard; Sun, Nuo; Gay-Andrieu, Francoise; Groutas, William; Weerawarna, Pathum; Prasad, Sridhar; Alex, Deepu; Li, Dongmei

    2014-01-01

    New data suggest that the global incidence of several types of fungal diseases have traditionally been under-documented. Of these, mortality caused by invasive fungal infections remains disturbingly high, equal to or exceeding deaths caused by drug-resistant tuberculosis and malaria. It is clear that basic research on new antifungal drugs, vaccines and diagnostic tools is needed. In this review, we focus upon antifungal drug discovery including in vitro assays, compound libraries and approaches to target identification. Genome mining has made it possible to identify fungal-specific targets; however, new compounds to these targets are apparently not in the antimicrobial pipeline. We suggest that 'repurposing' compounds (off patent) might be a more immediate starting point. Furthermore, we examine the dogma on antifungal discovery and suggest that a major thrust in technologies such as structural biology, homology modeling and virtual imaging is needed to drive discovery. PMID:25046525

  17. Discovery of a novel anti-cancer agent targeting both topoisomerase I and II in hepatocellular carcinoma Hep 3B cells in vitro and in vivo: Cinnamomum verum component 2-methoxycinnamaldehyde.

    Science.gov (United States)

    Perng, Daw-Shyong; Tsai, Yu-Hsin; Cherng, Jonathan; Kuo, Chih-Wei; Shiao, Chih-Chung; Cherng, Jaw-Ming

    2016-08-01

    Cinnamomum verum has been used as a traditional Chinese herbal medicine. We evaluated the anticancer effect of 2-methoxycinnamaldehyde (2-MCA), a constituent of the bark of the plant, in hepatocellular carcinoma Hep 3B cells. The results show that 2-MCA suppressed proliferation and induced apoptosis as indicated by an up-regulation of pro-apoptotic bax and bak genes and down-regulation of anti-apoptotic bcl-2 and bcl-XL genes, mitochondrial membrane potential loss, cytochrome c release, activation of caspase 3 and 9, increase in the DNA content in sub G1, and morphological characteristics of apoptosis. 2-MCA also induced lysosomal vacuolation with increased volume of acidic compartments (VAC), suppressions of nuclear transcription factors NF-κB, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and both topoisomerase I and II activities in a dose-dependent manner. Further study reveals the growth-inhibitory effect of 2-MCA was also evident in a nude mice model. Taken together, the data suggest that the growth-inhibitory effect of 2-MCA against Hep 3B cells is accompanied by downregulations of NF-κB binding activity, inflammatory responses involving COX-2 and PGE2, and proliferative control involving apoptosis, both topoisomerase I and II activities, together with an upregulation of lysosomal vacuolation and VAC. Our data suggest that 2-MCA could be a potential agent for anticancer therapy. PMID:26707867

  18. Stable Feature Selection for Biomarker Discovery

    CERN Document Server

    He, Zengyou

    2010-01-01

    Feature selection techniques have been used as the workhorse in biomarker discovery applications for a long time. Surprisingly, the stability of feature selection with respect to sampling variations has long been under-considered. It is only until recently that this issue has received more and more attention. In this article, we review existing stable feature selection methods for biomarker discovery using a generic hierarchal framework. We have two objectives: (1) providing an overview on this new yet fast growing topic for a convenient reference; (2) categorizing existing methods under an expandable framework for future research and development.

  19. On the 1932 Discovery of the Positron.

    OpenAIRE

    Lawncizak, Alexander; Åsbrink, Victor

    2014-01-01

    An experiment on Cosmic rays performed by Carl D Anderson led to the accidental discovery of the positron in 1932. The discovery was a turning point in particle physics which led to numerous other theories and has been discussed by scientists all over the world. Anderson had photographed a 63 MeV, upward moving electron. The possible origin of such a positron has never before been discussed and is what this report will aim to explain. The report will include some evidence that the particle is...

  20. From the nucleus discovery to DWBA

    International Nuclear Information System (INIS)

    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

  1. Opportunities for isotope discoveries at FRIB

    Science.gov (United States)

    Baumann, T.; Hausmann, M.; Sherrill, B. M.; Tarasov, O. B.

    2016-06-01

    Expected production yields of the Facility for Rare Isotope Beams (FRIB) were calculated for a wide range of rare isotopes using the code LISE++ and planned performance parameters (Tarasov and Bazin, 2008; Bollen et al., 2011 [2]). A comparison between isotope discoveries of the last decade and expected particle yields indicates the range of isotopes that can likely be detected at FRIB. This paper will highlight recent isotope discoveries at NSCL's Coupled Cyclotron Facility and deduce how far the limits could be pushed with the Facility for Rare Isotope Beams.

  2. The discovery of the tau lepton

    International Nuclear Information System (INIS)

    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

  3. What's new, Voyager: The discoveries continue

    Science.gov (United States)

    Miner, Ellis D.

    1995-01-01

    The twin Voyager spacecraft, launched nearly two decades ago, continue to operate and are now searching for the edge of our solar system, the heliopause. Voyager's giant-planet flybys of Jupiter, Saturn, Uranus, and Neptune have provided data that are likely to remain the definitive data set for the foreseeable future and have led to many ongoing discoveries. As the spacecraft move toward the heliopause, they are also providing data on the structure of the heliosphere. This article discusses the discoveries resulting from the flyby and heliosphere data that have been made within the past five years.

  4. Applying genetics in inflammatory disease drug discovery

    DEFF Research Database (Denmark)

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

    2015-01-01

    Recent groundbreaking work in genetics has identified thousands of small-effect genetic variants throughout the genome that are associated with almost all major diseases. These genome-wide association studies (GWAS) are often proposed as a source of future medical breakthroughs. However, with sev...... alongside existing drug discovery methods. Our aim is to evaluate human genetic confidence as a rationale for drug target selection....... 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...

  5. Discovery of convoys in trajectory databases

    DEFF Research Database (Denmark)

    Jeung, Hoyoung; Yiu, Man Lung; Zhou, Xiaofang;

    2008-01-01

    group of objects that have traveled together for some time. More specifically, this paper formalizes the concept of a convoy query using density-based notions, in order to capture groups of arbitrary extents and shapes. Convoy discovery is relevant for real-life applications in throughput planning of...... trucks and carpooling of vehicles. Although there has been extensive research on trajectories in the literature, none of this can be applied to retrieve correctly exact convoy result sets. Motivated by this, we develop three efficient algorithms for convoy discovery that adopt the well-known filter...

  6. Recent Discoveries in Nuclear Line Astrophysics

    Science.gov (United States)

    Boggs, Steven E.

    2016-06-01

    Nuclear gamma-ray lines provide a unique probe of supernovae and nuclear astrophysics. The potential for significant contributions to the understanding supernovae, as well as the large potential for new discoveries, has long been recognized. I will review several major discoveries in the past few years from the NuSTAR and INTEGRAL missions, including observations of SN 1987A, Cas A, and SN 2014J. In addition, I will look forward to the next generation of gamma-ray line instruments currently under development, including wide-field Compton telescopes and focusing lens telescopes.

  7. Pharmacophore modeling for COX-1 and-2 inhibitors with LigandScout in comparison to Discovery Studio

    OpenAIRE

    Temml, V; Kaserer, T.; Kutil, Z. (Zsófia); Landa, P. (Přemysl); Vaněk, T. (Tomáš); Schuster, D.

    2014-01-01

    Pharmacophore modeling has become an integrated tool in drug discovery. However, no prospective study compares the performance of the available software. Methods: The two widely used pharmacophore modeling and screening software programs Discovery Studio and LigandScout were used to generate, validate, and prospectively apply COX-1 and -2 models. Selected virtual hits were tested in cell-free enzymatic assays. The correct retrieval of active compounds was compared. Results: In the enzymatic t...

  8. Droplet Microfluidics for Virus Discovery

    Science.gov (United States)

    Rotem, Assaf; Cockrell, Shelley; Guo, Mira; Pipas, James; Weitz, David

    2012-02-01

    The ability to detect, isolate, and characterize an infectious agent is important for diagnosing and curing infectious diseases. Detecting new viral diseases is a challenge because the number of virus particles is often low and/or localized to a small subset of cells. Even if a new virus is detected, it is difficult to isolate it from clinical or environmental samples where multiple viruses are present each with very different properties. Isolation is crucial for whole genome sequencing because reconstructing a genome from fragments of many different genomes is practically impossible. We present a Droplet Microfluidics platform that can detect, isolate and sequence single viral genomes from complex samples containing mixtures of many viruses. We use metagenomic information about the sample of mixed viruses to select a short genomic sequence whose genome we are interested in characterizing. We then encapsulate single virions from the same sample in picoliter volume droplets and screen for successful PCR amplification of the sequence of interest. The selected drops are pooled and their contents sequenced to reconstruct the genome of interest. This method provides a general tool for detecting, isolating and sequencing genetic elements in clinical and environmental samples.

  9. Recent discoveries of influenza A drug target sites to combat virus replication.

    Science.gov (United States)

    Patel, Hershna; Kukol, Andreas

    2016-06-15

    Sequence variations in the binding sites of influenza A proteins are known to limit the effectiveness of current antiviral drugs. Clinically, this leads to increased rates of virus transmission and pathogenicity. Potential influenza A inhibitors are continually being discovered as a result of high-throughput cell based screening studies, whereas the application of computational tools to aid drug discovery has further increased the number of predicted inhibitors reported. This review brings together the aspects that relate to the identification of influenza A drug target sites and the findings from recent antiviral drug discovery strategies. PMID:27284062

  10. Open drug discovery for the Zika virus

    Science.gov (United States)

    Ekins, Sean; Mietchen, Daniel; Coffee, Megan; Stratton, Thomas P; Freundlich, Joel S; Freitas-Junior, Lucio; Muratov, Eugene; Siqueira-Neto, Jair; Williams, Antony J; Andrade, Carolina

    2016-01-01

    The Zika virus (ZIKV) outbreak in the Americas has caused global concern that we may be on the brink of a healthcare crisis. The lack of research on ZIKV in the over 60 years that we have known about it has left us with little in the way of starting points for drug discovery. Our response can build on previous efforts with virus outbreaks and lean heavily on work done on other flaviviruses such as dengue virus. We provide some suggestions of what might be possible and propose an open drug discovery effort that mobilizes global science efforts and provides leadership, which thus far has been lacking. We also provide a listing of potential resources and molecules that could be prioritized for testing as in vitro assays for ZIKV are developed. We propose also that in order to incentivize drug discovery, a neglected disease priority review voucher should be available to those who successfully develop an FDA approved treatment. Learning from the response to the ZIKV, the approaches to drug discovery used and the success and failures will be critical for future infectious disease outbreaks.

  11. Milestones in Cancer Research and Discovery

    Science.gov (United States)

    During the past 250 years, we have witnessed many landmark discoveries in our efforts to make progress against cancer, an affliction known to humanity for thousands of years. This timeline shows a few key milestones in the history of cancer research.

  12. 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...— (i) Is necessary for the expeditious, fair, and reasonable consideration of the issues; (ii) Is...

  13. Data mining and knowledge discovery handbook

    CERN Document Server

    Maimon, Oded

    2010-01-01

    This book organizes key concepts, theories, standards, methodologies, trends, challenges and applications of data mining and knowledge discovery in databases. It first surveys, then provides comprehensive yet concise algorithmic descriptions of methods, including classic methods plus the extensions and novel methods developed recently. It also gives in-depth descriptions of data mining applications in various interdisciplinary industries.

  14. 36 CFR 1150.63 - Discovery.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Discovery. 1150.63 Section 1150.63 Parks, Forests, and Public Property ARCHITECTURAL AND TRANSPORTATION BARRIERS COMPLIANCE BOARD... satisfactory to the judge, the judge may decide the fact or issue relating to the material requested to...

  15. Knowledge discovery data and text mining

    CERN Document Server

    Olmer, Petr

    2008-01-01

    Data mining and text mining refer to techniques, models, algorithms, and processes for knowledge discovery and extraction. Basic de nitions are given together with the description of a standard data mining process. Common models and algorithms are presented. Attention is given to text clustering, how to convert unstructured text to structured data (vectors), and how to compute their importance and position within clusters.

  16. Rule Discovery with a Parallel Genetic Algorithm

    OpenAIRE

    Araujo, Dieferson L.A.; Lopes, Heitor S.; Freitas, Alex. A.

    2000-01-01

    An important issue in data mining is scalability with respect to the size of the dataset being mined. In the paper we address this issue by presenting a parallel GA for rule discovery. This algorithm exploits both data parallelism, by distributing the data being mined across all available processors, and control parallelism, by distributing the population of individuals across all available processors.

