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Sample records for integrase reveals key

  1. Comparison Between Several Integrase-defective Lentiviral Vectors Reveals Increased Integration of an HIV Vector Bearing a D167H Mutant

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    Muhammad Qamar Saeed

    2014-01-01

    Full Text Available HIV-1 derived vectors are among the most efficient for gene transduction in mammalian tissues. As the parent virus, they carry out vector genome insertion into the host cell chromatin. Consequently, their preferential integration in transcribed genes raises several conceptual and safety issues. To address part of these questions, HIV-derived vectors have been engineered to be nonintegrating. This was mainly achieved by mutating HIV-1 integrase at functional hotspots of the enzyme enabling the development of streamlined nuclear DNA circles functional for transgene expression. Few integrase mutant vectors have been successfully tested so far for gene transfer. They are cleared with time in mitotic cells, but stable within nondividing retina cells or neurons. Here, we compared six HIV vectors carrying different integrases, either wild type or with different mutations (D64V, D167H, Q168A, K186Q+Q214L+Q216L, and RRK262-264AAH shown to modify integrase enzymatic activity, oligomerization, or interaction with key cellular cofactor of HIV DNA integration as LEDGF/p75 or TNPO3. We show that these mutations differently affect the transduction efficiency as well as rates and patterns of integration of HIV-derived vectors suggesting their different processing in the nucleus. Surprisingly and most interestingly, we report that an integrase carrying the D167H substitution improves vector transduction efficiency and integration in both HEK-293T and primary CD34+ cells.

  2. Resistance to pyridine-based inhibitor KF116 reveals an unexpected role of integrase in HIV-1 Gag-Pol polyprotein proteolytic processing.

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    Hoyte, Ashley C; Jamin, Augusta V; Koneru, Pratibha C; Kobe, Matthew J; Larue, Ross C; Fuchs, James R; Engelman, Alan N; Kvaratskhelia, Mamuka

    2017-12-01

    The pyridine-based multimerization selective HIV-1 integrase (IN) inhibitors (MINIs) are a distinct subclass of allosteric IN inhibitors. MINIs potently inhibit HIV-1 replication during virion maturation by inducing hyper- or aberrant IN multimerization but are largely ineffective during the early steps of viral replication. Here, we investigated the mechanism for the evolution of a triple IN substitution (T124N/V165I/T174I) that emerges in cell culture with a representative MINI, KF116. We show that HIV-1 NL4-3(IN T124N/V165I/T174I) confers marked (>2000-fold) resistance to KF116. Two IN substitutions (T124N/T174I) directly weaken inhibitor binding at the dimer interface of the catalytic core domain but at the same time markedly impair HIV-1 replication capacity. Unexpectedly, T124N/T174I IN substitutions inhibited proteolytic processing of HIV-1 polyproteins Gag and Gag-Pol, resulting in immature virions. Strikingly, the addition of the third IN substitution (V165I) restored polyprotein processing, virus particle maturation, and significant levels of replication capacity. These results reveal an unanticipated role of IN for polyprotein proteolytic processing during virion morphogenesis. The complex evolutionary pathway for the emergence of resistant viruses, which includes the need for the compensatory V165I IN substitution, highlights a relatively high genetic barrier exerted by MINI KF116. Additionally, we have solved the X-ray structure of the drug-resistant catalytic core domain protein, which provides means for rational development of second-generation MINIs. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. A historical sketch of the discovery and development of HIV-1 integrase inhibitors.

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    Savarino, Andrea

    2006-12-01

    The long process of HIV-1 integrase inhibitor discovery and development can be attributed to both the complexity of HIV-1 integration and poor 'integration' of these researches into mainstream investigations on antiretroviral therapy in the mid-1990s. Of note, some fungal extracts investigated during this period contain the beta-hydroxyketo group, later recognised to be a key structural requirement for keto-enol acids (also referred to as diketo acids) and other integrase inhibitors. This review reconstructs (in the general context of the history of AIDS research) the principal steps that led to the integrase inhibitors currently in clinical trials, and discusses possible future directions.

  4. Serine integrase chimeras with activity in E. coli and HeLa cells

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    Alfonso P. Farruggio

    2014-09-01

    Full Text Available In recent years, application of serine integrases for genomic engineering has increased in popularity. The factor-independence and unidirectionality of these large serine recombinases makes them well suited for reactions such as site-directed vector integration and cassette exchange in a wide variety of organisms. In order to generate information that might be useful for altering the specificity of serine integrases and to improve their efficiency, we tested a hybridization strategy that has been successful with several small serine recombinases. We created chimeras derived from three characterized members of the serine integrase family, phiC31, phiBT1, and TG1 integrases, by joining their amino- and carboxy-terminal portions. We found that several phiBT1-phiC31 (BC and phiC31-TG1 (CT hybrid integrases are active in E. coli. BC chimeras function on native att-sites and on att-sites that are hybrids between those of the two donor enzymes, while CT chimeras only act on the latter att-sites. A BC hybrid, BC{−1}, was also active in human HeLa cells. Our work is the first to demonstrate chimeric serine integrase activity. This analysis sheds light on integrase structure and function, and establishes a potentially tractable means to probe the specificity of the thousands of putative large serine recombinases that have been revealed by bioinformatics studies.

  5. Integrase of Mason-Pfizer monkey virus

    Czech Academy of Sciences Publication Activity Database

    Snášel, Jan; Krejčík, Zdeněk; Jenčová, Věra; Rosenberg, Ivan; Ruml, Tomáš; Alexandratos, J.; Gustchina, A.; Pichová, Iva

    2005-01-01

    Roč. 272, č. 1 (2005), s. 203-216 ISSN 1742-464X R&D Projects: GA AV ČR(CZ) IAA4055304 Institutional research plan: CEZ:AV0Z4055905 Keywords : integrase * Mason-Pfizer monkey virus * HIV-1 Subject RIV: CE - Biochemistry

  6. Comparison of Newly Assembled Full Length HIV-1 Integrase With Prototype Foamy Virus Integrase: Structure-Function Prospective.

    Science.gov (United States)

    Dayer, Mohammad Reza

    2016-05-01

    Drug design against human immunodeficiency virus type 1 (HIV-1) integrase through its mechanistic study is of great interest in the area in biological research. The main obstacle in this area is the absence of the full-length crystal structure for HIV-1 integrase to be used as a model. A complete structure, similar to HIV-1 of a prototype foamy virus integrase in complex with DNA, including all conservative residues, is available and has been extensively used in recent investigations. The aim of this study was to determine whether the above model is precisely representative of HIV-1 integrase. This would critically determine the success of any designed drug using the model in deactivation of integrase and AIDS treatment. Primarily, a new structure for HIV-1 was constructed, using a crystal structure of prototype foamy virus as the starting structure. The constructed structure of HIV-1 integrase was simultaneously simulated with a prototype foamy virus integrase on a separate occasion. Our results indicate that the HIV-1 system behaves differently from the prototype foamy virus in terms of folding, hydration, hydrophobicity of binding site and stability. Based on our findings, we can conclude that HIV-1 integrase is vastly different from the prototype foamy virus integrase and does not resemble it, and the modeling output of the prototype foamy virus simulations could not be simply generalized to HIV-1 integrase. Therefore, our HIV-1 model seems to be more representative and more useful for future research.

  7. Raltegravir: first in class HIV integrase inhibitor

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    Zelalem Temesgen

    2008-06-01

    Full Text Available Zelalem Temesgen1, Dawd S Siraj21Mayo Clinic, Rochester, MN, USA; 2East Carolina University Greenville, NC, USAAbstract: On October 16, 2007, the US Food and Drug Administration (FDA approved raltegravir for treatment of human immunodeficiency virus (HIV-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is first in a novel class of antiretroviral drugs known as integrase inhibitors. It has demonstrated potent anti HIV activity in both antiretroviral treatment-naïve and experienced patients. The most common adverse events reported with raltegravir during phase 2 and 3 clinical trials were diarrhea, nausea, and headache. Laboratory abnormalities include mild elevations in liver transaminases and creatine phosphokinase.Keywords: raltegravir, HIV, antiretroviral agents, integrase inhibitors

  8. Primary resistance to integrase strand-transfer inhibitors in Europe.

    NARCIS (Netherlands)

    M. Casadellá; P.M. van Ham (Petra); M. Noguera-Julian; A. van Kessel; C. Pou; L.M. Hofstra (Marije); G.A. Metcalf (Ginger A.); F. Garcia; D. Struck (Daniel); I. Alexiev (Ivailo); A.M. Bakken Kran; A.I.M. Hoepelman; L.G. Kostrikis (Leondios); S. Somogyi; K. Liitsola (Kirsi); M. Linka (Marek); C. Nielsen; D. Otelea (Dan); D. Paraskevis (Dimitrios); M. Poljak (Mario); E. Puchhammer-Stöckl (Elisabeth); D. Stanekova (Danica); M. Stanojevic (Maja); K. Van Laethem (Kristel); S. Zidovec Lepej (Snjezana); B. Clotet; C.A.B. Boucher (Charles); R. Paredes (Roger); A.M.J. Wensing (Annemarie)

    2015-01-01

    markdownabstractThe objective of this study was to define the natural genotypic variation of the HIV-1 integrase gene across Europe for epidemiological surveillance of integrase strand-transfer inhibitor (InSTI) resistance. This was a multicentre, cross-sectional study within the European SPREAD

  9. Primary resistance to integrase strand-transfer inhibitors in Europe

    NARCIS (Netherlands)

    Casadella, M.; van Ham, P. M.; Noguera-Julian, M.; van Kessel, A.; Pou, C.; Hofstra, L. M.; Santos, J. R.; Garcia, F.; Struck, D.; Alexiev, I.; Kran, A. M. Bakken; Hoepelman, A. I.; Kostrikis, L. G.; Somogyi, S.; Liitsola, K.; Linka, M.; Nielsen, C.; Otelea, D.; Paraskevis, D.; Poljak, M.; Puchhammer-Stoeckl, E.; Stanekova, D.; Stanojevic, M.; Van Laethem, K.; Lepej, S. Zidovec; Clotet, B.; Boucher, C. A. B.; Paredes, R.; Wensing, A. M. J.; Schuurman, R

    2015-01-01

    Objectives: The objective of this study was to define the natural genotypic variation of the HIV-1 integrase gene across Europe for epidemiological surveillance of integrase strand-transfer inhibitor (InSTI) resistance. Methods: This was a multicentre, cross-sectional study within the European

  10. Tight regulation of the intS gene of the KplE1 prophage: a new paradigm for integrase gene regulation.

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    Gaël Panis

    2010-10-01

    Full Text Available Temperate phages have the ability to maintain their genome in their host, a process called lysogeny. For most, passive replication of the phage genome relies on integration into the host's chromosome and becoming a prophage. Prophages remain silent in the absence of stress and replicate passively within their host genome. However, when stressful conditions occur, a prophage excises itself and resumes the viral cycle. Integration and excision of phage genomes are mediated by regulated site-specific recombination catalyzed by tyrosine and serine recombinases. In the KplE1 prophage, site-specific recombination is mediated by the IntS integrase and the TorI recombination directionality factor (RDF. We previously described a sub-family of temperate phages that is characterized by an unusual organization of the recombination module. Consequently, the attL recombination region overlaps with the integrase promoter, and the integrase and RDF genes do not share a common activated promoter upon lytic induction as in the lambda prophage. In this study, we show that the intS gene is tightly regulated by its own product as well as by the TorI RDF protein. In silico analysis revealed that overlap of the attL region with the integrase promoter is widely encountered in prophages present in prokaryotic genomes, suggesting a general occurrence of negatively autoregulated integrase genes. The prediction that these integrase genes are negatively autoregulated was biologically assessed by studying the regulation of several integrase genes from two different Escherichia coli strains. Our results suggest that the majority of tRNA-associated integrase genes in prokaryotic genomes could be autoregulated and that this might be correlated with the recombination efficiency as in KplE1. The consequences of this unprecedented regulation for excessive recombination are discussed.