  17. Open drug discovery for the Zika virus.

    Science.gov (United States)

    Ekins, Sean; Mietchen, Daniel; Coffee, Megan; Stratton, Thomas P; Freundlich, Joel S; Freitas-Junior, Lucio; Muratov, Eugene; Siqueira-Neto, Jair; Williams, Antony J; Andrade, Carolina

    2016-01-01

    The Zika virus (ZIKV) outbreak in the Americas has caused global concern that we may be on the brink of a healthcare crisis. The lack of research on ZIKV in the over 60 years that we have known about it has left us with little in the way of starting points for drug discovery. Our response can build on previous efforts with virus outbreaks and lean heavily on work done on other flaviviruses such as dengue virus. We provide some suggestions of what might be possible and propose an open drug discovery effort that mobilizes global science efforts and provides leadership, which thus far has been lacking. We also provide a listing of potential resources and molecules that could be prioritized for testing as in vitro assays for ZIKV are developed. We propose also that in order to incentivize drug discovery, a neglected disease priority review voucher should be available to those who successfully develop an FDA approved treatment. Learning from the response to the ZIKV, the approaches to drug discovery used and the success and failures will be critical for future infectious disease outbreaks. PMID:27134728

  18. Discoveries in Rubisco: a historical perspective

    Science.gov (United States)

    Historic discoveries and key observations related to Rubisco (ribulose 1,5-bisphosphate carboxylase/oxygenase), from 1947 to 2006, are presented. Currently, around 200 papers describing Rubisco research are published each year and the literature contains more than 5000 manuscripts on the subject. Wh...

  19. 2014 update of the discoveries of nuclides

    International Nuclear Information System (INIS)

    The 2014 update of the discovery of nuclide project is presented. Only six new nuclides were observed for the first time in 2014 while the assignments of 17 other nuclides were revised. In addition, for another 14 nuclides the laboratories where they were discovered were reassigned. (author)

  20. Current Discoveries and Interventions for Barlow's Disease.

    Science.gov (United States)

    Siordia, Juan A

    2016-08-01

    Mitral valve prolapse is a common valve pathology. One particular type of mitral valve prolapse that can be difficult to treat is Barlow's disease. This review serves to give insight on the current discoveries and therapeutic interventions of Barlow's disease. PMID:27312933

  1. Aztec Mexico: Discovery of Templo Mayor.

    Science.gov (United States)

    Breslav, Marc

    1982-01-01

    Describes the Aztec archaeological artifacts shown in the American Museum of Natural History exhibit: "Aztec Mexico: Discovery of Templo Mayor." More than 100 objects, ranging from human skulls to jewelry, found in the excavation of the Great Temple of Mexico located under the center of Mexico City, were displayed. (AM)

  2. Discovery – Methotrexate: Chemotherapy Treatment for Cancer

    Science.gov (United States)

    Prior to the 1950s, treatment for the majority of cancers was limited to either surgery or the use of radiation. The discovery of the use of methotrexate in curing a rare cancer marked the first time a cancer had been cured. This led to the development of many of today’s common cancer treatments.

  3. 24 CFR 26.18 - Discovery.

    Science.gov (United States)

    2010-04-01

    ... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Discovery. 26.18 Section 26.18 Housing and Urban Development Office of the Secretary, Department of Housing and Urban Development HEARING... will not compel the disclosure of privileged information, unduly delay the hearing, or result...

  4. Scientific Discoveries the Year I Was Born

    Science.gov (United States)

    Cherif, Abour

    2012-01-01

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

  5. Neutrino discoveries lead to precision measurements

    CERN Document Server

    Altmann, M

    2002-01-01

    The science of neutrino physics has reached a watershed, with discovery giving way to precision measurements. The author reports from the XXth International Conference on Neutrino Physics and Astrophysics. Topics covered are low-energy neutrinos, atmospheric neutrinos, long-baseline experiments, accelerator experiments, neutrino properties, neutrinos in astrophysics and cosmology, dark matter and neutrino telescopes.

  6. (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…

  7. 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.

  8. Routing Discovery Algorithm Using Parallel Chase Packet

    Directory of Open Access Journals (Sweden)

    Amera Al-Ameri

    2013-04-01

    Full Text Available On demand routing protocols for ad hoc networks such as Ad Hoc On Demand Distance Vector (AODV initiate a route discovery process when a route is needed by flooding the network with a route request packet. The route discovery process in such protocols depends on a simple flooding as a broadcast technique due to its simplicity. Simple flooding results in packet congestion, route request overhead and excessive collisions, namely broadcast storm problem. A number of routing techniques have been proposed to control the simple flooding technique. Ideally, the broadcast of route request or the route discovery process must be stopped as soon as the destination node is found. This will free the network from many redundant packets that may cause network collision and contention. In this paper, chasing packet technique is used with standard AODV routing protocol to end the fulfilled route requests. The chase packet is initiated by the source node and is broadcasted in parallel with route request packet. As soon as the destination is found the chase packet starts its work by trying to catch and discard the route request in early stages before it broadcasts further in the network. Performance evaluation is conducted using simulation to investigate the performance of the proposed scheme against the existing approach that uses chase packet technique such as Traffic Locality Route Discovery Algorithm with Chase (TLRDA-C. Results reveal that the proposed scheme minimizes end-to-end packet delays and achieves low routing request overhead.

  9. 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...

  10. 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...

  11. Knowledge Discovery from Communication Network Alarm Databases

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The technique of Knowledge Discovery in Databases(KDD) to learn valuable knowledge hidden in network alarm databases is introduced. To get such knowledge, we propose an efficient method based on sliding windows (named as Slidwin) to discover different episode rules from time sequential alarm data. The experimental results show that given different thresholds parameters, large amount of different rules could be discovered quickly.

  12. Discovery of the Isotopes with Z <= 10

    OpenAIRE

    Thoennessen, M

    2010-01-01

    A total of 126 isotopes with Z $\\le$ 10 have been identified to date. The discovery of these isotopes which includes the observation of unbound nuclei, is discussed. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.

  13. 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.

  14. Data mining and knowledge discovery handbook

    CERN Document Server

    Maimon, Oded

    2006-01-01

    Organizes major concepts, theories, methodologies, trends, challenges and applications of data mining (DM) and knowledge discovery in databases (KDD). This book provides algorithmic descriptions of classic methods, and also suitable for professionals in fields such as computing applications, information systems management, and more.

  15. OPTIMIZED GATEWAY DISCOVERY IN HYBRID MANETS

    Directory of Open Access Journals (Sweden)

    A.Triviño

    2009-10-01

    Full Text Available Mobile users are expected to demand access to the Internet anywhere and anytime. In a MANET context,a device which is about to connect to external hosts needs the route to the element which communicatesthe MANET with the Internet. This element is the Internet Gateway. To inform about its presence as wellas about some configuration parameters, the Gateway sends MRA messages. In a similar way to ad hocrouting protocols, the Gateway can generate the messages on demand (reactively, periodically(proactively or combining both previous strategies in a hybrid gateway discovery. Specifically, in thehybrid gateway discovery, the Gateway periodically sends the MRA messages in a restricted area. Thenodes that are outside this area demand the Gateway information reactively. This gateway discoveryrequires the setting of the number of hops that define the proactive area, also called the TTL value.Network performance can be improved when the Gateway uses information such as the position of thesources to adjust the TTL value. In this paper, we transfer the decision about the dimensions of theproactive zone to the mobile nodes so more network conditions are taken into account. Simulation resultsshow that the proposed gateway discovery outperforms other hybrid gateway discovery schemes.

  16. 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 natura

  17. The Discovery and Progress of AIDS

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    @@ 1 The Discovery It is a modern plague: the first great pandemic ofthe second half of the 20th century. The plat, clinic-sounding name given to the disease by epidemiolo-gists- acquired immune deficiency syndrome- hasbeen shortened to AIDS.

  18. 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.

  19. 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.

  20. 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.

  1. FLAVIdB: A data mining system for knowledge discovery in flaviviruses with direct applications in immunology and vaccinology

    DEFF Research Database (Denmark)

    Olsen, Lars Rønn; Zhang, Guang Lan; Reinherz, Ellis L.;

    2011-01-01

    -cell epitope prediction, and characterization of neutralizing components of B-cell epitopes. FLAVIdB is accessible at cvc.dfci.harvard.edu/flavi/  Conclusion: FLAVIdB represents a new generation of databases in which data and tools are integrated into a data mining infrastructures specifically designed to aid...... rational vaccine design by discovery of vaccine targets....

  2. Amyotrophic Lateral Sclerosis: An Emerging Era of Collaborative Gene Discovery

    Science.gov (United States)

    Gwinn, Katrina; Corriveau, Roderick A.; Mitsumoto, Hiroshi; Bednarz, Kate; Brown, Robert H.; Cudkowicz, Merit; Gordon, Paul H.; Hardy, John; Kasarskis, Edward J.; Kaufmann, Petra; Miller, Robert; Sorenson, Eric; Tandan, Rup; Traynor, Bryan J.; Nash, Josefina; Sherman, Alex; Mailman, Matthew D.; Ostell, James; Bruijn, Lucie; Cwik, Valerie; Rich, Stephen S.; Singleton, Andrew; Refolo, Larry; Andrews, Jaime; Zhang, Ran; Conwit, Robin; Keller, Margaret A.

    2007-01-01

    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. PMID:18060051

  3. Do Giant Oilfield Discoveries Fuel Internal Armed Conflicts?

    OpenAIRE

    Lei, Yu-Hsiang; Michaels, Guy

    2012-01-01

    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 conflict...

  4. Discovery of Potent, Selective and Reversible Caspase-3 Inhibitors

    Institute of Scientific and Technical Information of China (English)

    Han Yongxin; John Tam; Paul Tawa; Donald W. Nicholson; Robert J. Zamboni; André Giroux; John Colucci; Christopher I. Bayly; Daniel J. Mckay; Sophie Roy; Steve Xanthoudakis; John Vaillancourt; Dita M. Rasper

    2004-01-01

    Recent studies towards understanding the molecular mechanisms of apoptosis have revealed the importance of a group of cysteinyl aspartate specific proteases, the caspases, in the programmed cell death process (Hengartner, M.O. Nature 2000, 407, 770). Caspase-3, in particular,has been characterized as the dominant effector caspase involved in the proteolytic cleavage of a variety of protein substrates including cytoskeletal proteins, kinases and DNA repair enzymes during apoptosis (Nicholson, D. W. Cell Death Differ. 1999, 6, 1028). The development of potent and selective caspase-3 inhibitors has thus emerged as an attractive therapeutic target. In the presentation,the identification of a series of potent, selective and reversible non-peptidyl caspase-3 inhibitors containing a pyrazinone core (1) will be presented. SAR optimization at R1, R2, R3 and R4 led to the discovery of inhibitors such as 2 with excellent in vitro activities (IC50 against rh-caspase-3: 5 nM; IC50 against camptothecin induced apoptotic cell death in NT2 cells: 20 nM). Compounds such as 2 also displayed excellent in vivo activities in a number of animal models of acute injuries (see: Methot, N. et al, J. Exp. Med. 2004, 119, 199; Toulmond, S. et al, British J. Pharm. 2004, 141,689; Holtzman,D.M. et al, JBC, 2002, 277, 30128), and selected examples will be discussed during the presentation.

  5. Discovery learning and learner autonomy development in secondary vocational school

    Institute of Scientific and Technical Information of China (English)

    刘芩利

    2015-01-01

    It is imperative to cultivate learner autonomy in secondary vocational school and discovery learning is a good choice.The author reviews the definition and principle of discovery learning and learning autonomy,concludes the adaptation of discovery learning from characteristics of vocational students,and finally illustrates an example in teaching.

  6. 29 CFR 2200.52 - General provisions governing discovery.

    Science.gov (United States)

    2010-07-01

    ... the hearing through new requests for supplementation of prior responses. (j) Filing of discovery... 29 Labor 9 2010-07-01 2010-07-01 false General provisions governing discovery. 2200.52 Section... COMMISSION RULES OF PROCEDURE Prehearing Procedures and Discovery § 2200.52 General provisions...

  7. 5 CFR 1201.72 - Explanation and scope of discovery.

    Science.gov (United States)

    2010-01-01

    ... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Explanation and scope of discovery. 1201.72 Section 1201.72 Administrative Personnel MERIT SYSTEMS PROTECTION BOARD ORGANIZATION AND... of discovery. (a) Explanation. Discovery is the process, apart from the hearing, by which a party...

  8. 5 CFR 1201.73 - Initial disclosures and discovery procedures.

    Science.gov (United States)

    2010-01-01

    ... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Initial disclosures and discovery procedures. 1201.73 Section 1201.73 Administrative Personnel MERIT SYSTEMS PROTECTION BOARD ORGANIZATION AND... discovery from another party must start the process by serving a request for discovery on the...

  9. 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 real

  10. 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.

  11. Panorama 2014 - New oil and gas discoveries

    International Nuclear Information System (INIS)

    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)

  12. Semantic-Discovery of Construction Project Files

    Institute of Scientific and Technical Information of China (English)

    PAN Jiayi; Chimay J. Anumba

    2008-01-01

    The dynamics of a construction project generates a huge amount of information for processing.Most project information is recorded in digital files and managed in a decentralized way. Current document management tools do not consider the semantic relationships between files and then cannot discover files based on their content or ensure information consistency across various information repositories. This paper presents a semantic-discovery method for accessing project information across repositories. By adopting semantic web technologies, including extensible markup language (XML), ontology, and logic rules, the se-mantic-discovery tool can access project files by their properties and relations. The method has been ap-plied to searching for files using documents from a real project. The results show that the semantic content of a file can be used to ensure that only related files are retrieved.

  13. Shell appraising deepwater discovery off Philippines

    Energy Technology Data Exchange (ETDEWEB)

    Scherer, M. (Shell Philippines Exploration, Manila (Philippines)); Lambers, E.J.T.; Steffens, G.S. (Shell International Petroleum Co. Ltd., London (United Kingdom))

    1993-05-10

    Shell International Petroleum Co. Ltd. negotiated a farmout in 1990 from Occidental International Exploration and Production Co. for Block SC-38 in the South China Sea off Palawan, Philippines, following Oxy's discovery of gas in 1989 in a Miocene Nido limestone buildup. Under the terms of the farmout agreement, Shell became operator with a 50% share. Following the disappointing well North Iloc 1, Shell was successful in finding oil and gas in Malampaya 1. Water 700-1,000 m deep, remoteness, and adverse weather conditions have imposed major challenges for offshore operations. The paper describes the tectonic setting; the Nido limestone play; the Malampaya discovery; and Shell's appraisal studies.

  14. Knowledge Discovery in Databases and Libraries

    Directory of Open Access Journals (Sweden)

    Anil Kumar Dhiman

    2011-11-01

    Full Text Available The advancement in information and communication technology (ICT has outpaced our abilities to analyse, summarise, and extract knowledge from the data. Today, database technology has provided us with the basic tools for the efficient storage and lookup of large data sets, but the issue of how to help human beings to understand and analyse large bodies of data remains a difficult and unsolved problem. So, intelligent tools for automated data mining and knowledge discovery are needed to deal with enormous data. As library and information centre are considered the backbone of knowledge organisation, knowledge discovery in databases (KDD is also getting attention of library and information scientists. This paper highlights the basics of KDD process and its importance in digital libraries.

  15. Discovery of Invariants through Automated Theory Formation

    CERN Document Server

    Llano, Maria Teresa; Pease, Alison; 10.4204/EPTCS.55.1

    2011-01-01

    Refinement is a powerful mechanism for mastering the complexities that arise when formally modelling systems. Refinement also brings with it additional proof obligations -- requiring a developer to discover properties relating to their design decisions. With the goal of reducing this burden, we have investigated how a general purpose theory formation tool, HR, can be used to automate the discovery of such properties within the context of Event-B. Here we develop a heuristic approach to the automatic discovery of invariants and report upon a series of experiments that we undertook in order to evaluate our approach. The set of heuristics developed provides systematic guidance in tailoring HR for a given Event-B development. These heuristics are based upon proof-failure analysis, and have given rise to some promising results.

  16. 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...

  17. 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...

  18. Exploiting Social Annotation for Automatic Resource Discovery

    CERN Document Server

    Plangprasopchok, Anon

    2007-01-01

    Information integration applications, such as mediators or mashups, that require access to information resources currently rely on users manually discovering and integrating them in the application. Manual resource discovery is a slow process, requiring the user to sift through results obtained via keyword-based search. Although search methods have advanced to include evidence from document contents, its metadata and the contents and link structure of the referring pages, they still do not adequately cover information sources -- often called ``the hidden Web''-- that dynamically generate documents in response to a query. The recently popular social bookmarking sites, which allow users to annotate and share metadata about various information sources, provide rich evidence for resource discovery. In this paper, we describe a probabilistic model of the user annotation process in a social bookmarking system del.icio.us. We then use the model to automatically find resources relevant to a particular information dom...

  19. The proteomics in prostate cancer biomarker discovery

    Directory of Open Access Journals (Sweden)

    V. E. Shevchenko

    2015-06-01

    Full Text Available Prostate cancer (PC represents the second most frequent type of tumor in men worldwide. Proteomics represents a promising approach for the discovery of new biomarkers able to improve the management of PC patients. Markers more specific and sensitive than prostate-specific antigen are needed for PC diagnosis, prognosis and response to treatment. Moreover, proteomics could represent an important tool to identify new molecular targets for PC tailored therapy. Now several possible PC biomarkers sources, each with advantages and limitations, are under investigation, including tissues, urine, serum, plasma and prostatic fluids. Innovative high-throughput proteomic platforms are now identifying and quantifying new specific and sensitive biomarkers for PC detection, stratification and treatment. Nevertheless, many putative biomarkers are still far from being applied in clinical practice.This review aims to discuss the recent advances in PC proteomics, emphasizing biomarker discovery and their application to clinical utility for diagnosis and patient stratification.

  20. Discovery of Convoys in Trajectory Databases

    CERN Document Server

    Jeung, Hoyoung; Zhou, Xiaofang; Jensen, Christian S; Shen, Heng Tao

    2010-01-01

    As mobile devices with positioning capabilities continue to proliferate, data management for so-called trajectory databases that capture the historical movements of populations of moving objects becomes important. This paper considers the querying of such databases for convoys, a convoy being a group of objects that have traveled together for some time. More specifically, this paper formalizes the concept of a convoy query using density-based notions, in order to capture groups of arbitrary extents and shapes. Convoy discovery is relevant for real-life applications in throughput planning of trucks and carpooling of vehicles. Although there has been extensive research on trajectories in the literature, none of this can be applied to retrieve correctly exact convoy result sets. Motivated by this, we develop three efficient algorithms for convoy discovery that adopt the well-known filter-refinement framework. In the filter step, we apply line-simplification techniques on the trajectories and establish distance b...

  1. Secure Neighbor Position Discovery in VANETs

    CERN Document Server

    Fiore, Marco; Chiasserini, Carla Fabiana; Papadimitratos, Panagiotis

    2010-01-01

    Many significant functionalities of vehicular ad hoc networks (VANETs) require that nodes have knowledge of the positions of other vehicles, and notably of those within communication range. However, adversarial nodes could provide false position information or disrupt the acquisition of such information. Thus, in VANETs, the discovery of neighbor positions should be performed in a secure manner. In spite of a multitude of security protocols in the literature, there is no secure discovery protocol for neighbors positions. We address this problem in our paper: we design a distributed protocol that relies solely on information exchange among one-hop neighbors, we analyze its security properties in presence of one or multiple (independent or colluding) adversaries, and we evaluate its performance in a VANET environment using realistic mobility traces. We show that our protocol can be highly effective in detecting falsified position information, while maintaining a low rate of false positive detections.

  2. Supernova discoveries 2010: statistics and trends

    CERN Document Server

    Gal-Yam, Avishay

    2013-01-01

    We have inspected all supernova discoveries reported during 2010, a total of 538 events. This number includes a small number of "supernova impostors" (bright extragalactic eruptions) but not novae or events that turned out to be Galactic stars. We examine the statistics of all discovered objects, as well as those of the subset of spectroscopically-confirmed events. This year shows the rise of wide-field non-targeted supernova surveys to prominence, with the largest numbers of events contributed by the CRTS and PTF surveys (189 and 88 events respectively), followed by the integrated contribution of numerous amateurs (82 events). Among spectroscopically-confirmed events the PTF (88 events) leads, before amateur discoveries (69 events), closely followed by the CRTS and PS1 surveys (67 and 63 events, respectively). Traditional galaxy-targeted surveys such as LOSS and CHASE, maintain a strong contribution (50 and 36 events, respectively) with high spectroscopic completeness (96% for LOSS). It is interesting to not...

  3. Ontology Based Qos Driven Web Service Discovery

    Directory of Open Access Journals (Sweden)

    R Suganyakala

    2011-07-01

    Full Text Available In today's scenario web services have become a grand vision to implement the business process functionalities. With increase in number of similar web services, one of the essential challenges is to discover relevant web service with regard to user specification. Relevancy of web service discovery can be improved by augmenting semantics through expressive formats like OWL. QoS based service selection will play a significant role in meeting the non-functional user requirements. Hence QoS and semantics has been used as finer search constraints to discover the most relevant service. In this paper, we describe a QoS framework for ontology based web service discovery. The QoS factors taken into consideration are execution time, response time, throughput, scalability, reputation, accessibility and availability. The behavior of each web service at various instances is observed over a period of time and their QoS based performance is analyzed.

  4. In Silico Discovery of Aminoacyl-tRNA Synthetase Inhibitors

    Directory of Open Access Journals (Sweden)

    Yaxue Zhao

    2014-01-01

    Full Text Available Aminoacyl-tRNA synthetases (aaRSs are enzymes that catalyze the transfer of amino acids to their cognate tRNA. They play a pivotal role in protein synthesis and are essential for cell growth and survival. The aaRSs are one of the leading targets for development of antibiotic agents. In this review, we mainly focused on aaRS inhibitor discovery and development using in silico methods including virtual screening and structure-based drug design. These computational methods are relatively fast and cheap, and are proving to be of great benefit for the rational development of more potent aaRS inhibitors and other pharmaceutical agents that may usher in a much needed generation of new antibiotics.

  5. Lambda-Display: A Powerful Tool for Antigen Discovery

    Directory of Open Access Journals (Sweden)

    Nicola Gargano

    2011-04-01

    Full Text Available Since its introduction in 1985, phage display technology has been successfully used in projects aimed at deciphering biological processes and isolating molecules of practical value in several applications. Bacteriophage lambda, representing a classical molecular cloning and expression system has also been exploited for generating large combinatorial libraries of small peptides and protein domains exposed on its capsid. More recently, lambda display has been consistently and successfully employed for domain mapping, antigen discovery and protein interaction studies or, more generally, in functional genomics. We show here the results obtained by the use of large libraries of cDNA and genomic DNA for the molecular dissection of the human B-cell response against complex pathogens, including protozoan parasites, bacteria and viruses. Moreover, by reviewing the experimental work performed in recent investigations we illustrate the potential of lambda display in the diagnostics field and for identifying antigens useful as targets for vaccine development.

  6. Discovery pharmaceutics—Challenges and opportunities

    OpenAIRE

    Chen, Xue-Qing; Antman, Melissa D.; Gesenberg, Christoph; Gudmundsson, Olafur S.

    2006-01-01

    Most pharmaceutical companies are now evaluating compounds for druglike properties early in the discovery process. The data generated at these early stages allow upfront identification of potential development challenges and thus selection of the best candidates for lead nomination. Most often, lead nomination candidates are selected based on pharmacological and toxicological data. However, many drugs in development suffer from poor biopharmaceutical properties due to suboptimal physiochemica...

  7. Discovery of periodic patterns in spatiotemporal sequences

    OpenAIRE

    Cao, H.; Mamoulis, N; Cheung, DW

    2007-01-01

    In many applications that track and analyze spatiotemporal data, movements obey periodic patterns; the objects follow the same routes (approximately) over regular time intervals. For example, people wake up at the same time and follow more or less the same route to their work everyday. The discovery of hidden periodic patterns in spatiotemporal data could unveil important information to the data analyst. Existing approaches for discovering periodic patterns focus on symbol sequences. However,...

  8. New discoveries in Upper and Middle Magdalena

    International Nuclear Information System (INIS)

    In six association contracts and one risk participation contract may give Colombia the possibility of finding new oil reserves. These prospects, located in the Upper and Middle Magdalena Valleys and the Eastern Plains. the completion process, evaluation, confirmation and commercialization should be in the next two years, these new discoveries also reveal interesting geological aspects; some in fractured limestone, similar to the found at Maracaibo lake in Venezuela, where vast oil fields were discovered

  9. Decomposing PPI networks for complex discovery

    Directory of Open Access Journals (Sweden)

    Chua Hon Nian

    2011-10-01

    Full Text Available Abstract Background Protein complexes are important for understanding principles of cellular organization and functions. With the availability of large amounts of high-throughput protein-protein interactions (PPI, many algorithms have been proposed to discover protein complexes from PPI networks. However, existing algorithms generally do not take into consideration the fact that not all the interactions in a PPI network take place at the same time. As a result, predicted complexes often contain many spuriously included proteins, precluding them from matching true complexes. Results We propose two methods to tackle this problem: (1 The localization GO term decomposition method: We utilize cellular component Gene Ontology (GO terms to decompose PPI networks into several smaller networks such that the proteins in each decomposed network are annotated with the same cellular component GO term. (2 The hub removal method: This method is based on the observation that hub proteins are more likely to fuse clusters that correspond to different complexes. To avoid this, we remove hub proteins from PPI networks, and then apply a complex discovery algorithm on the remaining PPI network. The removed hub proteins are added back to the generated clusters afterwards. We tested the two methods on the yeast PPI network downloaded from BioGRID. Our results show that these methods can improve the performance of several complex discovery algorithms significantly. Further improvement in performance is achieved when we apply them in tandem. Conclusions The performance of complex discovery algorithms is hindered by the fact that not all the interactions in a PPI network take place at the same time. We tackle this problem by using localization GO terms or hubs to decompose a PPI network before complex discovery, which achieves considerable improvement.