  11. Molecular features related to HIV integrase inhibition obtained from structure- and ligand-based approaches.

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    Luciana L de Carvalho

    Full Text Available Among several biological targets to treat AIDS, HIV integrase is a promising enzyme that can be employed to develop new anti-HIV agents. The aim of this work is to propose a mechanistic interpretation of HIV-1 integrase inhibition and to rationalize the molecular features related to the binding affinity of studied ligands. A set of 79 HIV-1 integrase inhibitors and its relationship with biological activity are investigated employing 2D and 3D QSAR models, docking analysis and DFT studies. Analyses of docking poses and frontier molecular orbitals revealed important features on the main ligand-receptor interactions. 2D and 3D models presenting good internal consistency, predictive power and stability were obtained in all cases. Significant correlation coefficients (r(2 = 0.908 and q(2= 0.643 for 2D model; r(2= 0.904 and q(2= 0.719 for 3D model were obtained, indicating the potential of these models for untested compounds. The generated holograms and contribution maps revealed important molecular requirements to HIV-1 IN inhibition and several evidences for molecular modifications. The final models along with information resulting from molecular orbitals, 2D contribution and 3D contour maps should be useful in the design of new inhibitors with increased potency and selectivity within the chemical diversity of the data.

  12. Transcriptome analysis reveals key differentially expressed genes involved in wheat grain development

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    Yonglong Yu

    2016-04-01

    Full Text Available Wheat seed development is an important physiological process of seed maturation and directly affects wheat yield and quality. In this study, we performed dynamic transcriptome microarray analysis of an elite Chinese bread wheat cultivar (Jimai 20 during grain development using the GeneChip Wheat Genome Array. Grain morphology and scanning electron microscope observations showed that the period of 11–15 days post-anthesis (DPA was a key stage for the synthesis and accumulation of seed starch. Genome-wide transcriptional profiling and significance analysis of microarrays revealed that the period from 11 to 15 DPA was more important than the 15–20 DPA stage for the synthesis and accumulation of nutritive reserves. Series test of cluster analysis of differential genes revealed five statistically significant gene expression profiles. Gene ontology annotation and enrichment analysis gave further information about differentially expressed genes, and MapMan analysis revealed expression changes within functional groups during seed development. Metabolic pathway network analysis showed that major and minor metabolic pathways regulate one another to ensure regular seed development and nutritive reserve accumulation. We performed gene co-expression network analysis to identify genes that play vital roles in seed development and identified several key genes involved in important metabolic pathways. The transcriptional expression of eight key genes involved in starch and protein synthesis and stress defense was further validated by qRT-PCR. Our results provide new insight into the molecular mechanisms of wheat seed development and the determinants of yield and quality.

  13. Interrogating Key Positions of Size-Reduced TALE Repeats Reveals a Programmable Sensor of 5-Carboxylcytosine.

    Science.gov (United States)

    Maurer, Sara; Giess, Mario; Koch, Oliver; Summerer, Daniel

    2016-12-16

    Transcription-activator-like effector (TALE) proteins consist of concatenated repeats that recognize consecutive canonical nucleobases of DNA via the major groove in a programmable fashion. Since this groove displays unique chemical information for the four human epigenetic cytosine nucleobases, TALE repeats with epigenetic selectivity can be engineered, with potential to establish receptors for the programmable decoding of all human nucleobases. TALE repeats recognize nucleobases via key amino acids in a structurally conserved loop whose backbone is positioned very close to the cytosine 5-carbon. This complicates the engineering of selectivities for large 5-substituents. To interrogate a more promising structural space, we engineered size-reduced repeat loops, performed saturation mutagenesis of key positions, and screened a total of 200 repeat-nucleobase interactions for new selectivities. This provided insight into the structural requirements of TALE repeats for affinity and selectivity, revealed repeats with improved or relaxed selectivity, and resulted in the first selective sensor of 5-carboxylcytosine.

  14. Characterization of natural polymorphic sites of the HIV-1 integrase before the introduction of HIV-1 integrase inhibitors in Germany

    Science.gov (United States)

    Meixenberger, Karolin; Pouran Yousef, Kaveh; Somogyi, Sybille; Fiedler, Stefan; Bartmeyer, Barbara; von Kleist, Max; Kücherer, Claudia

    2014-01-01

    Introduction The aim of our study was to analyze the occurrence and evolution of HIV-1 integrase polymorphisms during the HIV-1 epidemic in Germany prior to the introduction of the first integrase inhibitor raltegravir in 2007. Materials and Methods Plasma samples from drug-naïve HIV-1 infected individuals newly diagnosed between 1986 and 2006 were used to determine PCR-based population sequences of the HIV-1 integrase (amino acids 1–278). The HIV-1 subtype was determined using the REGA HIV-1 subtyping tool. We calculated the frequency of amino acids at each position of the HIV-1 integrase in 337 subtype B strains for the time periods 1986–1989, 1991–1994, 1995–1998, 1999–2002, and 2003–2006. Positions were defined as polymorphic if amino acid variation was >1% in any period. Logistic regression was used to identify trends in amino acid variation over time. Resistance-associated mutations were identified according to the IAS 2013 list and the HIVdb, ANRS and GRADE algorithms. Results Overall, 56.8% (158/278) amino acid positions were polymorphic and 15.8% (25/158) of these positions exhibited a significant trend in amino acid variation over time. Proportionately, most polymorphic positions (63.3%, 31/49) were detected in the N-terminal zinc finger domain of the HIV-1 integrase. Motifs and residues essential for HIV-1 integrase activity were little polymorphic, but within the minimal non-specific DNA binding region I220-D270 up to 18.1% amino acid variation was noticed, including four positions with significant amino acid variation over time (S230, D232, D256, A265). No major resistance mutations were identified, and minor resistance mutations were rarely observed without trend over time. E157Q considered by HIVdb, ANRS, and GRADE algorithms was the most frequent resistance-associated polymorphism with an overall prevalence of 2.4%. Conclusions Detailed knowledge of the evolutionary variation of HIV-1 integrase polymorphisms is important to understand

  15. Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part II. Integrase inhibition

    International Nuclear Information System (INIS)

    Lee-Huang, Sylvia; Huang, Philip Lin; Zhang Dawei; Lee, Jae Wook; Bao Ju; Sun Yongtao; Chang, Young-Tae; Zhang, John; Huang, Paul Lee

    2007-01-01

    We report molecular modeling and functional confirmation of Ole and HT binding to HIV-1 integrase. Docking simulations identified two binding regions for Ole within the integrase active site. Region I encompasses the conserved D64-D116-E152 motif, while region II involves the flexible loop region formed by amino acid residues 140-149. HT, on the other hand, binds to region II. Both Ole and HT exhibit favorable interactions with important amino acid residues through strong H-bonding and van der Waals contacts, predicting integrase inhibition. To test and confirm modeling predictions, we examined the effect of Ole and HT on HIV-1 integrase activities including 3'-processing, strand transfer, and disintegration. Ole and HT exhibit dose-dependent inhibition on all three activities, with EC 50 s in the nanomolar range. These studies demonstrate that molecular modeling of target-ligand interaction coupled with structural-activity analysis should facilitate the design and identification of innovative integrase inhibitors and other therapeutics

  16. Novel key metabolites reveal further branching of the roquefortine/meleagrin biosynthetic pathway.

    Science.gov (United States)

    Ries, Marco I; Ali, Hazrat; Lankhorst, Peter P; Hankemeier, Thomas; Bovenberg, Roel A L; Driessen, Arnold J M; Vreeken, Rob J

    2013-12-27

    Metabolic profiling and structural elucidation of novel secondary metabolites obtained from derived deletion strains of the filamentous fungus Penicillium chrysogenum were used to reassign various previously ascribed synthetase genes of the roquefortine/meleagrin pathway to their corresponding products. Next to the structural characterization of roquefortine F and neoxaline, which are for the first time reported for P. chrysogenum, we identified the novel metabolite roquefortine L, including its degradation products, harboring remarkable chemical structures. Their biosynthesis is discussed, questioning the exclusive role of glandicoline A as key intermediate in the pathway. The results reveal that further enzymes of this pathway are rather unspecific and catalyze more than one reaction, leading to excessive branching in the pathway with meleagrin and neoxaline as end products of two branches.

  17. Systematic Prioritization and Integrative Analysis of Copy Number Variations in Schizophrenia Reveal Key Schizophrenia Susceptibility Genes

    Science.gov (United States)

    Luo, Xiongjian; Huang, Liang; Han, Leng; Luo, Zhenwu; Hu, Fang; Tieu, Roger; Gan, Lin

    2014-01-01

    Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and

  18. Quantitative proteomics reveals that peroxidases play key roles in post-flooding recovery in soybean roots.

    Science.gov (United States)

    Khan, Mudassar Nawaz; Sakata, Katsumi; Hiraga, Susumu; Komatsu, Setsuko

    2014-12-05

    Soybean is an important legume crop that exhibits markedly reduced growth and yields under flooding conditions. To unravel the mechanisms involved in recovery after flooding in soybean root, gel-free proteomic analysis was performed. Morphological analysis revealed that growth suppression was more severe with increased flooding duration. Out of a total of 1645 and 1707 identified proteins, 73 and 21 proteins were changed significantly during the recovery stage following 2 and 4 days flooding, respectively. Based on the proteomic, clustering, and in silico protein-protein interaction analyses, six key enzymes were analyzed at the mRNA level. Lipoxygenase 1, which was increased at the protein level during the recovery period, was steadily down-regulated at the mRNA level. The peroxidase superfamily protein continuously increased in abundance during the course of recovery and was up-regulated at the mRNA level. HAD acid phosphatase was decreased at the protein level and down-regulated at the transcript level, while isoflavone reductase and an unknown protein were increased at both the protein and mRNA levels. Consistent with these findings, the enzymatic activity of peroxidase was decreased under flooding stress but increased significantly during the recovery sage. These results suggest that peroxidases might play key roles in post-flooding recovery in soybean roots through the scavenging of toxic radicals.

  19. Many-objective optimization and visual analytics reveal key trade-offs for London's water supply

    Science.gov (United States)

    Matrosov, Evgenii S.; Huskova, Ivana; Kasprzyk, Joseph R.; Harou, Julien J.; Lambert, Chris; Reed, Patrick M.

    2015-12-01

    In this study, we link a water resource management simulator to multi-objective search to reveal the key trade-offs inherent in planning a real-world water resource system. We consider new supplies and demand management (conservation) options while seeking to elucidate the trade-offs between the best portfolios of schemes to satisfy projected water demands. Alternative system designs are evaluated using performance measures that minimize capital and operating costs and energy use while maximizing resilience, engineering and environmental metrics, subject to supply reliability constraints. Our analysis shows many-objective evolutionary optimization coupled with state-of-the art visual analytics can help planners discover more diverse water supply system designs and better understand their inherent trade-offs. The approach is used to explore future water supply options for the Thames water resource system (including London's water supply). New supply options include a new reservoir, water transfers, artificial recharge, wastewater reuse and brackish groundwater desalination. Demand management options include leakage reduction, compulsory metering and seasonal tariffs. The Thames system's Pareto approximate portfolios cluster into distinct groups of water supply options; for example implementing a pipe refurbishment program leads to higher capital costs but greater reliability. This study highlights that traditional least-cost reliability constrained design of water supply systems masks asset combinations whose benefits only become apparent when more planning objectives are considered.