  10. Discovery of the intermediate W boson

    CERN Multimedia

    1983-01-01

    Press conference on 25 January 1983 when the announcement was made of the discovery of the intermediate W boson at CERN. From right to left: Carlo Rubbia, spokesman of the UA1 experiment; Simon van der Meer, responsible for developing the stochastic cooling technique; Herwig Schopper, Director- General of CERN; Erwin Gabathuler, Research Director at CERN, and Pierre Darriulat, spokesman of the UA2 experiment, whose results confirmed those from Carlo Rubbia's experiment.

  11. Discovery stories in the science classroom

    OpenAIRE

    Arya, Diana Jaleh

    2010-01-01

    School science has been criticized for its lack of emphasis on the tentative, dynamic nature of science as a process of learning more about our world. This criticism is the guiding force for this present body of work, which focuses on the question: what are the educational benefits for middle school students of reading texts that highlight the process of science in the form of a discovery narrative? This dissertation traces my journey through a review of theoretical perspectives of narrative...

  12. CMB Anisotropies: Their Discovery and Utilization

    OpenAIRE

    Smoot, George F.

    2008-01-01

    This article is a written and modified version of a talk presented at the conference `A Century of Cosmology' held at San Servolo, Venice, Italy, in August 2007. The talk focuses on some of the cosmology history leading to the discovery and exploitation of Cosmic Microwave Background (CMB) Radiation anisotropies. We have made tremendous advances first in the development of the techniques to observe these anisotropies and in observing and interpreting them to extract their contained cosmologic...

  13. Discovery of antiprotozoal compounds from medicinal plants

    OpenAIRE

    Hata, Yoshie

    2014-01-01

    Tropical parasitic diseases such as malaria, human African trypanosomiasis, chagas disease, and leishmaniasis affect hundreds of millions of people worldwide and have devastating consequences. Current drugs available to treat these diseases have serious drawbacks. New drugs are urgently needed. Natural products (NPs) play a dominant role in drug discovery for the treatment of human diseases. Particularly, quinine and artemisinin have their origin in nature and have inspired successful dru...

  14. Discoveries and diversions in natural product synthesis

    OpenAIRE

    Reisman, Sarah E.

    2013-01-01

    Our lab. seeks to discover, develop, and study new chem. reactions within the context of natural product total synthesis. The chem. synthesis of natural products enables the study of their biol. properties, and can provide access to synthetic derivs. with improved therapeutic properties or that can serve as mechanistic probes. Importantly, these synthetic undertakings often highlight shortcomings of the existing state-of-the-art and inspire the discovery of new chem. Our lab. has ...

  15. Methods of Knowledge Discovery in Tweets

    OpenAIRE

    Yoon, Sunmoo; Bakken, Suzanne

    2012-01-01

    The purposes of this methodological paper are: 1) to describe web mining methods for knowledge discovery in Tweets, and 2) to illustrate application of the methods using the topic of physical activity. Methods described include: 1) structure mining to discover structures (macro-, meso-, and micro-level) of Tweet networks using social network analysis, and 2) content mining to discover Tweet contents using n-gram based text analysis and sentiment analysis. Specific web mining tools for each st...

  16. Causal discovery from medical textual data.

    OpenAIRE

    Mani, S.; Cooper, G. F.

    2000-01-01

    Medical records usually incorporate investigative reports, historical notes, patient encounters or discharge summaries as textual data. This study focused on learning causal relationships from intensive care unit (ICU) discharge summaries of 1611 patients. Identification of the causal factors of clinical conditions and outcomes can help us formulate better management, prevention and control strategies for the improvement of health care. For causal discovery we applied the Local Causal Discove...

  17. Knowledge Discovery in Databases for Competitive Advantage

    OpenAIRE

    Mark Gilchrist; Deana Lehmann Mooers; Glenn Skrubbeltrang; Francine Vachon

    2012-01-01

    In today¡¯s increasingly competitive business world, organizations are using ICT to advance their business strategies and increase their competitive advantage. One technological element that is growing in popularity is knowledge discovery in databases (KDD). In this paper, we propose an analytic framework which is applied to two cases concerning KDD. The first case presents an organization at the analysis stage of a KDD project. The second one shows how a multinational company leverages its d...

  18. Aspects of knowledge discovery in technical data

    Science.gov (United States)

    Brueckner, Steffen; Rudolph, Stephan

    2002-03-01

    In many engineering applications numerical software has reached a more or less satisfactory quality of predicting the system behavior. A major disadvantage with this kind of software is that it can only be used in a later step in the engineering design process since it requires a detailed system model, such as a finite element simulation model for structural mechanics. Finite element software can only give satisfying results when the complete geometry and all material parameters are specified. However, despite all the parameter definitions in such simulation models, still a severe validation effort with experiments is needed to investigate the model abstractions. Especially in the early conceptual design phase, a need for simplified modeling and the prediction of the system behavior using only little knowledge about a new design exists. This kind of conceptual knowledge can be given e.g. in simple algebraic equations. These equations can either be derived from first principles or from knowledge discovery in data of previous designs, the latter being the topic of this work. Huge amounts of experimental data have been recorded and stored by industry especially in the past ten years with microcomputers being available throughout the companies. Additionally the engineering domain, other than e.g. the business domain, has the advantage that at least a small number of planned experiments can be conducted to enhance the data quantity and quality and to validate the knowledge discovery results. This paper emphasizes the need for a modified knowledge discovery process for engineering (and other scientific domains) and shows the differences to the traditional knowledge discovery in data bases.

  19. 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...

  20. Pathways to new drug discovery in neuropsychiatry

    OpenAIRE

    Berk Michael

    2012-01-01

    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...

  1. Adaptation Knowledge Discovery from a Case Base

    OpenAIRE

    D'Aquin, Mathieu; Badra, Fadi; Lafrogne, Sandrine; Lieber, Jean; Napoli, Amedeo; Szathmary, Laszlo

    2006-01-01

    In case-based reasoning, the adaptation step depends in general on domain-dependent knowledge, which motivates studies on adaptation knowledge acquisition (AKA). CABAMAKA is an AKA system based on principles of knowledge discovery from databases. This system explores the variations within the case base to elicit adaptation knowledge. It has been successfully tested in an application of case-based decision support to breast cancer treatment.

  2. Export Discoveries, Diversification and Barriers to Entry

    OpenAIRE

    Klinger, Bailey; Lederman, Daniel

    2011-01-01

    The literature on the relationship between economic diversification and development established that diversification rises with development up to a point. Some have argued that market failures reduce private investments that are necessary to find out whether a new product can be exported profitably, thus implying that the threat of entry can reduce export discoveries and consequently hamper diversification. In parallel, the trade literature on the "extensive margin" of trade has focused on th...

  3. 43 CFR 10.4 - Inadvertent discoveries.

    Science.gov (United States)

    2010-10-01

    ... National Historical Preservation Act (16 U.S.C. 470 (f) et seq.), 36 CFR 800.11 or section 3 (a) of the... Preservation Act (16 U.S.C. 470 (f) et seq.), 36 CFR 800.11 or section 3 (a) of the Archeological and Historic... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Inadvertent discoveries. 10.4 Section...

  4. Choosing experiments to accelerate collective discovery

    OpenAIRE

    Rzhetsky, Andrey; Foster, Jacob G.; Foster, Ian T.; Evans, James A.

    2015-01-01

    Scientists perform a tiny subset of all possible experiments. What characterizes the experiments they choose? And what are the consequences of those choices for the pace of scientific discovery? We model scientific knowledge as a network and science as a sequence of experiments designed to gradually uncover it. By analyzing millions of biomedical articles published over 30 y, we find that biomedical scientists pursue conservative research strategies exploring the local neighborhood of central...

  5. Web Usage Mining: Pattern Discovery and Forecasting

    OpenAIRE

    Jagli, Mrs. Dhanamma; Oswal, Sangeeta

    2013-01-01

    Web usage mining: automatic discovery of patterns in clickstreams and associated data collected or generated as a result of user interactions with one or more Web sites. This paper describes web usage mining for our college log files to analyze the behavioral patterns and profiles of users interacting with a Web site. The discovered patterns are represented as clusters that are frequently accessed by groups of visitors with common interests. In this paper, the visitors and hits were forecaste...

  6. Pattern discovery techniques in Web mining

    OpenAIRE

    Mirela Pater; Popescu, Daniela E.; Daniela Maştei

    2008-01-01

    With the huge amount of information availableonline, the World Wide Web is a fertile area for datamining. Application of data mining techniques to theWorld Wide Web, referred to as Web mining, has beenthe focus of several recent research projects and papers.In this paper we define Web mining and present anoverview of the various research issues, techniques anddevelopment efforts. We briefly describe the strategies forpattern discovery techniques in Web mining.

  7. 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.

  8. Joining up 'discovery to delivery' services

    OpenAIRE

    A. Apps; R. MacIntyre

    2008-01-01

    Zetoc is a bibliographic current awareness service that provides discovery of relevant literature within the British Library's Electronic Table of Contents of journal articles and conference papers. A researcher having discovered an article of interest will wish to read it, preferring to locate an electronic copy of an article to be delivered directly to their desktop. However, until now, Zetoc was essentially the British Library's document delivery catalogue, containing details of journals t...

  9. Modeling and Discovery of Data Providing Services

    Czech Academy of Sciences Publication Activity Database

    Vaculín, Roman; Chen, H.; Neruda, Roman; Sycara, K.

    Los Alamitos: IEEE Computer Society, 2008, s. 54-61. ISBN 978-0-7695-3310-0. [ICWS 2008. IEEE International Conference on Web Services. Beijing (CN), 23.09.2008-26.09.2008] R&D Projects: GA AV ČR 1ET100300517; GA MŠk ME08095 Institutional research plan: CEZ:AV0Z10300504 Keywords : discovery of web services * data providing services * databases as web services * semantic web services Subject RIV: IN - Informatics, Computer Science

  10. 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.

  11. Systems approaches to polypharmacology and drug discovery

    OpenAIRE

    Boran, Aislyn DW; Iyengar, Ravi

    2010-01-01

    Systems biology uses experimental and computational approaches to characterize large sample populations systematically, process large datasets, examine and analyze regulatory networks, and model reactions to determine how components are joined to form functional systems. Systems biology technologies, data and knowledge are particularly useful in understanding disease processes and drug actions. An important area of integration between systems biology and drug discovery is the concept of polyp...

  12. Bisociative Discovery of Interesting Relations between Domains

    OpenAIRE

    Nagel, Uwe; Thiel, Kilian; Kötter, Tobias; Piatek, Dawid; Berthold, Michael

    2011-01-01

    The discovery of surprising relations in large, heterogeneous information repositories is gaining increasing importance in real world data analysis. If these repositories come from diverse origins, forming different domains, domain bridging associations between otherwise weakly connected domains can provide insights into the data that can otherwise not be accomplished. In this paper, we propose a first formalization for the detection of such potentially interesting, domain-crossing relations ...

  13. Discoveries in Phononic Crystals and Acoustic Metamaterials

    OpenAIRE

    Wang, Pai

    2015-01-01

    Phononic crystals and acoustic metamaterials are heterogeneous materials that enable manipulation of elastic waves. An important characteristic of these heterogeneous systems is their ability to tailor the propagation of elastic waves due to the existence of band gaps -- frequency ranges of strong wave attenuation. In this Thesis, I report discoveries of three new types of band gaps: i) Band gaps induced by geometric frustration in periodic acoustic channel networks; ii) Band gap induced by h...

  14. Drug Discovery Targeted to Transthyretin Related Amyloidosis

    OpenAIRE

    Blasi Pérez, Daniel

    2013-01-01

    [eng] Several drug discovery approaches has been performed to find new compounds able to interact with high affinity with the hormone binding site of the homotetrameric protein transthyretin (TTR), and stabilize this tetramer, becoming drug candidates to treat several rare amyloid diseases associated with TTR. With this aim, several computational workflows and chemico-biological databases have been developed, and in collaboration with two experimental research laboratories of our TTR Con...

  15. Services Discovery for Distributed Network Measurement

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    More and more distributed applications are deployed around interconnected network, which makes it necessary for network measurement services to address the scalability and robustness requirements. This paper discusses a service discovery for integrated network measurement architecture (INMA), including finding the location of measurement agent, the path of the measurement and the network attributes of the end-to-end path or host. It also describes the functions of the major building blocks used to construct the measurement architecture.

  16. 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.