  20. Integrated bioinformatics analysis reveals key candidate genes and pathways in breast cancer.

    Science.gov (United States)

    Wang, Yuzhi; Zhang, Yi; Huang, Qian; Li, Chengwen

    2018-04-19

    Breast cancer (BC) is the leading malignancy in women worldwide, yet relatively little is known about the genes and signaling pathways involved in BC tumorigenesis and progression. The present study aimed to elucidate potential key candidate genes and pathways in BC. Five gene expression profile data sets (GSE22035, GSE3744, GSE5764, GSE21422 and GSE26910) were downloaded from the Gene Expression Omnibus (GEO) database, which included data from 113 tumorous and 38 adjacent non‑tumorous tissue samples. Differentially expressed genes (DEGs) were identified using t‑tests in the limma R package. These DEGs were subsequently investigated by pathway enrichment analysis and a protein‑protein interaction (PPI) network was constructed. The most significant module from the PPI network was selected for pathway enrichment analysis. In total, 227 DEGs were identified, of which 82 were upregulated and 145 were downregulated. Pathway enrichment analysis results revealed that the upregulated DEGs were mainly enriched in 'cell division', the 'proteinaceous extracellular matrix (ECM)', 'ECM structural constituents' and 'ECM‑receptor interaction', whereas downregulated genes were mainly enriched in 'response to drugs', 'extracellular space', 'transcriptional activator activity' and the 'peroxisome proliferator‑activated receptor signaling pathway'. The PPI network contained 174 nodes and 1,257 edges. DNA topoisomerase 2‑a, baculoviral inhibitor of apoptosis repeat‑containing protein 5, cyclin‑dependent kinase 1, G2/mitotic‑specific cyclin‑B1 and kinetochore protein NDC80 homolog were identified as the top 5 hub genes. Furthermore, the genes in the most significant module were predominantly involved in 'mitotic nuclear division', 'mid‑body', 'protein binding' and 'cell cycle'. In conclusion, the DEGs, relative pathways and hub genes identified in the present study may aid in understanding of the molecular mechanisms underlying BC progression and provide

  1. Data integration reveals key homeostatic mechanisms following low dose radiation exposure

    Energy Technology Data Exchange (ETDEWEB)

    Tilton, Susan C.; Matzke, Melissa M. [Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, WA 99338 (United States); Sowa, Marianne B.; Stenoien, David L.; Weber, Thomas J. [Health Impacts and Exposure Science, Pacific Northwest National Laboratory, Richland, WA 99338 (United States); Morgan, William F. [Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99338 (United States); Waters, Katrina M., E-mail: katrina.waters@pnnl.gov [Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99338 (United States)

    2015-05-15

    The goal of this study was to define pathways regulated by low dose radiation to understand how biological systems respond to subtle perturbations in their environment and prioritize pathways for human health assessment. Using an in vitro 3-D human full thickness skin model, we have examined the temporal response of dermal and epidermal layers to 10 cGy X-ray using transcriptomic, proteomic, phosphoproteomic and metabolomic platforms. Bioinformatics analysis of each dataset independently revealed potential signaling mechanisms affected by low dose radiation, and integrating data shed additional insight into the mechanisms regulating low dose responses in human tissue. We examined direct interactions among datasets (top down approach) and defined several hubs as significant regulators, including transcription factors (YY1, MYC and CREB1), kinases (CDK2, PLK1) and a protease (MMP2). These data indicate a shift in response across time — with an increase in DNA repair, tissue remodeling and repression of cell proliferation acutely (24–72 h). Pathway-based integration (bottom up approach) identified common molecular and pathway responses to low dose radiation, including oxidative stress, nitric oxide signaling and transcriptional regulation through the SP1 factor that would not have been identified by the individual data sets. Significant regulation of key downstream metabolites of nitrative stress was measured within these pathways. Among the features identified in our study, the regulation of MMP2 and SP1 was experimentally validated. Our results demonstrate the advantage of data integration to broadly define the pathways and networks that represent the mechanisms by which complex biological systems respond to perturbation. - Highlights: • Low dose ionizing radiation altered homeostasis in 3D skin tissue model. • Global gene/protein/metabolite data integrated using complementary statistical approaches • Time and location-specific change in matrix regulation

  2. Developing a Dynamic Pharmacophore Model for HIV-1 Integrase

    International Nuclear Information System (INIS)

    Carlson, Heather A.; Masukawa, Keven M.; Rubins, Kathleen; Bushman, Frederic; Jorgensen, William L.; Lins, Roberto; Briggs, James; Mccammon, Andy

    2000-01-01

    We present the first receptor-based pharmacophore model for HIV-1 integrase. The development of ''dynamic'' pharmacophore models is a new method that accounts for the inherent flexibility of the active site and aims to reduce the entropic penalties associated with binding a ligand. Furthermore, this new drug discovery method overcomes the limitation of an incomplete crystal structure of the target protein. A molecular dynamics (MD) simulation describes the flexibility of the uncomplexed protein. Many conformational models of the protein are saved from the MD simulations and used in a series of multi-unit search for interacting conformers (MUSIC) simulations. MUSIC is a multiple-copy minimization method, available in the BOSS program; it is used to determine binding regions for probe molecules containing functional groups that complement the active site. All protein conformations from the MD are overlaid, and conserved binding regions for the probe molecules are identified. Those conserved binding regions define the dynamic pharmacophore model. Here, the dynamic model is compared to known inhibitors of the integrase as well as a three-point, ligand-based pharmacophore model from the literature. Also, a ''static'' pharmacophore model was determined in the standard fashion, using a single crystal structure. Inhibitors thought to bind in the active site of HIV-1 integrase fit the dynamic model but not the static model. Finally, we have identified a set of compounds from the Available Chemicals Directory that fit the dynamic pharmacophore model, and experimental testing of the compounds has confirmed several new inhibitors

  3. Valuing snorkeling visits to the Florida Keys with stated and revealed preference models

    Science.gov (United States)

    Timothy Park; J. Michael Bowker; Vernon R. Leeworthy

    2002-01-01

    Coastal coral reefs, especially in the Florida Keys, are declining at a disturbing rate. Marine ecologists and reef scientists have emphasized the importance of establishing nonmarket values of coral reefs to assess the cost effectiveness of coral reef management and remediation programs. The purpose of this paper is to develop a travel cost--contingent valuation model...

  4. Inhibition of HIV-1 Integrase gene expression by 10-23 DNAzyme

    Indian Academy of Sciences (India)

    We have designed three novel DNAzymes, DIN54, DIN116, and DIN152, against HIV-1 Integrase gene using Mfold software and evaluated them for target site cleavage activity on the in vitro transcribed mRNA. All DNAzymes were tested for its inhibition of expression of HIV Integrase protein in the transiently transfected cell ...

  5. Key Players in I-DmoI Endonuclease Catalysis Revealed from Structure and Dynamics

    DEFF Research Database (Denmark)

    Molina, Rafael; Besker, Neva; Marcaida, Maria Jose

    2016-01-01

    . The cleavage mechanism was related both to key structural effects, such as the position of water molecules and ions participating in the cleavage reaction, and to dynamical effects related to protein behavior. In particular, we found that the protein perturbation pattern significantly changes between cleaved......Homing endonucleases, such as I-DmoI, specifically recognize and cleave long DNA target sequences (∼20 bp) and are potentially powerful tools for genome manipulation. However, inefficient and off-target DNA cleavage seriously limits specific editing in complex genomes. One approach to overcome...

  6. Thalassiolins A-C: new marine-derived inhibitors of HIV cDNA integrase.

    Science.gov (United States)

    Rowley, David C; Hansen, Mark S T; Rhodes, Denise; Sotriffer, Christoph A; Ni, Haihong; McCammon, J Andrew; Bushman, Frederic D; Fenical, William

    2002-11-01

    Human immunodeficiency virus (HIV) replication requires integration of viral cDNA into the host genome, a process mediated by the viral enzyme integrase. We describe a new series of HIV integrase inhibitors, thalassiolins A-C (1-3), isolated from the Caribbean sea grass Thalassia testudinum. The thalassiolins are distinguished from other flavones previously studied by the substitution of a sulfated beta-D-glucose at the 7-position, a substituent that imparts increased potency against integrase in biochemical assays. The most active of these molecules, thalassiolin A (1), displays in vitro inhibition of the integrase catalyzed strand transfer reaction (IC50=0.4 microM) and an antiviral IC50 of 30 microM. Molecular modeling studies indicate a favorable binding mode is probable at the catalytic core domain of HIV-1 integrase.

  7. Quantitative transcription dynamic analysis reveals candidate genes and key regulators for ethanol tolerance in Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Ma Menggen

    2010-06-01

    Full Text Available Abstract Background Derived from our lignocellulosic conversion inhibitor-tolerant yeast, we generated an ethanol-tolerant strain Saccharomyces cerevisiae NRRL Y-50316 by enforced evolutionary adaptation. Using a newly developed robust mRNA reference and a master equation unifying gene expression data analyses, we investigated comparative quantitative transcription dynamics of 175 genes selected from previous studies for an ethanol-tolerant yeast and its closely related parental strain. Results A highly fitted master equation was established and applied for quantitative gene expression analyses using pathway-based qRT-PCR array assays. The ethanol-tolerant Y-50316 displayed significantly enriched background of mRNA abundance for at least 35 genes without ethanol challenge compared with its parental strain Y-50049. Under the ethanol challenge, the tolerant Y-50316 responded in consistent expressions over time for numerous genes belonging to groups of heat shock proteins, trehalose metabolism, glycolysis, pentose phosphate pathway, fatty acid metabolism, amino acid biosynthesis, pleiotropic drug resistance gene family and transcription factors. The parental strain showed repressed expressions for many genes and was unable to withstand the ethanol stress and establish a viable culture and fermentation. The distinct expression dynamics between the two strains and their close association with cell growth, viability and ethanol fermentation profiles distinguished the tolerance-response from the stress-response in yeast under the ethanol challenge. At least 82 genes were identified as candidate and key genes for ethanol-tolerance and subsequent fermentation under the stress. Among which, 36 genes were newly recognized by the present study. Most of the ethanol-tolerance candidate genes were found to share protein binding motifs of transcription factors Msn4p/Msn2p, Yap1p, Hsf1p and Pdr1p/Pdr3p. Conclusion Enriched background of transcription abundance

  8. Novel personalized pathway-based metabolomics models reveal key metabolic pathways for breast cancer diagnosis

    DEFF Research Database (Denmark)

    Huang, Sijia; Chong, Nicole; Lewis, Nathan

    2016-01-01

    diagnosis. We applied this method to predict breast cancer occurrence, in combination with correlation feature selection (CFS) and classification methods. Results: The resulting all-stage and early-stage diagnosis models are highly accurate in two sets of testing blood samples, with average AUCs (Area Under.......993. Moreover, important metabolic pathways, such as taurine and hypotaurine metabolism and the alanine, aspartate, and glutamate pathway, are revealed as critical biological pathways for early diagnosis of breast cancer. Conclusions: We have successfully developed a new type of pathway-based model to study...... metabolomics data for disease diagnosis. Applying this method to blood-based breast cancer metabolomics data, we have discovered crucial metabolic pathway signatures for breast cancer diagnosis, especially early diagnosis. Further, this modeling approach may be generalized to other omics data types for disease...

  9. DNA microarray revealed and RNAi plants confirmed key genes conferring low Cd accumulation in barley grains

    DEFF Research Database (Denmark)

    Sun, Hongyan; Chen, Zhong-Hua; Chen, Fei

    2015-01-01

    Background Understanding the mechanism of low Cd accumulation in crops is crucial for sustainable safe food production in Cd-contaminated soils. Results Confocal microscopy, atomic absorption spectrometry, gas exchange and chlorophyll fluorescence analyses revealed a distinct difference in Cd...... with a substantial difference between the two genotypes. Cd stress led to higher expression of genes involved in transport, carbohydrate metabolism and signal transduction in the low-grain-Cd-accumulating genotype. Novel transporter genes such as zinc transporter genes were identified as being associated with low Cd...... accumulation. Quantitative RT-PCR confirmed our microarray data. Furthermore, suppression of the zinc transporter genes HvZIP3 and HvZIP8 by RNAi silencing showed increased Cd accumulation and reduced Zn and Mn concentrations in barley grains. Thus, HvZIP3 and HvZIP8 could be candidate genes related to low...

  10. The Chlamydomonas Genome Reveals the Evolution of Key Animal and Plant Functions

    Energy Technology Data Exchange (ETDEWEB)

    Merchant, Sabeeha S

    2007-04-09

    Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the 120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella.

  11. High Pressure ZZ-Exchange NMR Reveals Key Features of Protein Folding Transition States.

    Science.gov (United States)

    Zhang, Yi; Kitazawa, Soichiro; Peran, Ivan; Stenzoski, Natalie; McCallum, Scott A; Raleigh, Daniel P; Royer, Catherine A

    2016-11-23

    Understanding protein folding mechanisms and their sequence dependence requires the determination of residue-specific apparent kinetic rate constants for the folding and unfolding reactions. Conventional two-dimensional NMR, such as HSQC experiments, can provide residue-specific information for proteins. However, folding is generally too fast for such experiments. ZZ-exchange NMR spectroscopy allows determination of folding and unfolding rates on much faster time scales, yet even this regime is not fast enough for many protein folding reactions. The application of high hydrostatic pressure slows folding by orders of magnitude due to positive activation volumes for the folding reaction. We combined high pressure perturbation with ZZ-exchange spectroscopy on two autonomously folding protein domains derived from the ribosomal protein, L9. We obtained residue-specific apparent rates at 2500 bar for the N-terminal domain of L9 (NTL9), and rates at atmospheric pressure for a mutant of the C-terminal domain (CTL9) from pressure dependent ZZ-exchange measurements. Our results revealed that NTL9 folding is almost perfectly two-state, while small deviations from two-state behavior were observed for CTL9. Both domains exhibited large positive activation volumes for folding. The volumetric properties of these domains reveal that their transition states contain most of the internal solvent excluded voids that are found in the hydrophobic cores of the respective native states. These results demonstrate that by coupling it with high pressure, ZZ-exchange can be extended to investigate a large number of protein conformational transitions.

  12. A novel function for spumaretrovirus integrase: an early requirement for integrase-mediated cleavage of 2 LTR circles

    Directory of Open Access Journals (Sweden)

    Mouscadet Jean-François

    2005-05-01

    Full Text Available Abstract Retroviral integration is central to viral persistence and pathogenesis, cancer as well as host genome evolution. However, it is unclear why integration appears essential for retrovirus production, especially given the abundance and transcriptional potential of non-integrated viral genomes. The involvement of retroviral endonuclease, also called integrase (IN, in replication steps apart from integration has been proposed, but is usually considered to be accessory. We observe here that integration of a retrovirus from the spumavirus family depends mainly on the quantity of viral DNA produced. Moreover, we found that IN directly participates to linear DNA production from 2-LTR circles by specifically cleaving the conserved palindromic sequence found at LTR-LTR junctions. These results challenge the prevailing view that integrase essential function is to catalyze retroviral DNA integration. Integrase activity upstream of this step, by controlling linear DNA production, is sufficient to explain the absolute requirement for this enzyme. The novel role of IN over 2-LTR circle junctions accounts for the pleiotropic effects observed in cells infected with IN mutants. It may explain why 1 2-LTR circles accumulate in vivo in mutants carrying a defective IN while their linear and integrated DNA pools decrease; 2 why both LTRs are processed in a concerted manner. It also resolves the original puzzle concerning the integration of spumaretroviruses. More generally, it suggests to reassess 2-LTR circles as functional intermediates in the retrovirus cycle and to reconsider the idea that formation of the integrated provirus is an essential step of retrovirus production.

  13. Identification of TOEFAZ1-interacting proteins reveals key regulators of Trypanosoma brucei cytokinesis.

    Science.gov (United States)

    Hilton, Nicholas A; Sladewski, Thomas E; Perry, Jenna A; Pataki, Zemplen; Sinclair-Davis, Amy N; Muniz, Richard S; Tran, Holly L; Wurster, Jenna I; Seo, Jiwon; de Graffenried, Christopher L

    2018-05-21

    The protist parasite Trypanosoma brucei is an obligate extracellular pathogen that retains its highly-polarized morphology during cell division and has evolved a novel cytokinetic process independent of non-muscle myosin II. The polo-like kinase homolog TbPLK is essential for transmission of cell polarity during division and for cytokinesis. We previously identified a putative TbPLK substrate named Tip of the Extending FAZ 1 (TOEFAZ1) as an essential kinetoplastid-specific component of the T. brucei cytokinetic machinery. We performed a proximity-dependent biotinylation (BioID) screen using TOEFAZ1 as a means to identify additional proteins that are involved in cytokinesis. Using quantitative proteomic methods, we identified nearly 500 TOEFAZ1-proximal proteins and characterized 59 in further detail. Among the candidates, we identified an essential putative phosphatase that regulates the expression level and localization of both TOEFAZ1 and TbPLK, a previously uncharacterized protein that is necessary for the assembly of a new cell posterior, and a microtubule plus-end directed orphan kinesin that is required for completing cleavage furrow ingression. The identification of these proteins provides new insight into T. brucei cytokinesis and establishes TOEFAZ1 as a key component of this essential and uniquely-configured process in kinetoplastids. This article is protected by copyright. All rights reserved. © 2018 John Wiley & Sons Ltd.

  14. Proteomic analysis reveals heat shock protein 70 has a key role in polycythemia Vera.

    Science.gov (United States)

    Gallardo, Miguel; Barrio, Santiago; Fernandez, Marisol; Paradela, Alberto; Arenas, Alicia; Toldos, Oscar; Ayala, Rosa; Albizua, Enriqueta; Jimenez, Ana; Redondo, Santiago; Garcia-Martin, Rosa Maria; Gilsanz, Florinda; Albar, Juan Pablo; Martinez-Lopez, Joaquin

    2013-11-19

    JAK-STAT signaling through the JAK2V617F mutation is central to the pathogenesis of myeloproliferative neoplasms (MPN). However, other events could precede the JAK2 mutation. The aim of this study is to analyze the phenotypic divergence between polycytemia vera (PV) and essential thrombocytemia (ET) to find novel therapeutics targets by a proteomic and functional approach to identify alternative routes to JAK2 activation. Through 2D-DIGE and mass spectrometry of granulocyte protein from 20 MPN samples, showed differential expression of HSP70 in PV and ET besides other 60 proteins. Immunohistochemistry of 46 MPN bone marrow samples confirmed HSP70 expression. The median of positive granulocytes was 80% in PV (SD 35%) vs. 23% in ET (SD 34.25%). In an ex vivo model KNK437 was used as an inhibition model assay of HSP70, showed dose-dependent inhibition of cell growth and burst formation unit erythroid (BFU-E) in PV and ET, increased apoptosis in the erythroid lineage, and decreased pJAK2 signaling, as well as a specific siRNA for HSP70. These data suggest a key role for HSP70 in proliferation and survival of the erythroid lineage in PV, and may represent a potential therapeutic target in MPN, especially in PV.

  15. Transcriptomic analysis reveals key genes related to betalain biosynthesis in pulp coloration of Hylocereus polyrhizus

    Directory of Open Access Journals (Sweden)

    Hua eQingzhu

    2016-01-01

    Full Text Available Betalains have high nutritional value and bioactivities. Red pulp pitaya (Hylocereus polyrhizus is the only fruit containing abundant betalains for consumer. However, no information is available about genes involved in betalain biosynthesis in H. polyrhizus. Herein, two cDNA libraries of pitaya pulps with two different coloration stages (white and red pulp stages of Guanhuahong (H. polyrhizus were constructed. A total of about 12 Gb raw RNA-Seq data was generated and was de novo assembled into 122,677 transcripts with an average length of 1,183 bp and an N50 value of 2008. Approximately 99.99% of all transcripts were annotated based on seven public databases. A total of 8,871 transcripts were significantly regulated. Thirty-three candidate transcripts related to betalain biosynthesis were obtained from the transcriptome data. Transcripts encoding enzymes involved in betalain biosynthesis were analyzed using RT-qPCR at the whole pulp coloration stages of H. Polyrhizus (7-1 and H. Undatus (132-4. Nine key transcripts of betalain biosynthesis were identified. They were assigned to four kinds of genes in betalain biosynthetic pathway, including tyrosinase, 4, 5-DOPA dioxygenase extradiol, cytochrome P450 and glucosyltransferase. Ultimately, a preliminary betalain biosynthetic pathway for pitaya was proposed based on betalain analyses and gene expression profiles.

  16. Logic programming reveals alteration of key transcription factors in multiple myeloma.

    Science.gov (United States)

    Miannay, Bertrand; Minvielle, Stéphane; Roux, Olivier; Drouin, Pierre; Avet-Loiseau, Hervé; Guérin-Charbonnel, Catherine; Gouraud, Wilfried; Attal, Michel; Facon, Thierry; Munshi, Nikhil C; Moreau, Philippe; Campion, Loïc; Magrangeas, Florence; Guziolowski, Carito

    2017-08-23

    Innovative approaches combining regulatory networks (RN) and genomic data are needed to extract biological information for a better understanding of diseases, such as cancer, by improving the identification of entities and thereby leading to potential new therapeutic avenues. In this study, we confronted an automatically generated RN with gene expression profiles (GEP) from a cohort of multiple myeloma (MM) patients and normal individuals using global reasoning on the RN causality to identify key-nodes. We modeled each patient by his or her GEP, the RN and the possible automatically detected repairs needed to establish a coherent flow of the information that explains the logic of the GEP. These repairs could represent cancer mutations leading to GEP variability. With this reasoning, unmeasured protein states can be inferred, and we can simulate the impact of a protein perturbation on the RN behavior to identify therapeutic targets. We showed that JUN/FOS and FOXM1 activities are altered in almost all MM patients and identified two survival markers for MM patients. Our results suggest that JUN/FOS-activation has a strong impact on the RN in view of the whole GEP, whereas FOXM1-activation could be an interesting way to perturb an MM subgroup identified by our method.