  17. Women, breast lump discovery, and associated stress.

    Science.gov (United States)

    MacFarlane, M E; Sony, S D

    1992-01-01

    To learn about anxiety experienced by women before they undergo breast biopsy, we surveyed by telephone 42 females aged 18 or over who were scheduled for this procedure. Unlike other studies, the present investigation explores retrospectively the impact of the discovery of a breast lump, hospitalization, and factors that aggravate and alleviate anxiety. An interview guide and an adaptation of the Spielberger, Gorsuch, and Lushene (1970) State Trait Anxiety Inventory Scale were used for data collection. The stress and coping models developed by Lazarus and Launier (1978) and Lazarus and Folkman (1984) contributed to the conceptual framework used in this study. Findings indicate that the anxiety levels of women after the discovery of a breast lump and prior to knowledge of biopsy results were extremely high. Age and time delay in contacting the physician had a statistically significant relationship on the participants' stress levels. The findings provide information that contributes to understanding the problem of anxiety originating from the discovery of a breast lump. PMID:1556029

  18. The prepared mind. [Serendipitous discovery of demulsifier

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, N.E.S. (Western Unichem Technology, The Woodlands, TX (United States))

    1994-09-01

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

  19. 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.

  20. Enhancing Service Discovery Performance Over Home Networks

    Directory of Open Access Journals (Sweden)

    Intisar Al-Mejibli

    2012-04-01

    Full Text Available Service discovery protocols are used to facilitate dynamic cooperation among devices / services with minimal user intervention. These protocols work by exchanging messages to identify and locate the relevant services. When new devices and services are added the flow of messages often appears as a burst. These bursts act as a critical factor that may cause the loss messages which dramatically influences the performance of the service discovery process. Thus, the loss of messages results in uncompleted discovery process which will directly affect the sharing of resources in home networks. This paper proposes an algorithm that computes the minimum period of time required between a consecutive burst of messages and determines the minimum required queue sizes for the routers to manage the traffic and avoid dropped messages. The algorithm has been applied to the Universal Plug and Play (UPnP protocol and considered the used of Active Queue Management (AQM. It was tested when the routers were connected in two configurations; decentralised and centralised. The message length and bandwidth of the links among the routers were taken into consideration. The result shows better improvement in number of dropped messages `among the routers.

  1. 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

  2. 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.

  3. Discovery of Conservation Laws via Matrix Search

    Science.gov (United States)

    Schulte, Oliver; Drew, Mark S.

    One of the main goals of Discovery Science is the development and analysis of methods for automatic knowledge discovery in the natural sciences. A central area of natural science research concerns reactions: how entities in a scientific domain interact to generate new entities. Classic AI research due to Valdés-Pérez, Żytkow, Langley and Simon has shown that many scientific discovery tasks that concern reaction models can be formalized as a matrix search. In this paper we present a method for finding conservation laws, based on two criteria for selecting a conservation law matrix: (1) maximal strictness: rule out as many unobserved reactions as possible, and (2) parsimony: minimize the L1-norm of the matrix. We provide an efficient and scalable minimization method for the joint optimization of criteria (1) and (2). For empirical evaluation, we applied the algorithm to known particle accelerator data of the type that are produced by the Large Hadron Collider in Geneva. It matches the important Standard Model of particles that physicists have constructed through decades of research: the program rediscovers Standard Model conservation laws and the corresponding particle families of baryon, muon, electron and tau number. The algorithm also discovers the correct molecular structure of a set of chemical substances.

  4. Light Higgs boson discovery from fermion mixing

    CERN Document Server

    Aguilar-Saavedra, J A

    2006-01-01

    We evaluate the LHC discovery potential for a light Higgs boson in t tbar H (-> l nu bbbbjj) production, within the Standard Model and if a new Q=2/3 quark singlet T with a moderate mass exists. In the latter case, T pair production with decays T Tbar -> W+ b H tbar, H t W- bbar -> W+ b W- bbar H provides an important additional source of Higgs bosons giving the same experimental signature. Both analyses are carried out with particle-level simulations of signals and backgrounds. Our estimate for SM Higgs discovery in t tbar H production, 2.25 sigma significance for M_H = 115 GeV and an integrated luminosity of 30 fb^-1, is more pessimistic than previous ones. We show that, if a quark singlet with a mass m_T = 500 GeV exists, the luminosity required for Higgs discovery in this final state is reduced by a factor of 25, and 5 sigma significance can be achieved already with 6 fb^-1. This new Higgs signal will not be seen unless we look for it: with this aim, a new specific final state reconstruction method is pre...

  5. Parallel Frequent Pattern Discovery: Challenges and Methodology

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Parallel frequent pattern discovery algorithms exploit parallel and distributed computing resources to relieve the sequential bottlenecks of current frequent pattern mining (FPM) algorithms. Thus, parallel FPM algorithms achieve better scalability and performance, so they are attracting much attention in the data mining research community. This paper presents a comprehensive survey of the state-of-the-art parallel and distributed frequent pattern mining algorithms with more emphasis on pattern discovery from complex data (e.g., sequences and graphs) on various platforms. A review of typical parallel FPM algorithms uncovers the major challenges, methodologies, and research problems in the field of parallel frequent pattern discovery,such as work-load balancing, finding good data layouts, and data decomposition. This survey also indicates a dramatic shift of the research interest in the field from the simple parallel frequent itemset mining on traditional parallel and distributed platforms to parallel pattern mining of more complex data on emerging architectures, such as multi-core systems and the increasingly mature grid infrastructure.

  6. A Technique Socratic Questioning-Guided Discovery

    Directory of Open Access Journals (Sweden)

    M. Hakan Türkçapar

    2012-03-01

    Full Text Available “Socratic Method” is a way of teaching philosophical thinking and knowledge by asking questions which was used by antique period greek philosopher Socrates. Socrates was teaching knowledge to his followers by asking questions and the conversation between them was named “Socratic Dialogues”. In this meaning, no novel knowledge is taught to the individual but only what is formerly known is reminded and rediscovered. The form of socratic questioning which is used during the process of cognitive behavioral therapy is known as Guided Discovery. In this method it is aimed to make the client notice the piece of knowledge which he could notice but is not aware with a series of questions. Socratic method or guided discovery consists of several steps which are: Identifying the problem by listening to the client and making reflections, finding alternatives by examining and evaluating, reidentification by using the newly found information and questioning the old distorted belief and reaching to a conclusion and applying it. Question types used during these procedures are, questions for gaining information, questions revealing the meanings, questions revealing the beliefs, questions about behaviours during the similar past experiences, analyse questions and analytic synthesis questions. In order to make the patient feel understood it is important to be empathetic and summarising the problem during the interview. In this text, steps of Socratic Questioning-Guided Discovery will be reviewed with sample dialogues after each step

  7. 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. PMID:25163620

  8. Systems Pharmacology in Small Molecular Drug Discovery.

    Science.gov (United States)

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

    2016-01-01

    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. PMID:26901192

  9. Scientific Discoveries: What Is Required for Lasting Impact.

    Science.gov (United States)

    Lømo, Terje

    2016-01-01

    I have been involved in two scientific discoveries of some impact. One is the discovery of long-term potentiation (LTP), the phenomenon that brief, high-frequency impulse activity at synapses in the brain can lead to long-lasting increases in their efficiency of transmission. This finding demonstrated that synapses are plastic, a property thought to be necessary for learning and memory. The other discovery is that nerve-evoked muscle impulse activity, rather than putative trophic factors, controls the properties of muscle fibers. Here I describe how these two discoveries were made, the unexpected difficulties of reproducing the first discovery, and the controversies that followed the second discovery. I discuss why the first discovery took many years to become generally recognized, whereas the second caused an immediate sensation and entered textbooks and major reviews but is now largely forgotten. In the long run, discovering a new phenomenon has greater impact than falsifying a popular hypothesis. PMID:26273911

  10. Subgroup Discovery Algorithms:A Survey and Empirical Evaluation

    Institute of Scientific and Technical Information of China (English)

    Sumyea Helal

    2016-01-01

    Subgroup discovery is a data mining technique that discovers interesting associations among different variables with respect to a property of interest. Existing subgroup discovery methods employ different strategies for searching, pruning and ranking subgroups. It is very crucial to learn which features of a subgroup discovery algorithm should be considered for generating quality subgroups. In this regard, a number of reviews have been conducted on subgroup discovery. Although they provide a broad overview on some popular subgroup discovery methods, they employ few datasets and measures for subgroup evaluation. In the light of the existing measures, the subgroups cannot be appraised from all perspectives. Our work performs an extensive analysis on some popular subgroup discovery methods by using a wide range of datasets and by defining new measures for subgroup evaluation. The analysis result will help with understanding the major subgroup discovery methods, uncovering the gaps for further improvement and selecting the suitable category of algorithms for specific application domains.

  11. Discovery of tetrahydroisoquinoline-based CXCR4 antagonists.

    Science.gov (United States)

    Truax, Valarie M; Zhao, Huanyu; Katzman, Brooke M; Prosser, Anthony R; Alcaraz, Ana A; Saindane, Manohar T; Howard, Randy B; Culver, Deborah; Arrendale, Richard F; Gruddanti, Prahbakar R; Evers, Taylor J; Natchus, Michael G; Snyder, James P; Liotta, Dennis C; Wilson, Lawrence J

    2013-11-14

    A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1IIIB virus in MAGI-CCR5/CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(R)-stereoisomer 15 as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of 15 were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where 15 was shown to have oral bioavailability (F = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner. PMID:24936240

  12. 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...

  13. Automatic discovery of cell types and microcircuitry from neural connectomics

    OpenAIRE

    Jonas, Eric; Kording, Konrad

    2014-01-01

    eLife digest The human brain is made up of billions of neurons, which are organised into networks via trillions of connections. The study of the nature of these connections will be central to understanding how the brain works. In recent years, a number of new methods for imaging the brain have made it possible to visualise and map these connections, generating striking images and creating an additional field of neuroscience known as ‘connectomics’. However, the sheer volume of data generated ...

  14. Microfluidic tools for cell biological research

    OpenAIRE

    Velve-Casquillas, Guilhem; Le Berre, Maël; Piel, Matthieu; Tran, Phong T.

    2010-01-01

    Microfluidic technology is creating powerful tools for cell biologists to control the complete cellular microenvironment, leading to new questions and new discoveries. We review here the basic concepts and methodologies in designing microfluidic devices, and their diverse cell biological applications.

  15. Engineering stem cell niches in bioreactors

    OpenAIRE

    2013-01-01

    Stem cells, including embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells and amniotic fluid stem cells have the potential to be expanded and differentiated into various cell types in the body. Efficient differentiation of stem cells with the desired tissue-specific function is critical for stem cell-based cell therapy, tissue engineering, drug discovery and disease modeling. Bioreactors provide a great platform to regulate the stem cell microenvironment, known as “ni...

  16. Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery.

    Science.gov (United States)

    Kothiwale, Sandeepkumar; Borza, Corina M; Lowe, Edward W; Pozzi, Ambra; Meiler, Jens

    2015-02-01

    Discoidin domain receptor (DDR) 1 and 2 are transmembrane receptors that belong to the family of receptor tyrosine kinases (RTK). Upon collagen binding, DDRs transduce cellular signaling involved in various cell functions, including cell adhesion, proliferation, differentiation, migration, and matrix homeostasis. Altered DDR function resulting from either mutations or overexpression has been implicated in several types of disease, including atherosclerosis, inflammation, cancer, and tissue fibrosis. Several established inhibitors, such as imatinib, dasatinib, and nilotinib, originally developed as Abelson murine leukemia (Abl) kinase inhibitors, have been found to inhibit DDR kinase activity. As we review here, recent discoveries of novel inhibitors and their co-crystal structure with the DDR1 kinase domain have made structure-based drug discovery for DDR1 amenable. PMID:25284748

  17. Strategies for Human Tumor Virus Discoveries: From Microscopic Observation to Digital Transcriptome Subtraction.

    Science.gov (United States)

    Mirvish, Ezra D; Shuda, Masahiro

    2016-01-01

    Over 20% of human cancers worldwide are associated with infectious agents, including viruses, bacteria, and parasites. Various methods have been used to identify human tumor viruses, including electron microscopic observations of viral particles, immunologic screening, cDNA library screening, nucleic acid hybridization, consensus PCR, viral DNA array chip, and representational difference analysis. With the Human Genome Project, a large amount of genetic information from humans and other organisms has accumulated over the last decade. Utilizing the available genetic databases, Feng et al. (2007) developed digital transcriptome subtraction (DTS), an in silico method to sequentially subtract human sequences from tissue or cellular transcriptome, and discovered Merkel cell polyomavirus (MCV) from Merkel cell carcinoma. Here, we review the background and methods underlying the human tumor virus discoveries and explain how DTS was developed and used for the discovery of MCV. PMID:27242703

  18. Integrating proteomic and functional genomic technologies in discovery-driven translational breast cancer research

    DEFF Research Database (Denmark)

    Celis, Julio E; Gromov, Pavel; Gromova, Irina;

    2003-01-01

    . Here we describe the essence of a long-term initiative undertaken by The Danish Centre for Translational Breast Cancer Research and currently underway for cancer biomarker discovery using fresh tissue biopsies and bio-fluids. The Centre is a virtual hub that brings together scientists working......The application of state-of-the-art proteomics and functional genomics technologies to the study of cancer is rapidly shifting toward the analysis of clinically relevant samples derived from patients, as the ultimate aim of translational research is to bring basic discoveries closer to the bedside...... in various areas of basic cancer research such as cell cycle control, invasion and micro-environmental alterations, apoptosis, cell signaling, and immunology, with clinicians (oncologists, surgeons), pathologists, and epidemiologists, with the aim of understanding the molecular mechanisms underlying breast...

  19. False Discovery Rate Control under Archimedean Copula

    OpenAIRE

    Bodnar, Taras; Dickhaus, Thorsten

    2013-01-01

    We are concerned with the false discovery rate (FDR) of the linear step-up test $\\varphi^{LSU}$ considered by Benjamini and Hochberg (1995). It is well known that $\\varphi^{LSU}$ controls the FDR at level $m_{0}q/m$ if the joint distribution of $p$-values is multivariate totally positive of order $2$. In this, $m$ denotes the total number of hypotheses, $m_{0}$ the number of true null hypotheses, and $q$ the nominal FDR level. Under the assumption of an Archimedean $p$-value copula with compl...

  20. The discovery potential of laser polarization experiments

    International Nuclear Information System (INIS)

    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.)

  1. CMB Anisotropies: Their Discovery and Utilization

    CERN Document Server

    Smoot, George F

    2008-01-01

    This article is a written and modified version of a talk presented at the conference `A Century of Cosmology' held at San Servolo, Venice, Italy, in August 2007. The talk focuses on some of the cosmology history leading to the discovery and exploitation of Cosmic Microwave Background (CMB) Radiation anisotropies. We have made tremendous advances first in the development of the techniques to observe these anisotropies and in observing and interpreting them to extract their contained cosmological information. CMB anisotropies are now a cornerstone in our understanding of the cosmos and our future progress in the field. This is an outcome that Dennis Sciama hoped for and encouraged.

  2. Repurposing strategies for tropical disease drug discovery.

    Science.gov (United States)

    Klug, Dana M; Gelb, Michael H; Pollastri, Michael P

    2016-06-01

    Neglected tropical diseases (NTDs) and other diseases of the developing world, such as malaria, attract research investments that are disproportionately low compared to their impact on human health worldwide. Therefore, pragmatic methods for launching new drug discovery programs have emerged that repurpose existing chemical matter as new drugs or new starting points for optimization. In this Digest we describe applications of different repurposing approaches for NTDs, and provide a means by which these approaches may be differentiated from each other. These include drug repurposing, target repurposing, target class repurposing, and lead repurposing. PMID:27080183

  3. 60 years of CERN experiments and discoveries

    CERN Document Server

    Di Lella, Luigi

    2015-01-01

    The book contains a description of the most important experimental results achieved at CERN during the past 60 years, from the mid-1950s to the latest discovery of the Higgs particle. It covers the results from early accelerators at CERN to the most recent results at the LHC and thus provides an excellent review of the achievements of this outstanding laboratory. It reflects not only the impressive scientific progress achieved during the past six decades but demonstrates also the special way of successful international collaboration developed at CERN.

  4. Open drug discovery for the Zika virus

    OpenAIRE

    Sean Ekins; Daniel Mietchen; Megan Coffee; Stratton, Thomas P.; Freundlich, Joel S.; Lucio Freitas-Junior; Eugene Muratov; Jair Siqueira-Neto; Williams, Antony J.; Carolina Andrade

    2016-01-01

    The Zika virus (ZIKV) outbreak in the Americas has caused global concern that we may be on the brink of a healthcare crisis. The lack of research on ZIKV in the over 60 years that we have known about it has left us with little in the way of starting points for drug discovery. Our response can build on previous efforts with virus outbreaks and lean heavily on work done on other flaviviruses such as dengue virus. We provide some suggestions of what might be possible and propose an open drug dis...

  5. Fifty years of discoveries in nuclear structure

    International Nuclear Information System (INIS)

    The complementary nature of the Vanderbilt experimental work and the theoretical work of the Frankfurt group on the rotation-vibration model, the generalized collective model, shape coexistence and cluster radioactivity is described. Recent discoveries in neutron-rich nuclei γ-vibrational bands compared with RVM and GCM are presented. Ultimate examples of cluster radioactivity in cold binary and ternary fission are discussed. Finally, we present evidence for the evolution from axial symmetry in 101Y to maximum triaxiality in 113Rh and for chiral doublet bands in neutron-rich triaxial even-even nuclei between A=106 - 112. (author)

  6. Matched molecular pair analysis in drug discovery.

    Science.gov (United States)

    Dossetter, Alexander G; Griffen, Edward J; Leach, Andrew G

    2013-08-01

    Multiple parameter optimisation in drug discovery is difficult, but Matched Molecular Pair Analysis (MMPA) can help. Computer algorithms can process data in an unbiased way to yield design rules and suggest better molecules, cutting the number of design cycles. The approach often makes more suggestions than can be processed manually and methods to deal with this are proposed. However, there is a paucity of contextually specific design rules, which would truly make the technique powerful. By combining extracted information from multiple sources there is an opportunity to solve this problem and advance medicinal chemistry in a matter of months rather than years. PMID:23557664

  7. Biological Networks for Cancer Candidate Biomarkers Discovery

    Science.gov (United States)

    Yan, Wenying; Xue, Wenjin; Chen, Jiajia; Hu, Guang

    2016-01-01

    Due to its extraordinary heterogeneity and complexity, cancer is often proposed as a model case of a systems biology disease or network disease. There is a critical need of effective biomarkers for cancer diagnosis and/or outcome prediction from system level analyses. Methods based on integrating omics data into networks have the potential to revolutionize the identification of cancer biomarkers. Deciphering the biological networks underlying cancer is undoubtedly important for understanding the molecular mechanisms of the disease and identifying effective biomarkers. In this review, the networks constructed for cancer biomarker discovery based on different omics level data are described and illustrated from recent advances in the field.

  8. Discovery program for bright quasars: preliminary results

    International Nuclear Information System (INIS)

    A program has been undertaken to obtain a complete sample of bright quasars on the basis of ultraviolet color excess. Spectroscopic examination of candidates selected from two-color Schmidt telescope films has yielded four new quasars brighter than B = 16/sup m/5, with the candidate list containing two more previously identified. Magnitudes, color indices, and redshifts are presented for the new discoveries, along with positions and finding charts. Although the sample is not yet complete, these first results suggest that bright quasars have a low surface density

  9. 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.  

  10. 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.

  11. Usability as a Method for Assessing Discovery

    OpenAIRE

    Ipri, Tom; Yunkin, Michael; Brown, Jeanne M.

    2013-01-01

    The University of Nevada Las Vegas Libraries engaged in three projects that helped identify areas of its website that had inhibited discovery of services and resources. These projects also helped generate staff interest in the Usability Working Group, which led these endeavors. The first project studied student responses to the site. The second focused on a usability test with the Libraries’ peer research coaches and resulted in a presentation of those findings to the Libraries staff. The fin...

  12. The Discovery of Direct CP Violation

    CERN Document Server

    Iconomidou-Fayard, L

    2015-01-01

    Soon after the discovery in 1964 of the non-conservation of CP symmetry in the neutral kaon system, the hunt was launched for a component arising from direct violation on top of the dominant effect due to mixing. It took almost 20 years until the first evidence of a signal was reported by NA31 and another 10 years to establish the effect with a significance of more than 5 standard deviations. This article describes the beams, detectors and analysis methods used by the two CERN experiments, NA31 and NA48, which made key contributions to these results and established new standards for precision measurements.

  13. Biological Networks for Cancer Candidate Biomarkers Discovery.

    Science.gov (United States)

    Yan, Wenying; Xue, Wenjin; Chen, Jiajia; Hu, Guang

    2016-01-01

    Due to its extraordinary heterogeneity and complexity, cancer is often proposed as a model case of a systems biology disease or network disease. There is a critical need of effective biomarkers for cancer diagnosis and/or outcome prediction from system level analyses. Methods based on integrating omics data into networks have the potential to revolutionize the identification of cancer biomarkers. Deciphering the biological networks underlying cancer is undoubtedly important for understanding the molecular mechanisms of the disease and identifying effective biomarkers. In this review, the networks constructed for cancer biomarker discovery based on different omics level data are described and illustrated from recent advances in the field. PMID:27625573

  14. The discovery of the intermediate vector bosons

    International Nuclear Information System (INIS)

    The discovery of the intermediate vector bosons in 1983 at CERN marked the culmination of a long effort to unify the theory of weak and electromagnetic forces. Here a brief outline of development of the electroweak theory which unifies these forces is given first. Its essential feature is the prediction of the existence of the W+- and Z0 bosons with rest masses of about ninety times the proton mass and lifetimes around 10-24s. Then the experimental methods used at CERN to produce and to detect these very massive and short-lived particles are described. (author)

  15. Comprehensive discovery and characterization of small RNAs in Corynebacterium glutamicum ATCC 13032

    OpenAIRE

    Mentz, Almut; Neshat, Armin; Pfeifer, Katharina; Pühler, Alfred; Rückert, Christian; Kalinowski, Jörn

    2013-01-01

    Background Recent discoveries on bacterial transcriptomes gave evidence that small RNAs (sRNAs) have important regulatory roles in prokaryotic cells. Modern high-throughput sequencing approaches (RNA-Seq) enable the most detailed view on transcriptomes offering an unmatched comprehensiveness and single-base resolution. Whole transcriptome data obtained by RNA-Seq can be used to detect and characterize all transcript species, including small RNAs. Here, we describe an RNA-Seq approach for comp...

  16. Rapid discovery and optimization of therapeutic antibodies against emerging infectious diseases

    OpenAIRE

    Rogers, J.; Schoepp, R J; Schröder, O; Clements, T.L.; Holland, T.F.; Li, J. Q.; Li, J.; Lewis, L.M.; Dirmeier, R.P.; Frey, G.J.; Tan, X; Wong, K.; Woodnutt, G; M. Keller; Reed, D.S.

    2008-01-01

    Using a comprehensive set of discovery and optimization tools, antibodies were produced with the ability to neutralize SARS coronavirus (SARS-CoV) infection in Vero E6 cells and in animal models. These anti-SARS antibodies were discovered using a novel DNA display method, which can identify new antibodies within days. Once neutralizing antibodies were identified, a comprehensive and effective means of converting the mouse sequences to human frameworks was accomplished using HuFR™ (human frame...

  17. Tales of one gene discovery of a novel candidate receptor in mammalian taste

    OpenAIRE

    Huang, Angela Lilly

    2007-01-01

    There are five basic taste modalities in mammals: bitter, sweet, sour, salty, and Umami (taste of MSG and L-amino acids). Receptors for bitter, sweet, and Umami were previously discovered. Identities of receptors for salty and sour taste modalities remained elusive. In this dissertation, I will present: 1) development of a novel bioinformatics screen to discover candidate receptors; 2) discovery of a novel gene, PKD2L1, in taste receptor cells; 3) evidence demonstrating PKD2L1-expressing tast...

  18. Quantitative proteomics in resected renal cancer tissue for biomarker discovery and profiling

    OpenAIRE

    Atrih, A; Mudaliar, M A V; Zakikhani, P; Lamont, D J; Huang, J T-J; Bray, S.E.; Barton, G.; Fleming, S; Nabi, G.

    2014-01-01

    Background: Proteomics-based approaches for biomarker discovery are promising strategies used in cancer research. We present state-of-art label-free quantitative proteomics method to assess proteome of renal cell carcinoma (RCC) compared with noncancer renal tissues. Methods: Fresh frozen tissue samples from eight primary RCC lesions and autologous adjacent normal renal tissues were obtained from surgically resected tumour-bearing kidneys. Proteins were extracted by complete solubilisation of...

  19. Discovery and structural characterization of an allosteric inhibitor of bacterial cis-prenyltransferase

    OpenAIRE

    Danley, Dennis E; Baima, Eric T.; Mansour, Mahmoud; Fennell, Kimberly F.; Chrunyk, Boris A.; Mueller, John P.; Liu, Shenping; Qiu, Xiayang

    2014-01-01

    Undecaprenyl pyrophosphate synthase (UPPs) is an essential enzyme in a key bacterial cell wall synthesis pathway. It catalyzes the consecutive condensations of isopentenyl pyrophosphate (IPP) groups on to a trans-farnesyl pyrophosphate (FPP) to produce a C55 isoprenoid, undecaprenyl pyrophosphate (UPP). Here we report the discovery and co-crystal structures of a drug-like UPPs inhibitor in complex with Streptococcus pneumoniae UPPs, with and without substrate FPP, at resolutions of 2.2 and 2....