  17. Microarray analysis reveals key genes and pathways in Tetralogy of Fallot

    Science.gov (United States)

    He, Yue-E; Qiu, Hui-Xian; Jiang, Jian-Bing; Wu, Rong-Zhou; Xiang, Ru-Lian; Zhang, Yuan-Hai

    2017-01-01

    The aim of the present study was to identify key genes that may be involved in the pathogenesis of Tetralogy of Fallot (TOF) using bioinformatics methods. The GSE26125 microarray dataset, which includes cardiovascular tissue samples derived from 16 children with TOF and five healthy age-matched control infants, was downloaded from the Gene Expression Omnibus database. Differential expression analysis was performed between TOF and control samples to identify differentially expressed genes (DEGs) using Student's t-test, and the R/limma package, with a log2 fold-change of >2 and a false discovery rate of <0.01 set as thresholds. The biological functions of DEGs were analyzed using the ToppGene database. The ReactomeFIViz application was used to construct functional interaction (FI) networks, and the genes in each module were subjected to pathway enrichment analysis. The iRegulon plugin was used to identify transcription factors predicted to regulate the DEGs in the FI network, and the gene-transcription factor pairs were then visualized using Cytoscape software. A total of 878 DEGs were identified, including 848 upregulated genes and 30 downregulated genes. The gene FI network contained seven function modules, which were all comprised of upregulated genes. Genes enriched in Module 1 were enriched in the following three neurological disorder-associated signaling pathways: Parkinson's disease, Alzheimer's disease and Huntington's disease. Genes in Modules 0, 3 and 5 were dominantly enriched in pathways associated with ribosomes and protein translation. The Xbox binding protein 1 transcription factor was demonstrated to be involved in the regulation of genes encoding the subunits of cytoplasmic and mitochondrial ribosomes, as well as genes involved in neurodegenerative disorders. Therefore, dysfunction of genes involved in signaling pathways associated with neurodegenerative disorders, ribosome function and protein translation may contribute to the pathogenesis of TOF

  18. Gene expression profiles reveal key genes for early diagnosis and treatment of adamantinomatous craniopharyngioma.

    Science.gov (United States)

    Yang, Jun; Hou, Ziming; Wang, Changjiang; Wang, Hao; Zhang, Hongbing

    2018-04-23

    Adamantinomatous craniopharyngioma (ACP) is an aggressive brain tumor that occurs predominantly in the pediatric population. Conventional diagnosis method and standard therapy cannot treat ACPs effectively. In this paper, we aimed to identify key genes for ACP early diagnosis and treatment. Datasets GSE94349 and GSE68015 were obtained from Gene Expression Omnibus database. Consensus clustering was applied to discover the gene clusters in the expression data of GSE94349 and functional enrichment analysis was performed on gene set in each cluster. The protein-protein interaction (PPI) network was built by the Search Tool for the Retrieval of Interacting Genes, and hubs were selected. Support vector machine (SVM) model was built based on the signature genes identified from enrichment analysis and PPI network. Dataset GSE94349 was used for training and testing, and GSE68015 was used for validation. Besides, RT-qPCR analysis was performed to analyze the expression of signature genes in ACP samples compared with normal controls. Seven gene clusters were discovered in the differentially expressed genes identified from GSE94349 dataset. Enrichment analysis of each cluster identified 25 pathways that highly associated with ACP. PPI network was built and 46 hubs were determined. Twenty-five pathway-related genes that overlapped with the hubs in PPI network were used as signatures to establish the SVM diagnosis model for ACP. The prediction accuracy of SVM model for training, testing, and validation data were 94, 85, and 74%, respectively. The expression of CDH1, CCL2, ITGA2, COL8A1, COL6A2, and COL6A3 were significantly upregulated in ACP tumor samples, while CAMK2A, RIMS1, NEFL, SYT1, and STX1A were significantly downregulated, which were consistent with the differentially expressed gene analysis. SVM model is a promising classification tool for screening and early diagnosis of ACP. The ACP-related pathways and signature genes will advance our knowledge of ACP pathogenesis

  19. Automatic generation of predictive dynamic models reveals nuclear phosphorylation as the key Msn2 control mechanism.

    Science.gov (United States)

    Sunnåker, Mikael; Zamora-Sillero, Elias; Dechant, Reinhard; Ludwig, Christina; Busetto, Alberto Giovanni; Wagner, Andreas; Stelling, Joerg

    2013-05-28

    Predictive dynamical models are critical for the analysis of complex biological systems. However, methods to systematically develop and discriminate among systems biology models are still lacking. We describe a computational method that incorporates all hypothetical mechanisms about the architecture of a biological system into a single model and automatically generates a set of simpler models compatible with observational data. As a proof of principle, we analyzed the dynamic control of the transcription factor Msn2 in Saccharomyces cerevisiae, specifically the short-term mechanisms mediating the cells' recovery after release from starvation stress. Our method determined that 12 of 192 possible models were compatible with available Msn2 localization data. Iterations between model predictions and rationally designed phosphoproteomics and imaging experiments identified a single-circuit topology with a relative probability of 99% among the 192 models. Model analysis revealed that the coupling of dynamic phenomena in Msn2 phosphorylation and transport could lead to efficient stress response signaling by establishing a rate-of-change sensor. Similar principles could apply to mammalian stress response pathways. Systematic construction of dynamic models may yield detailed insight into nonobvious molecular mechanisms.

  20. Structural and Functional Insights into Foamy Viral Integrase

    Directory of Open Access Journals (Sweden)

    Cha-Gyun Shin

    2013-07-01

    Full Text Available Successful integration of retroviral DNA into the host chromosome is an essential step for viral replication. The process is mediated by virally encoded integrase (IN and orchestrated by 3'-end processing and the strand transfer reaction. In vitro reaction conditions, such as substrate specificity, cofactor usage, and cellular binding partners for such reactions by the three distinct domains of prototype foamy viral integrase (PFV-IN have been described well in several reports. Recent studies on the three‑dimensional structure of the interacting complexes between PFV-IN and DNA, cofactors, binding partners, or inhibitors have explored the mechanistic details of such interactions and shown its utilization as an important target to develop anti-retroviral drugs. The presence of a potent, non-transferable nuclear localization signal in the PFV C-terminal domain extends its use as a model for investigating cellular trafficking of large molecular complexes through the nuclear pore complex and also to identify novel cellular targets for such trafficking. This review focuses on recent advancements in the structural analysis and in vitro functional aspects of PFV-IN.

  1. Long-term monitoring reveals carbon-nitrogen metabolism key to microcystin production in eutrophic lakes

    Directory of Open Access Journals (Sweden)

    Lucas J Beversdorf

    2015-05-01

    Full Text Available The environmental drivers contributing to cyanobacterial dominance in aquatic systems have been extensively studied. However, understanding of toxic versus non-toxic cyanobacterial population dynamics and the mechanisms regulating cyanotoxin production remain elusive, both physiologically and ecologically. One reason is the disconnect between laboratory and field-based studies. Here, we combined three years of temporal data, including microcystin (MC concentrations, 16 years of long-term ecological research, and 10 years of molecular data to investigate the potential factors leading to the selection of toxic Microcystis and MC production. Our analysis revealed that nitrogen (N speciation and inorganic carbon (C availability might be important drivers of Microcystis population dynamics and that an imbalance in cellular C: N ratios may trigger MC production. More specifically, precipitous declines in ammonium concentrations lead to a transitional period of N stress, even in the presence of high nitrate concentrations, that we call the toxic phase. Following the toxic phase, temperature and cyanobacterial abundance remained elevated but MC concentrations drastically declined. Increases in ammonium due to lake turnover may have led to down regulation of MC synthesis or a shift in the community from toxic to non-toxic species. While total phosphorus (P to total N ratios were relatively low over the time-series, MC concentrations were highest when total N to total P ratios were also highest. Similarly, high C: N ratios were also strongly correlated to the toxic phase. We propose a metabolic model that corroborates molecular studies and reflects our ecological observations that C and N metabolism may regulate MC production physiologically and ecologically. In particular, we hypothesize that an imbalance between 2-oxoglutarate and ammonium in the cell regulates MC synthesis in the environment.

  2. Dynamic Proteomic Characteristics and Network Integration Revealing Key Proteins for Two Kernel Tissue Developments in Popcorn.

    Directory of Open Access Journals (Sweden)

    Yongbin Dong

    Full Text Available The formation and development of maize kernel is a complex dynamic physiological and biochemical process that involves the temporal and spatial expression of many proteins and the regulation of metabolic pathways. In this study, the protein profiles of the endosperm and pericarp at three important developmental stages were analyzed by isobaric tags for relative and absolute quantification (iTRAQ labeling coupled with LC-MS/MS in popcorn inbred N04. Comparative quantitative proteomic analyses among developmental stages and between tissues were performed, and the protein networks were integrated. A total of 6,876 proteins were identified, of which 1,396 were nonredundant. Specific proteins and different expression patterns were observed across developmental stages and tissues. The functional annotation of the identified proteins revealed the importance of metabolic and cellular processes, and binding and catalytic activities for the development of the tissues. The whole, endosperm-specific and pericarp-specific protein networks integrated 125, 9 and 77 proteins, respectively, which were involved in 54 KEGG pathways and reflected their complex metabolic interactions. Confirmation for the iTRAQ endosperm proteins by two-dimensional gel electrophoresis showed that 44.44% proteins were commonly found. However, the concordance between mRNA level and the protein abundance varied across different proteins, stages, tissues and inbred lines, according to the gene cloning and expression analyses of four relevant proteins with important functions and different expression levels. But the result by western blot showed their same expression tendency for the four proteins as by iTRAQ. These results could provide new insights into the developmental mechanisms of endosperm and pericarp, and grain formation in maize.

  3. Network analysis of ChIP-Seq data reveals key genes in prostate cancer.

    Science.gov (United States)

    Zhang, Yu; Huang, Zhen; Zhu, Zhiqiang; Liu, Jianwei; Zheng, Xin; Zhang, Yuhai

    2014-09-03

    Prostate cancer (PC) is the second most common cancer among men in the United States, and it imposes a considerable threat to human health. A deep understanding of its underlying molecular mechanisms is the premise for developing effective targeted therapies. Recently, deep transcriptional sequencing has been used as an effective genomic assay to obtain insights into diseases and may be helpful in the study of PC. In present study, ChIP-Seq data for PC and normal samples were compared, and differential peaks identified, based upon fold changes (with P-values calculated with t-tests). Annotations of these peaks were performed. Protein-protein interaction (PPI) network analysis was performed with BioGRID and constructed with Cytoscape, following which the highly connected genes were screened. We obtained a total of 5,570 differential peaks, including 3,726 differentially enriched peaks in tumor samples and 1,844 differentially enriched peaks in normal samples. There were eight significant regions of the peaks. The intergenic region possessed the highest score (51%), followed by intronic (31%) and exonic (11%) regions. The analysis revealed the top 35 highly connected genes, which comprised 33 differential genes (such as YWHAQ, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein and θ polypeptide) from ChIP-Seq data and 2 differential genes retrieved from the PPI network: UBA52 (ubiquitin A-52 residue ribosomal protein fusion product (1) and SUMO2 (SMT3 suppressor of mif two 3 homolog (2) . Our findings regarding potential PC-related genes increase the understanding of PC and provides direction for future research.

  4. Bovine Lactoferrampin, Human Lactoferricin, and Lactoferrin 1-11 Inhibit Nuclear Translocation of HIV Integrase.

    Science.gov (United States)

    Wang, Winston Yan; Wong, Jack Ho; Ip, Denis Tsz Ming; Wan, David Chi Cheong; Cheung, Randy Chifai; Ng, Tzi Bun

    2016-08-01

    This study aimed to investigate fragments derived from human and bovine lactoferrins for ability to inhibit nuclear translocation of HIV-1 integrase. It was shown that human lactoferricin, human lactoferrin 1-11, and bovine lactoferrampin reduced nuclear distribution of HIV-1 integrase. Bovine lactoferrampin could inhibit both the activity and nuclear translocation of HIV-1 integrase. Human lactoferrampin, bovine lactoferricin, and bovine lactoferrin 1-11 had no effect on HIV-1 integrase nuclear translocation. Human lactoferrampin which inhibited the activity of integrase did not prevent its nuclear translocation. Human lactoferricin and lactoferrin 1-11 did not inhibit HIV-1 integrase nuclear translocation despite their ability to attenuate the enzyme activity. The discrepancy between the findings on reduction of HIV-1 activity and inhibition of nuclear translocation of HIV-1 integrase was due to the different mechanisms involved. A similar reasoning can also be applied to the different inhibitory potencies of the milk peptides on different HIV enzymes, i.e., nuclear translocation.

  5. Sketching the historical development of pyrimidones as the inhibitors of the HIV integrase

    Czech Academy of Sciences Publication Activity Database

    Patel, Rahul V.; Keum, Y.S.; Park, S.W.