  20. Thresholds for Discovery: EAD Tag Analysis in ArchiveGrid, and Implications for Discovery Systems

    Directory of Open Access Journals (Sweden)

    M. Proffitt

    2013-10-01

    Full Text Available The ArchiveGrid discovery system is made up in part of an aggregation of EAD (Encoded Archival Description encoded finding aids from hundreds of contributing institutions. In creating the ArchiveGrid discovery interface, the OCLC Research project team has long wrestled with what we can reasonably do with the large (120,000+ corpus of EAD documents. This paper presents an analysis of the EAD documents (the largest analysis of EAD documents to date. The analysis is paired with an evaluation of how well the documents support various aspects of online discovery. The paper also establishes a framework for thresholds of completeness and consistency to evaluate the results. We find that, while the EAD standard and encoding practices have not offered support for all aspects of online discovery, especially in a large and heterogeneous aggregation of EAD documents, current trends suggest that the evolution of the EAD standard and the shift from retrospective conversion to new shared tools for improved encoding hold real promise for the future.

  1. Integrated expressional analysis: application to the drug discovery process.

    Science.gov (United States)

    Ilyin, Sergey E; Horowitz, Daniel; Belkowski, Stanley M; Xin, Hong; Eckardt, Annette J; Darrow, Andrew L; Chen, Cailin; Maley, Derrick; D'Andrea, Michael; Plata-Salamán, Carlos R; Derian, Claudia K

    2005-11-01

    Microarray technology enables high-throughput testing of gene expression to investigate various neuroscience related questions. This in turn creates a demand for scalable methods to confirm microarray results and the opportunity to use this information to discover and test novel pathways and therapeutic applications. Discovery of new central nervous system (CNS) treatments requires a comprehensive understanding of multiple aspects including the biology of a target, the pathophysiology of a disease/disorder, and the selection of successful lead compounds as well as efficient biomarker and drug disposition strategies such as absorption (how a drug is absorbed), distribution (how a drug spreads through an organism), metabolism (chemical conversion of a drug, if any, and into which substances), and elimination (how is a drug eliminated) (ADME). Understanding of the toxicity is also of paramount importance. These approaches, in turn, require novel high-content integrative assay technologies that provide thorough information about changes in cell biology. To increase efficiency of profiling, characterization, and validation, we established a new screening strategy that combines high-content image-based testing on Array Scan (Cellomics) with a confocal system and the multiplexed TaqMan RT-PCR method for quantitative mRNA expression analysis. This approach could serve as an interface between high-throughput microarray testing and specific application of markers discovered in the course of a microarray experiment. Markers could pinpoint activation or inhibition of a molecular pathway related, for instance, to neuronal viability. We demonstrate the successful testing of the same cell population in an image-based translocational assay followed by poly(A) mRNA capture and multiplexed single tube RT-PCR. In addition, Ciphergen ProteinChip analysis can be performed on the supernatant, thus allowing significant complementarity in the data output and interpretation by also

  2. Discovery Mondays - The detectors: tracking particles

    CERN Multimedia

    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...

  3. 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...

  4. 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.

  5. 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 ...

  6. Sublinear Time Motif Discovery from Multiple Sequences

    Directory of Open Access Journals (Sweden)

    Yunhui Fu

    2013-10-01

    Full Text Available In this paper, a natural probabilistic model for motif discovery has been used to experimentally test the quality of motif discovery programs. In this model, there are k background sequences, and each character in a background sequence is a random character from an alphabet, Σ. A motif G = g1g2 ... gm is a string of m characters. In each background sequence is implanted a probabilistically-generated approximate copy of G. For a probabilistically-generated approximate copy b1b2 ... bm of G, every character, bi, is probabilistically generated, such that the probability for bi ≠ gi is at most α. We develop two new randomized algorithms and one new deterministic algorithm. They make advancements in the following aspects: (1 The algorithms are much faster than those before. Our algorithms can even run in sublinear time. (2 They can handle any motif pattern. (3 The restriction for the alphabet size is a lower bound of four. This gives them potential applications in practical problems, since gene sequences have an alphabet size of four. (4 All algorithms have rigorous proofs about their performances. The methods developed in this paper have been used in the software implementation. We observed some encouraging results that show improved performance for motif detection compared with other software.

  7. Service discovery with routing protocols for MANETs

    Science.gov (United States)

    Gu, Xuemai; Shi, Shuo

    2005-11-01

    Service discovery is becoming an important topic as its use throughout the Internet becomes more widespread. In Mobile Ad hoc Networks (MANETs), the routing protocol is very important because it is special network. To find a path for data, and destination nodes, nodes send packets to each node, creating substantial overhead traffic and consuming much time. Even though a variety of routing protocols have been developed for use in MANETs, they are insufficient for reducing overhead traffic and time. In this paper, we propose SDRP: a new service discovery protocol combined with routing policies in MANETs. The protocol is performed upon a distributed network. We describe a service by a unique ID number and use a group-cast routing policy in advertisement and request. The group-cast routing policy decreases the traffic in networks, and it is efficient to find destination node. In addition, the nodes included in the reply path also cache the advertisement information, and it means when each node finds a node next time, they can know where it is as soon as possible, so they minimize the time. Finally, we compare SDRP with both Flood and MAODV in terms of overload, and average delay. Simulation results show SDRP can spend less response time and accommodate even high mobility network environments.

  8. Midwest Lake uranium discovery, Saskatchewan, Canada

    International Nuclear Information System (INIS)

    The discovery of the Midwest Lake uranium deposit in Saskatchewan came some ten years after the start of exploration. The original mining rights were acquired on the basis of regional published, geology and proximity to the earlier discovery. Aerial radiometric surveys led to the location of a train of radioactive, glacially transported sandstone boulders and cobbles. The source of these mineralized erratics did not outcrop, and an extensive series of magnetic, electromagnetic, seismic and gravity surveys was carried out in an unsuccessful attempt to identify the source location. These surveys were followed by several programmes of diamond drilling, geochemical surveys and Pleistocene geological studies. None of these programmes or surveys encountered bedrock mineralization. When information about ore controls in the Athabasca Basin became available, a limited programme of three 300-m wildcat diamond-drill holes was proposed. The second of these holes cut weak radioactivity in a poorly cored intersection. This intersection was at an unconformity at a depth of 200 m. The programme terminated prematurely with early melting of lake ice. The first hole in the subsequent winter's follow-up drilling intersected uranium values in excess of 8%. (author)

  9. Discovery of a New Nearby Star

    Science.gov (United States)

    Teegarden, B. J.; Pravdo, S. H.; Covey, K.; Frazier, O.; Hawley, S. L.; Hicks, M.; Lawrence, K.; McGlynn, T.; Reid, I. N.; Shaklan, S. B.

    2003-01-01

    We report the discovery of a nearby star with a very large proper motion of 5.06 +/- 0.03 arcsec/yr. The star is called SO025300.5+165258 and referred to herein as HPMS (high proper motion star). The discovery came as a result of a search of the SkyMorph database, a sensitive and persistent survey that is well suited for finding stars with high proper motions. There are currently only 7 known stars with proper motions greater than 5 arcsec/yr. We have determined a preliminary value for the parallax of pi = 0.43 +/- 0.13 arcsec. If this value holds our new star ranks behind only the Alpha Centauri system (including Proxima Centauri) and Barnard's star in the list of our nearest stellar neighbours. The spectrum and measured tangential velocity indicate that HPMS is a main-sequence star with spectral type M6.5. However, if our distance measurement is correct, the HPMS is underluminous by 1.2 +/- 0.7 mag.

  10. Wide Field Surveys and Astronomical Discovery Space

    CERN Document Server

    Lawrence, A

    2007-01-01

    I review the status of science with wide field surveys. For many decades surveys have been the backbone of astronomy, and the main engine of discovery, as we have mapped the sky at every possible wavelength. Surveys are an efficient use of resources. They are important as a fundamental resource; to map intrinsically large structures; to gain the necessary statistics to address some problems; and to find very rare objects. I summarise major recent wide field surveys - 2MASS, SDSS, 2dfGRS, and UKIDSS - and look at examples of the exciting science they have produced, covering the structure of the Milky Way, the measurement of cosmological parameters, the creation of a new field studying substellar objects, and the ionisation history of the Universe. I then look briefly at upcoming projects in the optical-IR survey arena - VISTA, PanSTARRS, WISE, and LSST. Finally I ask, now we have opened up essentially all wavelength windows, whether the exploration of survey discovery space is ended. I examine other possible a...

  11. 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.

  12. 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.

  13. DISCOVERY OF TWO ADDITIONAL JOVIAN IRREGULARS

    Energy Technology Data Exchange (ETDEWEB)

    Alexandersen, M.; Gladman, B. [Department of Physics and Astronomy, 6224 Agricultural Road, University of British Columbia, Vancouver BC (Canada); Veillet, C. [Canada-France-Hawaii Telescope Corporation, P.O. Box 1597, Kamuela, HI 96743 (United States); Jacobson, R.; Brozovic, M. [Jet Propulsion Laboratory, California Institute of Technology, 4800 Oak Grove Drive, Pasadena, CA 91109-8099 (United States); Rousselot, P., E-mail: mikea@astro.ubc.ca [Institut UTINAM, CNRS-UMR 6213, Observatoire de Besancon, BP 1615, 25010 Besancon Cedex (France)

    2012-07-15

    We report on the discovery of two previously undetected irregular satellites of Jupiter (S/2010 J 1 and S/2010 J 2) during recovery observations of other known satellites. S/2010 J 1 was discovered with the Palomar 200 inch Hale telescope on September 7 UT of 2011, while S/2010 J 2 was discovered on September 8 with the 3.5 m Canada-France-Hawaii Telescope. The satellites have r-band magnitudes of 23.2 {+-} 0.3 and 24.0 {+-} 0.3, for S/2010 J 1 and S/2010 J 2, respectively, indicating diameters of {approx}2-3 km. Both S/2010 J 1 and S/2010 J 2 are on bound retrograde orbits. Time-averaged integrated orbits suggest the association to the Carme and Ananke groups, respectively. Given that the satellites were discovered within a small field during the routine observations of the previously known irregulars, their discovery agrees with predictions that other moons of similar sizes remain undetected in the Jovian Hill sphere.

  14. 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.

  15. Discovery Mondays - The detectors: tracking particles

    CERN Multimedia

    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...

  16. 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...

  17. Indoloquinolines as scaffolds for drug discovery.

    Science.gov (United States)

    Lavrado, J; Moreira, R; Paulo, A

    2010-01-01

    Traditional medicines have contributed greatly over the centuries to the discovery and development of new therapeutic agents and indoloquinoline alkaloids may represent a new class of drug leads. Cryptolepine (5-methyl-5Hindolo[3,2-b]quinoline), neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline), isocryptolepine (5-methyl-5H-indolo[3,2-c]quinoline, extracted from the African medicinal plant Cryptolepis sanguinolenta, and isoneocryptolepine (5-methyl-5Hindolo[2,3-c]quinoline), which has never been found in nature, are isomeric tetracyclic compounds of particular interest due to their broad spectrum of biological activities including antiparasitic, antifungal, antibacterial, cytotoxic, anti-inflammatory and antihyperglycaemic. As a result, in the last 30 years hundreds of indoloquinoline analogues were synthesized and their biological activities evaluated. In this paper, we present an overview of the potential of indoloquinolines as scaffolds in drug discovery by reviewing the in vitro and in vivo biological activities of natural and synthetic analogues, as well as the proposed mechanisms of action and structure-activity relationships. PMID:20491639

  18. Motif Discovery in Tissue-Specific Regulatory Sequences Using Directed Information

    Directory of Open Access Journals (Sweden)

    James Douglas Engel

    2007-12-01

    Full Text Available Motif discovery for the identification of functional regulatory elements underlying gene expression is a challenging problem. Sequence inspection often leads to discovery of novel motifs (including transcription factor sites with previously uncharacterized function in gene expression. Coupled with the complexity underlying tissue-specific gene expression, there are several motifs that are putatively responsible for expression in a certain cell type. This has important implications in understanding fundamental biological processes such as development and disease progression. In this work, we present an approach to the identification of motifs (not necessarily transcription factor sites and examine its application to some questions in current bioinformatics research. These motifs are seen to discriminate tissue-specific gene promoter or regulatory regions from those that are not tissue-specific. There are two main contributions of this work. Firstly, we propose the use of directed information for such classification constrained motif discovery, and then use the selected features with a support vector machine (SVM classifier to find the tissue specificity of any sequence of interest. Such analysis yields several novel interesting motifs that merit further experimental characterization. Furthermore, this approach leads to a principled framework for the prospective examination of any chosen motif to be discriminatory motif for a group of coexpressed/coregulated genes, thereby integrating sequence and expression perspectives. We hypothesize that the discovery of these motifs would enable the large-scale investigation for the tissue-specific regulatory role of any conserved sequence element identified from genome-wide studies.