    2015-01-01

    Roč. 97, JUN 5 (2015), s. 649-663 ISSN 0223-5234 Institutional support: RVO:61389030 Keywords : Pyrimidones * Anti-HIV * Integrase inhibitors Subject RIV: CE - Biochemistry Impact factor: 3.902, year: 2015

  6. Molecular dynamics simulation studies of the wild type and E92Q/N155H mutant of Elvitegravir-resistance HIV-1 integrase.

    Science.gov (United States)

    Chen, Qi; Cheng, Xiaolin; Wei, Dongqing; Xu, Qin

    2015-03-01

    Although Elvitegravir (EVG) is a newly developed antiretrovirals drug to treat the acquired immunodeficiency syndrome (AIDS), drug resistance has already been found in clinic, such as E92Q/N155H and Q148H/G140S. Several structural investigations have already been reported to reveal the molecular mechanism of the drug resistance. As full length crystal structure for HIV-1 integrase is still unsolved, we herein use the crystal structure of the full length prototype foamy virus (PFV) in complex with virus DNA and inhibitor Elvitegravir as a template to construct the wild type and E92Q/N155H mutant system of HIV-1 integrase. Molecular dynamic simulations was used to revel the binding mode and the drug resistance of the EVG ligand in E92Q/N155H. Several important interactions were discovered between the mutated residues and the residues in the active site of the E92Q/N155H double mutant pattern, and cross correlation and clustering methods were used for detailed analysis. The results from the MD simulation studies will be used to guide the experimental efforts of developing novel inhibitors against drug-resistant HIV integrase mutants.

  7. Molecular dynamics simulation studies of the wild type and E92Q/N155H mutant of Elvitegravir-resistance HIV-1 integrase

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Qi [Shanghai Jiao Tong Univ., Shanghai (China). State Key Lab. of Microbial Metabolism and College of Life Science and Biotechnology; Cheng, Xiaolin [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Molecular Biophysics; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry and Cellular and Molecular Biology; Wei, Dongqing [Shanghai Jiao Tong Univ., Shanghai (China). State Key Lab. of Microbial Metabolism and College of Life Science and Biotechnology; Xu, Qin [Shanghai Jiao Tong Univ., Shanghai (China). State Key Lab. of Microbial Metabolism and College of Life Science and Biotechnology

    2014-11-06

    Although Elvitegravir (EVG) is a newly developed antiretrovirals drug to treat the acquired immunodeficiency syndrome (AIDS), drug resistance has already been found in clinic, such as E92Q/N155H and Q148H/G140S. Several structural investigations have already been reported to reveal the molecular mechanism of the drug resistance. As full length crystal structure for HIV-1 integrase is still unsolved, we use in this paper the crystal structure of the full length prototype foamy virus (PFV) in complex with virus DNA and inhibitor Elvitegravir as a template to construct the wild type and E92Q/N155H mutant system of HIV-1 integrase. Molecular dynamic simulations was used to revel the binding mode and the drug resistance of the EVG ligand in E92Q/N155H. Several important interactions were discovered between the mutated residues and the residues in the active site of the E92Q/N155H double mutant pattern, and cross correlation and clustering methods were used for detailed analysis. The results from the MD simulation studies will be used to guide the experimental efforts of developing novel inhibitors against drug-resistant HIV integrase mutants.

  8. Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design.

    Directory of Open Access Journals (Sweden)

    Thomas S Peat

    Full Text Available A fragment-based screen against human immunodeficiency virus type 1 (HIV integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme.

  9. Striking Plasticity of CRISPR-Cas9 and Key Role of Non-target DNA, as Revealed by Molecular Simulations.

    Science.gov (United States)

    Palermo, Giulia; Miao, Yinglong; Walker, Ross C; Jinek, Martin; McCammon, J Andrew

    2016-10-26

    The CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system recently emerged as a transformative genome-editing technology that is innovating basic bioscience and applied medicine and biotechnology. The endonuclease Cas9 associates with a guide RNA to match and cleave complementary sequences in double stranded DNA, forming an RNA:DNA hybrid and a displaced non-target DNA strand. Although extensive structural studies are ongoing, the conformational dynamics of Cas9 and its interplay with the nucleic acids during association and DNA cleavage are largely unclear. Here, by employing multi-microsecond time scale molecular dynamics, we reveal the conformational plasticity of Cas9 and identify key determinants that allow its large-scale conformational changes during nucleic acid binding and processing. We show how the "closure" of the protein, which accompanies nucleic acid binding, fundamentally relies on highly coupled and specific motions of the protein domains, collectively initiating the prominent conformational changes needed for nucleic acid association. We further reveal a key role of the non-target DNA during the process of activation of the nuclease HNH domain, showing how the nontarget DNA positioning triggers local conformational changes that favor the formation of a catalytically competent Cas9. Finally, a remarkable conformational plasticity is identified as an intrinsic property of the HNH domain, constituting a necessary element that allows for the HNH repositioning. These novel findings constitute a reference for future experimental studies aimed at a full characterization of the dynamic features of the CRISPR-Cas9 system, and-more importantly-call for novel structure engineering efforts that are of fundamental importance for the rational design of new genome-engineering applications.

  10. The key microorganisms for anaerobic degradation of pentachlorophenol in paddy soil as revealed by stable isotope probing

    International Nuclear Information System (INIS)

    Tong, Hui; Liu, Chengshuai; Li, Fangbai; Luo, Chunling; Chen, Manjia; Hu, Min

    2015-01-01

    Highlights: • SIP suggested that Dechloromonas can mineralize PCP in soil. • Methanosaeta and Methanocella acquired PCP-derived carbon. • Lactate enhanced microbial degradation of PCP in soil. - Abstract: Pentachlorophenol (PCP) is a common residual persistent pesticide in paddy soil and has resulted in harmful effect on soil ecosystem. The anaerobic microbial transformation of PCP, therefore, has been received much attentions, especially the functional microbial communities for the reductive transformation. However, the key functional microorganisms for PCP mineralization in the paddy soil still remain unknown. In this work, DNA-based stable isotope probing (SIP) was applied to explore the key microorganisms responsible for PCP mineralization in paddy soil. The SIP results indicated that the dominant bacteria responsible for PCP biodegradation belonged to the genus Dechloromonas of the class β-Proteobacteria. In addition, the increased production of 13 CH 4 and 13 CO 2 indicated that the addition of lactate enhanced the rate of biodegradation and mineralization of PCP. Two archaea classified as the genera of Methanosaeta and Methanocella of class Methanobacteria were enriched in the heavy fraction when with lactate, whereas no archaea was detected in the absence of lactate. These findings provide direct evidence for the species of bacteria and archaea responsible for anaerobic PCP or its breakdown products mineralization and reveal a new insight into the microorganisms linked with PCP degradation in paddy soil

  11. The key microorganisms for anaerobic degradation of pentachlorophenol in paddy soil as revealed by stable isotope probing

    Energy Technology Data Exchange (ETDEWEB)

    Tong, Hui [Guangdong Key Laboratory of Agricultural Environment Pollution Integrated Control, Guangdong Institute of Eco-Environmental and Soil Sciences, Guangzhou 510650 (China); Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Liu, Chengshuai [State Key Laboratory of Environmental Geochemistry, Institute of Geochemistry, Chinese Academy of Sciences, Guiyang 550009 (China); Li, Fangbai, E-mail: cefbli@soil.gd.cn [Guangdong Key Laboratory of Agricultural Environment Pollution Integrated Control, Guangdong Institute of Eco-Environmental and Soil Sciences, Guangzhou 510650 (China); Luo, Chunling [Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); Chen, Manjia; Hu, Min [Guangdong Key Laboratory of Agricultural Environment Pollution Integrated Control, Guangdong Institute of Eco-Environmental and Soil Sciences, Guangzhou 510650 (China)

    2015-11-15

    Highlights: • SIP suggested that Dechloromonas can mineralize PCP in soil. • Methanosaeta and Methanocella acquired PCP-derived carbon. • Lactate enhanced microbial degradation of PCP in soil. - Abstract: Pentachlorophenol (PCP) is a common residual persistent pesticide in paddy soil and has resulted in harmful effect on soil ecosystem. The anaerobic microbial transformation of PCP, therefore, has been received much attentions, especially the functional microbial communities for the reductive transformation. However, the key functional microorganisms for PCP mineralization in the paddy soil still remain unknown. In this work, DNA-based stable isotope probing (SIP) was applied to explore the key microorganisms responsible for PCP mineralization in paddy soil. The SIP results indicated that the dominant bacteria responsible for PCP biodegradation belonged to the genus Dechloromonas of the class β-Proteobacteria. In addition, the increased production of {sup 13}CH{sub 4} and {sup 13}CO{sub 2} indicated that the addition of lactate enhanced the rate of biodegradation and mineralization of PCP. Two archaea classified as the genera of Methanosaeta and Methanocella of class Methanobacteria were enriched in the heavy fraction when with lactate, whereas no archaea was detected in the absence of lactate. These findings provide direct evidence for the species of bacteria and archaea responsible for anaerobic PCP or its breakdown products mineralization and reveal a new insight into the microorganisms linked with PCP degradation in paddy soil.

  12. Nucleic acid amplification of HIV-1 integrase sequence subtypes CRF01_AE and B for development of HIV anti-integrase drug resistance genotyping assay

    Science.gov (United States)

    Adlar, F. R.; Bela, B.

    2017-08-01

    To anticipate the potential use of anti-integrase drugs in Indonesia for treatment of HIV-1 infection, the development of a drug resistance genotyping assay for anti-integrase is crucial in identifying the genetic drug resistance profile of Indonesian HIV-1 strains. This experiment aimed to amplify a target region in the integrase gene of Indonesian HIV-1 subtypes CRF01_AE and B that contain genetic mutations known to confer resistance to anti-integrase drug. Eleven archived plasma samples from individuals living with HIV-1 were obtained from the Virology and Cancer Pathobiology Research Center for Health Service (VCPRC FKUI-RSCM) laboratory. One of the plasma samples contained HIV-1 subtype B, and the remaining plasma samples contained subtype CRF01_AE. The target regions for all samples were amplified through RT-PCR, with an annealing temperature of 55 °C, using the primer pair AE_POL 4086F and AE_POL 5232R that were designed by VCPRC FKUI-RSCM. The results of this experiment show that 18.2% (2/11) of the samples were successfully amplified using the one-step RT-PCR. While the primer pair was effective in amplifying the target region in the integrase gene sequence for subtype B (100%; 1/1), it had a low efficacy (10%, 1/10) for subtype CRF01_AE. In conclusion, the primer pair can be used to amplify the target region in Indonesian HIV-1 strain subtypes CRF01_AE and B. However, optimization of the PCR condition and an increased number of samples would help to determine an accurate representation of the efficacy of the primer pair.

  13. Transcriptome Analysis of Three Sheep Intestinal Regions reveals Key Pathways and Hub Regulatory Genes of Large Intestinal Lipid Metabolism.

    Science.gov (United States)

    Chao, Tianle; Wang, Guizhi; Ji, Zhibin; Liu, Zhaohua; Hou, Lei; Wang, Jin; Wang, Jianmin

    2017-07-13

    The large intestine, also known as the hindgut, is an important part of the animal digestive system. Recent studies on digestive system development in ruminants have focused on the rumen and the small intestine, but the molecular mechanisms underlying sheep large intestine metabolism remain poorly understood. To identify genes related to intestinal metabolism and to reveal molecular regulation mechanisms, we sequenced and compared the transcriptomes of mucosal epithelial tissues among the cecum, proximal colon and duodenum. A total of 4,221 transcripts from 3,254 genes were identified as differentially expressed transcripts. Between the large intestine and duodenum, differentially expressed transcripts were found to be significantly enriched in 6 metabolism-related pathways, among which PPAR signaling was identified as a key pathway. Three genes, CPT1A, LPL and PCK1, were identified as higher expression hub genes in the large intestine. Between the cecum and colon, differentially expressed transcripts were significantly enriched in 5 lipid metabolism related pathways, and CEPT1 and MBOAT1 were identified as hub genes. This study provides important information regarding the molecular mechanisms of intestinal metabolism in sheep and may provide a basis for further study.