  19. Motif Discovery in Tissue-Specific Regulatory Sequences Using Directed Information

    Directory of Open Access Journals (Sweden)

    States David

    2007-01-01

    Full Text Available Motif discovery for the identification of functional regulatory elements underlying gene expression is a challenging problem. Sequence inspection often leads to discovery of novel motifs (including transcription factor sites with previously uncharacterized function in gene expression. Coupled with the complexity underlying tissue-specific gene expression, there are several motifs that are putatively responsible for expression in a certain cell type. This has important implications in understanding fundamental biological processes such as development and disease progression. In this work, we present an approach to the identification of motifs (not necessarily transcription factor sites and examine its application to some questions in current bioinformatics research. These motifs are seen to discriminate tissue-specific gene promoter or regulatory regions from those that are not tissue-specific. There are two main contributions of this work. Firstly, we propose the use of directed information for such classification constrained motif discovery, and then use the selected features with a support vector machine (SVM classifier to find the tissue specificity of any sequence of interest. Such analysis yields several novel interesting motifs that merit further experimental characterization. Furthermore, this approach leads to a principled framework for the prospective examination of any chosen motif to be discriminatory motif for a group of coexpressed/coregulated genes, thereby integrating sequence and expression perspectives. We hypothesize that the discovery of these motifs would enable the large-scale investigation for the tissue-specific regulatory role of any conserved sequence element identified from genome-wide studies.

  20. Epigenetics and cancer: implications for drug discovery and safety assessment

    International Nuclear Information System (INIS)

    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

  1. Mass Production of Stem Cell-Derived Progeny in Bioreactors

    OpenAIRE

    Li, Yan; Sart, Sébastien; Agathos, Spiros N.

    2013-01-01

    Stem cells, including mesenchymal stem cells (MSCs) and pluripotent stem cells (PSCs), have shown great potential for various biomedical applications including drug discovery, disease modeling, and tissue engineering. Especially, the discovery of induced pluripotent stem cells (iPSCs) with similar characteristics to embryonic stem cells (ESCs) opens a new era for stem cell research and transplantations. Bioprocess engineering provides a platform to generate a controlled microenvironment that ...

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

    DEFF Research Database (Denmark)

    Wilkowski, Bartlomiej; Fiszman, Marcelo; Miller, Christopher M; Hristovski, Dimitar; Arabandi, Sivaram; Rosemblat, Graciela; Rindflesch, Thomas C

    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...... illustrated with depressive disorder and focuses on the interaction of inflammation, circadian phenomena, and the neurotransmitter norepinephrine. Insight provided may contribute to enhanced understanding of the pathophysiology, treatment, and prevention of this disorder....

  3. Ocular and systemic pharmacokinetic models for drug discovery and development

    OpenAIRE

    del Amo Páez, Eva María

    2015-01-01

    Drug discovery and development is a long process: it takes usually 12 to 15 years before a drug candidate reaches the market. The pharmacokinetics of the drug is an important aspect of drug discovery and development, because the drug must reach its target site and exert the therapeutic response. The pharmacokinetic parameters of new compounds should be investigated early in drug discovery. Pharmacokinetic predictions can be made with Quantitative Structure-Property Relationships (QSPR) which ...

  4. A Metadata Schema for Geospatial Resource Discovery Use Cases

    OpenAIRE

    Darren Hardy; Kim Durante

    2014-01-01

    We introduce a metadata schema that focuses on GIS discovery use cases for patrons in a research library setting. Text search, faceted refinement, and spatial search and relevancy are among GeoBlacklight's primary use cases for federated geospatial holdings. The schema supports a variety of GIS data types and enables contextual, collection-oriented discovery applications as well as traditional portal applications. One key limitation of GIS resource discovery is the general lack of normative m...

  5. Launching the "Journal of Biomedical Discovery and Collaboration"

    OpenAIRE

    Smalheiser, Neil R.

    2006-01-01

    The Journal of Biomedical Discovery and Collaboration was created to provide, for the first time, a unified forum to consider all factors that affect scientific practice and scientific discovery – with an emphasis on the changing face of contemporary biomedical science. In this endeavor we are bringing together three different groups of scholars: a) laboratory investigators, who make the discoveries that are the currency of the scientific enterprise; b) computer science and informatics invest...

  6. Discovery potential of the Standard Model Higgs at the LHC

    International Nuclear Information System (INIS)

    We discuss the discovery potential of a Standard Model Higgs at the LHC. We focus on a channel of the Higgs HSM0->ττ in a vector boson fusion process, where one tau decays leptonically and the other hadronically. This channel plays an important role for the Higgs discovery in the low mass region (115HSM0<140GeV). We describe a method of hadronic tau identification, which is one of key issues for this discovery, at ATLAS

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

    OpenAIRE

    Wilkowski, Bartlomiej; Fiszman, Marcelo; Miller, Christopher M.; Hristovski, Dimitar; Arabandi, Sivaram; Rosemblat, Graciela; Rindflesch, Thomas C.

    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 phenomenon. Poorly understood relationships may be explored through novel points of view, and potentially interesting relationships need not be known ahead of time. In a process of “cooperative reciprocity” t...

  8. Models of scientific discovery: what do they explain?

    OpenAIRE

    Heeffer, Albrecht

    2011-01-01

    Motivated by the renewed interest in knowledge discovery from data (KDD) by the artificial intelligence community, this paper provides a critical assessment of models of discovery in science. The most influential research program, called BACON, is using the model of data-driven induction. Two of the main claims by this research program, the descriptive and constructive power of data-driven induction, are evaluated by means of two historical cases studies: the discovery of the sine law of refr...

  9. [Nobel Prize winning laureates in physiology or medicine for the year 2000--a few comments on discoveries related to signal transduction].

    Science.gov (United States)

    Klenerová, V; Hynie, S

    2001-05-01

    The Nobel Assembly awarded The Nobel Prize in Physiology or Medicine for 2000 jointly to Arvid Carlsson, Paul Greengard and Eric Kandel for their discoveries concerning signal transduction in the nervous system. On the examples of their predecessors we attempted to demonstrate how results of basic research serve as building blocks for new discoveries and for the application of research results into the praxis. We presented not only the basic discoveries of laureates of Nobel Prize for year 2000 (biological role of dopamine, regulation of cell functions by phosphorylation of proteins, changes in transduction of signals during processes of memory), but we also mentioned previous discoveries that helped in the research of the last laureates. These discoveries concerned not only the storage and metabolism of transmitters, formulation of the concept of cyclic AMP as a second messenger of hormonal action, the role of G-proteins in transduction processes in receptor-effector complexes, processes of phosphorylation of proteins as regulators of cell functions, but we also mentioned the discovery of other second messengers and substances functioning as local hormones (prostaglandins and related compounds). Most of the described discoveries have not only the value as stones that can help to fill still incomplete mosaic of our present knowledge, but they also represent the immediate basis for the development and use of very important remedies, such as are antiparkinsonics, antidepressive drugs, nonsteroidal antiinflammatory drugs, etc. PMID:11409355

  10. Aneuploidy in stem cells

    OpenAIRE

    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 reality. However, as somatic cells might have accumulated various chromosomal abnormalities, including aneuploidies throughout their lives, the resulting IPSCs might no longer carry the perfect bluepri...

  11. From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151.

    Science.gov (United States)

    Mirguet, Olivier; Lamotte, Yann; Donche, Frédéric; Toum, Jérôme; Gellibert, Françoise; Bouillot, Anne; Gosmini, Romain; Nguyen, Van-Loc; Delannée, Delphine; Seal, Jonathan; Blandel, Florence; Boullay, Anne-Bénédicte; Boursier, Eric; Martin, Sandrine; Brusq, Jean-Marie; Krysa, Gael; Riou, Alizon; Tellier, Rémi; Costaz, Agnès; Huet, Pascal; Dudit, Yann; Trottet, Lionel; Kirilovsky, Jorge; Nicodeme, Edwige

    2012-04-15

    The discovery, synthesis and biological evaluation of a novel series of 7-isoxazoloquinolines is described. Several analogs are shown to increase ApoA1 expression within the nanomolar range in the human hepatic cell line HepG2. PMID:22386529

  12. 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

  13. Knowledge Discovery in Mega-Spectra Archives

    Science.gov (United States)

    Škoda, P.; Bromová, P.; Lopatovsk'y, L.; Palička, A.; Vávzný, J.

    2015-09-01

    The recent progress of astronomical instrumentation resulted in the construction of multi-object spectrographs with hundreds to thousands of micro-slits or optical fibres allowing the acquisition of tens of thousands of spectra of celestial objects per observing night. Currently there are two spectroscopic surveys containing millions of spectra. These surveys are being processed by automatic pipelines, spectrum by spectrum, in order to estimate physical parameters of individual objects resulting in extensive catalogues, used typically to construct the better models of space-kinematic structure and evolution of the Universe or its subsystems. Such surveys are, however, very good source of homogenised, pre-processed data for application of machine learning techniques common in Astroinformatics. We present challenges of knowledge discovery in such surveys as well as practical examples of machine learning based on specific shapes of spectral features used in searching for new candidates of interesting astronomical objects, namely Be and B[e] stars and quasars.

  14. Financing drug discovery for orphan diseases.

    Science.gov (United States)

    Fagnan, David E; Gromatzky, Austin A; Stein, Roger M; Fernandez, Jose-Maria; Lo, Andrew W

    2014-05-01

    Recently proposed 'megafund' financing methods for funding translational medicine and drug development require billions of dollars in capital per megafund to de-risk the drug discovery process enough to issue long-term bonds. Here, we demonstrate that the same financing methods can be applied to orphan drug development but, because of the unique nature of orphan diseases and therapeutics (lower development costs, faster FDA approval times, lower failure rates and lower correlation of failures among disease targets) the amount of capital needed to de-risk such portfolios is much lower in this field. Numerical simulations suggest that an orphan disease megafund of only US$575 million can yield double-digit expected rates of return with only 10-20 projects in the portfolio. PMID:24269746

  15. 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.

  16. Laboratory Astrophysics: Enabling Scientific Discovery and Understanding

    Science.gov (United States)

    Kirby, K.

    2006-01-01

    NASA's Science Strategic Roadmap for Universe Exploration lays out a series of science objectives on a grand scale and discusses the various missions, over a wide range of wavelengths, which will enable discovery. Astronomical spectroscopy is arguably the most powerful tool we have for exploring the Universe. Experimental and theoretical studies in Laboratory Astrophysics convert "hard-won data into scientific understanding". However, the development of instruments with increasingly high spectroscopic resolution demands atomic and molecular data of unprecedented accuracy and completeness. How to meet these needs, in a time of severe budgetary constraints, poses a significant challenge both to NASA, the astronomical observers and model-builders, and the laboratory astrophysics community. I will discuss these issues, together with some recent examples of productive astronomy/lab astro collaborations.

  17. Granular Approach of Knowledge Discovery in Databases

    Directory of Open Access Journals (Sweden)

    P. R. Pal

    2011-02-01

    Full Text Available The main objective of this paper is to examine the basic principles of granular computing and apply them for knowledge discovery in databases. Granular computing is an emerging field of research that provides a way of studying many issues and solving problems related to them. The paper consist introduction and overview of granular computing. It also examines some of those issues, including data and knowledge representation and processing. It is demonstrated that one of fundamental task of data mining is finding for knowledge up to right level of granularity in data and knowledge representation. Finally it concludes on that granular computing is powerful view that can be used to model many problems.

  18. 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. PMID:26708982

  19. Behavioural Rule Discovery from Swarm Systems

    Science.gov (United States)

    Stoops, David; Wang, Hui; Moore, George; Bi, Yaxin

    Rules determine the functionality of a given system, in either natural or man-made systems. Man-made systems, such as computer applications, use a set of known rules to control the behaviours applied in a strict manner. Biological or natural systems employ unknown rules, these being undiscovered rules which are more complex. These rules are unknown due to the inability to determine how they are applied, unless observed by a third party. The swarm is one of the largest naturally observed systems, with bird flocks and ant colonies being the most notable. It is a collection or group of individuals who use behaviours to complete a given goal or objective. It is the aim of this paper to present rule discovery methods for the mining of these unknown rules within a swarm system, employing a bird flock simulation environment to gather data.

  20. Reflections on the discovery of fission

    International Nuclear Information System (INIS)

    In this article an eminent scientist looks back on the fifty years since the discovery of nuclear fission. Starting with Enrico Fermi's work with neutrons in the 1930s, the author then introduces Neils Bohr's ideas about atomic structure. The puzzle of what happens when uranium was bombarded by neutrons was gradually unravelled. Finally by 1939 it was becoming realised that the uranium nucleus had split in two. Gradually physicists began to speculate on the possibility of harnessing some of the energy stored in the nucleus and on the idea of a chain reaction. As the end of the decade approached, workers in the field combined with military forces to develop a weapon based on this reaction, the Manhatton Project. The author notes how fast an obscure, esoteric piece of physics research, can be taken up into the military and political area. (UK)