  14. Bimodal voltage dependence of TRPA1: mutations of a key pore helix residue reveal strong intrinsic voltage-dependent inactivation.

    Science.gov (United States)

    Wan, Xia; Lu, Yungang; Chen, Xueqin; Xiong, Jian; Zhou, Yuanda; Li, Ping; Xia, Bingqing; Li, Min; Zhu, Michael X; Gao, Zhaobing

    2014-07-01

    Transient receptor potential A1 (TRPA1) is implicated in somatosensory processing and pathological pain sensation. Although not strictly voltage-gated, ionic currents of TRPA1 typically rectify outwardly, indicating channel activation at depolarized membrane potentials. However, some reports also showed TRPA1 inactivation at high positive potentials, implicating voltage-dependent inactivation. Here we report a conserved leucine residue, L906, in the putative pore helix, which strongly impacts the voltage dependency of TRPA1. Mutation of the leucine to cysteine (L906C) converted the channel from outward to inward rectification independent of divalent cations and irrespective to stimulation by allyl isothiocyanate. The mutant, but not the wild-type channel, displayed exclusively voltage-dependent inactivation at positive potentials. The L906C mutation also exhibited reduced sensitivity to inhibition by TRPA1 blockers, HC030031 and ruthenium red. Further mutagenesis of the leucine to all natural amino acids individually revealed that most substitutions at L906 (15/19) resulted in inward rectification, with exceptions of three amino acids that dramatically reduced channel activity and one, methionine, which mimicked the wild-type channel. Our data are plausibly explained by a bimodal gating model involving both voltage-dependent activation and inactivation of TRPA1. We propose that the key pore helix residue, L906, plays an essential role in responding to the voltage-dependent gating.

  15. Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. Integrase inhibition

    International Nuclear Information System (INIS)

    Lee-Huang, Sylvia; Huang, Philip Lin; Zhang Dawei; Lee, Jae Wook; Bao Ju; Sun Yongtao; Chang, Young-Tae; Zhang, John; Huang, Paul Lee

    2007-01-01

    We have identified oleuropein (Ole) and hydroxytyrosol (HT) as a unique class of HIV-1 inhibitors from olive leaf extracts effective against viral fusion and integration. We used molecular docking simulation to study the interactions of Ole and HT with viral targets. We find that Ole and HT bind to the conserved hydrophobic pocket on the surface of the HIV-gp41 fusion domain by hydrogen bonds with Q577 and hydrophobic interactions with I573, G572, and L568 on the gp41 N-terminal heptad repeat peptide N36, interfering with formation of the gp41 fusion-active core. To test and confirm modeling predications, we examined the effect of Ole and HT on HIV-1 fusion complex formation using native polyacrylamide gel electrophoresis and circular dichroism spectroscopy. Ole and HT exhibit dose-dependent inhibition on HIV-1 fusion core formation with EC 50 s of 66-58 nM, with no detectable toxicity. Our findings on effects of HIV-1 integrase are reported in the subsequent article

  16. HIV-1 integrase inhibitor resistance among treatment naïve patients in the West of Scotland.

    Science.gov (United States)

    Bradley-Stewart, A; Urcia, C; MacLean, A; Aitken, C; Gunson, R

    2017-07-01

    Transmitted integrase inhibitor resistance is rare, with only a small number of cases reported world-wide to date. The aim of this study was to assess whether transmitted integrase inhibitor resistance has occurred in Scotland and if so, could there be a case for performing genotypic integrase resistance testing at baseline. The study population consisted of 106 treatment naïve, newly diagnosed, HIV positive patients. The patient samples were collected between October 2015 and March 2016 at the time of HIV diagnosis and prior to initiation of anti-retroviral therapy. The integrase region was amplified and sequenced. We detected integrase inhibitor resistance (T66I/T) at baseline in one patient sample. This is a non-polymorphic mutation seen in patients receiving elvitegravir which confers high-level resistance to elvitegravir and intermediate resistance to raltegravir. A further 10 patients had accessory mutations which have minimal or no effect on susceptibility to integrase inhibitors. Transmitted integrase inhibitor resistance remains rare. The results of the present study do not support performing integrase resistance testing at baseline. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  17. In vivo phosphoproteome characterization reveals key starch granule-binding phosphoproteins involved in wheat water-deficit response.

    Science.gov (United States)

    Chen, Guan-Xing; Zhen, Shou-Min; Liu, Yan-Lin; Yan, Xing; Zhang, Ming; Yan, Yue-Ming

    2017-10-23

    Drought stress during grain development causes significant yield loss in cereal production. The phosphorylated modification of starch granule-binding proteins (SGBPs) is an important mechanism regulating wheat starch biosynthesis. In this study, we performed the first proteomics and phosphoproteomics analyses of SGBPs in elite Chinese bread wheat (Triticum aestivum L.) cultivar Jingdong 17 under well-watered and water-stress conditions. Water stress treatment caused significant reductions in spike grain numbers and weight, total starch and amylopectin content, and grain yield. Two-dimensional gel electrophoresis revealed that the quantity of SGBPs was reduced significantly by water-deficit treatment. Phosphoproteome characterization of SGBPs under water-deficit treatment demonstrated a reduced level of phosphorylation of main starch synthesis enzymes, particularly for granule-bound starch synthase (GBSS I), starch synthase II-a (SS II-a), and starch synthase III (SS III). Specifically, the Ser34 site of the GBSSI protein, the Tyr358 site of SS II-a, and the Ser837 site of SS III-a exhibited significant less phosphorylation under water-deficit treatment than well-watered treatment. Furthermore, the expression levels of several key genes related with starch biosynthesis detected by qRT-PCR were decreased significantly at 15 days post-anthesis under water-deficit treatment. Immunolocalization showed a clear movement of GBSS I from the periphery to the interior of starch granules during grain development, under both water-deficit and well-watered conditions. Our results demonstrated that the reduction in gene expression or transcription level, protein expression and phosphorylation levels of starch biosynthesis related enzymes under water-deficit conditions is responsible for the significant decrease in total starch content and grain yield.

  18. Representing Microbial Dormancy in Soil Decomposition Models Improves Model Performance and Reveals Key Ecosystem Controls on Microbial Activity

    Science.gov (United States)

    He, Y.; Yang, J.; Zhuang, Q.; Wang, G.; Liu, Y.

    2014-12-01

    Climate feedbacks from soils can result from environmental change and subsequent responses of plant and microbial communities and nutrient cycling. Explicit consideration of microbial life history traits and strategy may be necessary to predict climate feedbacks due to microbial physiology and community changes and their associated effect on carbon cycling. In this study, we developed an explicit microbial-enzyme decomposition model and examined model performance with and without representation of dormancy at six temperate forest sites with observed soil efflux ranged from 4 to 10 years across different forest types. We then extrapolated the model to all temperate forests in the Northern Hemisphere (25-50°N) to investigate spatial controls on microbial and soil C dynamics. Both models captured the observed soil heterotrophic respiration (RH), yet no-dormancy model consistently exhibited large seasonal amplitude and overestimation in microbial biomass. Spatially, the total RH from temperate forests based on dormancy model amounts to 6.88PgC/yr, and 7.99PgC/yr based on no-dormancy model. However, no-dormancy model notably overestimated the ratio of microbial biomass to SOC. Spatial correlation analysis revealed key controls of soil C:N ratio on the active proportion of microbial biomass, whereas local dormancy is primarily controlled by soil moisture and temperature, indicating scale-dependent environmental and biotic controls on microbial and SOC dynamics. These developments should provide essential support to modeling future soil carbon dynamics and enhance the avenue for collaboration between empirical soil experiment and modeling in the sense that more microbial physiological measurements are needed to better constrain and evaluate the models.

  19. A method for producing transgenic cells using a multi-integrase system on a human artificial chromosome vector.

    Directory of Open Access Journals (Sweden)

    Shigeyuki Yamaguchi

    Full Text Available The production of cells capable of expressing gene(s of interest is important for a variety of applications in biomedicine and biotechnology, including gene therapy and animal transgenesis. The ability to insert transgenes at a precise location in the genome, using site-specific recombinases such as Cre, FLP, and ΦC31, has major benefits for the efficiency of transgenesis. Recent work on integrases from ΦC31, R4, TP901-1 and Bxb1 phages demonstrated that these recombinases catalyze site-specific recombination in mammalian cells. In the present study, we examined the activities of integrases on site-specific recombination and gene expression in mammalian cells. We designed a human artificial chromosome (HAC vector containing five recombination sites (ΦC31 attP, R4 attP, TP901-1 attP, Bxb1 attP and FRT; multi-integrase HAC vector and de novo mammalian codon-optimized integrases. The multi-integrase HAC vector has several functions, including gene integration in a precise locus and avoiding genomic position effects; therefore, it was used as a platform to investigate integrase activities. Integrases carried out site-specific recombination at frequencies ranging from 39.3-96.8%. Additionally, we observed homogenous gene expression in 77.3-87.5% of colonies obtained using the multi-integrase HAC vector. This vector is also transferable to another cell line, and is capable of accepting genes of interest in this environment. These data suggest that integrases have high DNA recombination efficiencies in mammalian cells. The multi-integrase HAC vector enables us to produce transgene-expressing cells efficiently and create platform cell lines for gene expression.

  20. Ethyl malonate amides: a diketo acid offspring fragment for HIV integrase inhibition.

    Science.gov (United States)

    Serafin, Katarzyna; Mazur, Pawel; Bak, Andrzej; Laine, Elodie; Tchertanov, Luba; Mouscadet, Jean-François; Polanski, Jaroslaw

    2011-08-15

    While searching for new HIV integrase inhibitors we discovered that some ethyl malonate amides (EMA) are active against this enzyme. Surprisingly, the main function can only very rarely be found among the reported drug candidates. We synthesised a series of compounds in order to establish and analyse the structure-activity relationship. The similarity to the important classes of HIV integrase inhibitors as well as the synthetic availability of the different targets including this pharmacophore makes EMA compounds an interesting object of investigations. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. RNA Sequencing and Coexpression Analysis Reveal Key Genes Involved in α-Linolenic Acid Biosynthesis in Perilla frutescens Seed

    Directory of Open Access Journals (Sweden)

    Tianyuan Zhang

    2017-11-01

    Full Text Available Perilla frutescen is used as traditional food and medicine in East Asia. Its seeds contain high levels of α-linolenic acid (ALA, which is important for health, but is scarce in our daily meals. Previous reports on RNA-seq of perilla seed had identified fatty acid (FA and triacylglycerol (TAG synthesis genes, but the underlying mechanism of ALA biosynthesis and its regulation still need to be further explored. So we conducted Illumina RNA-sequencing in seven temporal developmental stages of perilla seeds. Sequencing generated a total of 127 million clean reads, containing 15.88 Gb of valid data. The de novo assembly of sequence reads yielded 64,156 unigenes with an average length of 777 bp. A total of 39,760 unigenes were annotated and 11,693 unigenes were found to be differentially expressed in all samples. According to Kyoto Encyclopedia of Genes and Genomes (KEGG pathway analysis, 486 unigenes were annotated in the “lipid metabolism” pathway. Of these, 150 unigenes were found to be involved in fatty acid (FA biosynthesis and triacylglycerol (TAG assembly in perilla seeds. A coexpression analysis showed that a total of 104 genes were highly coexpressed (r > 0.95. The coexpression network could be divided into two main subnetworks showing over expression in the medium or earlier and late phases, respectively. In order to identify the putative regulatory genes, a transcription factor (TF analysis was performed. This led to the identification of 45 gene families, mainly including the AP2-EREBP, bHLH, MYB, and NAC families, etc. After coexpression analysis of TFs with highly expression of FAD2 and FAD3 genes, 162 TFs were found to be significantly associated with two FAD genes (r > 0.95. Those TFs were predicted to be the key regulatory factors in ALA biosynthesis in perilla seed. The qRT-PCR analysis also verified the relevance of expression pattern between two FAD genes and partial candidate TFs. Although it has been reported that some TFs

  2. Cancer-specific binary expression system activated in mice by bacteriophage HK022 Integrase

    DEFF Research Database (Denmark)

    Elias, Amer; Spector, Itay; Sogolovsky-Bard, Ilana

    2016-01-01

    Binary systems based on site-specific recombination have been used for tumor specific transcription targeting of suicide genes in animal models. In these binary systems a site specific recombinase or integrase that is expressed from a tumor specific promoter drives tumor specific expression of a ...

  3. A Mos1 transposase in vivo assay to screen new HIV-1 integrase inhibitors.

    Science.gov (United States)

    Cancian, Mariana; Loreto, Elgion L S

    2018-04-01

    The integrase and transposase enzymes of retrovirus and transposons, respectively, share the catalytic DDE domain. In vitro assays showed that inhibitors of HIV-1 integrase generally inhibit the mariner Mos1 transposase. Using a Drosophila strain in which the mobilisation of the mariner element can be quantified by mosaic eyes, we showed that flies maintained in medium containing 210 µM to 4 mM of raltegravir, or 1 or 2 mM of dolutegravir, which are HIV-1 integrase inhibitor used in AIDS treatment, have 23-33% less somatic mobilisation in mosaic eyes when treated with raltegravir and 28-32% when treated with dolutegravir. The gene expression of the mariner transposase gene, estimated by qPCR, is similar among treated and control flies. The results suggest that in vivo assays using Drosophila can be used as a primary screening of inhibitory drugs for transposase and retroviral integrase. The advantages of this assay are that it is easy, quick, cheap and is an in vivo test, meaning that the tested substance has to have been taken in by cells and has arrived at the target site, which is not the case when in vitro assays are applied.

  4. Revealing of photon-number splitting attack on quantum key distribution system by photon-number resolving devices

    International Nuclear Information System (INIS)

    Gaidash, A A; Egorov, V I; Gleim, A V

    2016-01-01

    Quantum cryptography allows distributing secure keys between two users so that any performed eavesdropping attempt would be immediately discovered. However, in practice an eavesdropper can obtain key information from multi-photon states when attenuated laser radiation is used as a source of quantum states. In order to prevent actions of an eavesdropper, it is generally suggested to implement special cryptographic protocols, like decoy states or SARG04. In this paper, we describe an alternative method based on monitoring photon number statistics after detection. We provide a useful rule of thumb to estimate approximate order of difference of expected distribution and distribution in case of attack. Formula for calculating a minimum value of total pulses or time-gaps to resolve attack is shown. Also formulas for actual fraction of raw key known to Eve were derived. This method can therefore be used with any system and even combining with mentioned special protocols. (paper)

  5. Museum specimens reveal loss of pollen host plants as key factor driving wild bee decline in The Netherlands

    NARCIS (Netherlands)

    Scheper, J.A.; Reemer, M.; Kats, van R.J.M.; Ozinga, W.A.; Linden, van der G.T.J.; Schaminee, J.H.J.; Siepel, H.; Kleijn, D.

    2014-01-01

    Evidence for declining populations of both wild and managed bees has raised concern about a potential global pollination crisis. Strategies to mitigate bee loss generally aim to enhance floral resources. However, we do not really know whether loss of preferred floral resources is the key driver of

  6. The γ Dor stars as revealed by Kepler: A key to reveal deep-layer rotation in A and F stars

    Directory of Open Access Journals (Sweden)

    Salmon S. J. A. J.

    2017-01-01

    Full Text Available The γ Dor pulsating stars present high-order gravity modes, which make them important targets in the intermediate-and low-mass main-sequence region of the Hertzsprung-Russell diagram. Whilst we have only access to rotation in the envelope of the Sun, the g modes of γ Dor stars can in principle deliver us constraints on the inner layers. With the puzzling discovery of unexpectedly low rotation rates in the core of red giants, the γ Dor stars appear now as unique targets to explore internal angular momentum transport in the progenitors of red giants. Yet, the γ Dor pulsations remain hard to detect from the ground for their periods are close to 1 day. While the CoRoT space mission first revealed intriguing frequency spectra, the almost uninterrupted 4-year photometry from the Kepler mission eventually shed a new light on them. It revealed regularities in the spectra, expected to bear signature of physical processes, including rotation, in the shear layers close to the convective core. We present here the first results of our effort to derive exploitable seismic diagnosis for mid- to fast rotators among γ Dor stars. We confirm their potential to explore the rotation history of this early phase of stellar evolution.

  7. HIV-1 integrase resistance among antiretroviral treatment naive and experienced patients from Northwestern Poland

    Directory of Open Access Journals (Sweden)

    Parczewski Miłosz

    2012-12-01

    Full Text Available Abstract Background HIV integrase inhibitor use is limited by low genetic barrier to resistance and possible cross-resistance among representatives of this class of antiretrovirals. The aim of this study was to analyse integrase sequence variability among antiretroviral treatment naive and experienced patients with no prior integrase inhibitor (InI exposure and investigate development of the InI drug resistance mutations following the virologic failure of the raltegravir containing regimen. Methods Sequencing of HIV-1 integrase region from plasma samples of 80 integrase treatment naive patients and serial samples from 12 patients with observed virologic failure on raltegravir containing treatment whenever plasma vireamia exceeded >50 copies/ml was performed. Drug resistance mutations were called with Stanford DB database and grouped into major and minor variants. For subtyping bootstrapped phylogenetic analysis was used; Bayesian Monte Carlo Marcov Chain (MCMC model was implemented to infer on the phylogenetic relationships between the serial sequences from patients failing on raltegravir. Results Majority of the integrase region sequences were classified as subtype B; the remaining ones being subtype D, C, G, as well as CRF01_AE , CRF02_AG and CRF13_cpx recombinants. No major integrase drug resistance mutations have been observed in InI-treatment naive patients. In 30 (38.5% cases polymorphic variation with predominance of the E157Q mutation was observed. This mutation was more common among subtype B (26 cases, 54.2% than non-B sequences (5 cases, 16.7%, p=0.00099, OR: 5.91 (95% CI:1.77-22.63]. Other variants included L68V, L74IL, T97A, E138D, V151I, R263K. Among 12 (26.1% raltegravir treated patients treatment failure was observed; major InI drug resistance mutations (G140S, Q148H and N155H, V151I, E92EQ, V151I, G163R were noted in four of these cases (8.3% of the total InI-treated patients. Time to the development of drug resistance ranged

  8. Museum specimens reveal loss of pollen host plants as key factor driving wild bee decline in The Netherlands

    Science.gov (United States)

    Scheper, Jeroen; Reemer, Menno; van Kats, Ruud; Ozinga, Wim A.; van der Linden, Giel T. J.; Schaminée, Joop H. J.; Siepel, Henk; Kleijn, David

    2014-01-01

    Evidence for declining populations of both wild and managed bees has raised concern about a potential global pollination crisis. Strategies to mitigate bee loss generally aim to enhance floral resources. However, we do not really know whether loss of preferred floral resources is the key driver of bee decline because accurate assessment of host plant preferences is difficult, particularly for species that have become rare. Here we examine whether population trends of wild bees in The Netherlands can be explained by trends in host plants, and how this relates to other factors such as climate change. We determined host plant preference of bee species using pollen loads on specimens in entomological collections that were collected before the onset of their decline, and used atlas data to quantify population trends of bee species and their host plants. We show that decline of preferred host plant species was one of two main factors associated with bee decline. Bee body size, the other main factor, was negatively related to population trend, which, because larger bee species have larger pollen requirements than smaller species, may also point toward food limitation as a key factor driving wild bee loss. Diet breadth and other potential factors such as length of flight period or climate change sensitivity were not important in explaining twentieth century bee population trends. These results highlight the species-specific nature of wild bee decline and indicate that mitigation strategies will only be effective if they target the specific host plants of declining species. PMID:25422416

  9. Uncovering SUMOylation Dynamics during Cell-Cycle Progression Reveals FoxM1 as a Key Mitotic SUMO Target Protein

    DEFF Research Database (Denmark)

    Schimmel, Joost; Eifler, Karolin; Sigurdsson, Jón Otti

    2014-01-01

    Loss of small ubiquitin-like modification (SUMOylation) in mice causes genomic instability due to the missegregation of chromosomes. Currently, little is known about the identity of relevant SUMO target proteins that are involved in this process and about global SUMOylation dynamics during cell......-cycle progression. We performed a large-scale quantitative proteomics screen to address this and identified 593 proteins to be SUMO-2 modified, including the Forkhead box transcription factor M1 (FoxM1), a key regulator of cell-cycle progression and chromosome segregation. SUMOylation of FoxM1 peaks during G2 and M...... relieving FoxM1 autorepression. Cells deficient for FoxM1 SUMOylation showed increased levels of polyploidy. Our findings contribute to understanding the role of SUMOylation during cell-cycle progression....

  10. Network theory inspired analysis of time-resolved expression data reveals key players guiding P. patens stem cell development.

    Science.gov (United States)

    Busch, Hauke; Boerries, Melanie; Bao, Jie; Hanke, Sebastian T; Hiss, Manuel; Tiko, Theodhor; Rensing, Stefan A

    2013-01-01

    Transcription factors (TFs) often trigger developmental decisions, yet, their transcripts are often only moderately regulated and thus not easily detected by conventional statistics on expression data. Here we present a method that allows to determine such genes based on trajectory analysis of time-resolved transcriptome data. As a proof of principle, we have analysed apical stem cells of filamentous moss (P. patens) protonemata that develop from leaflets upon their detachment from the plant. By our novel correlation analysis of the post detachment transcriptome kinetics we predict five out of 1,058 TFs to be involved in the signaling leading to the establishment of pluripotency. Among the predicted regulators is the basic helix loop helix TF PpRSL1, which we show to be involved in the establishment of apical stem cells in P. patens. Our methodology is expected to aid analysis of key players of developmental decisions in complex plant and animal systems.

  11. Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood-brain barrier models.

    Directory of Open Access Journals (Sweden)

    Eduard Urich

    Full Text Available Brain microvascular endothelial cells (BEC constitute the blood-brain barrier (BBB which forms a dynamic interface between the blood and the central nervous system (CNS. This highly specialized interface restricts paracellular diffusion of fluids and solutes including chemicals, toxins and drugs from entering the brain. In this study we compared the transcriptome profiles of the human immortalized brain endothelial cell line hCMEC/D3 and human primary BEC. We identified transcriptional differences in immune response genes which are directly related to the immortalization procedure of the hCMEC/D3 cells. Interestingly, astrocytic co-culturing reduced cell adhesion and migration molecules in both BECs, which possibly could be related to regulation of immune surveillance of the CNS controlled by astrocytic cells within the neurovascular unit. By matching the transcriptome data from these two cell lines with published transcriptional data from freshly isolated mouse BECs, we discovered striking differences that could explain some of the limitations of using cultured BECs to study BBB properties. Key protein classes such as tight junction proteins, transporters and cell surface receptors show differing expression profiles. For example, the claudin-5, occludin and JAM2 expression is dramatically reduced in the two human BEC lines, which likely explains their low transcellular electric resistance and paracellular leakiness. In addition, the human BEC lines express low levels of unique brain endothelial transporters such as Glut1 and Pgp. Cell surface receptors such as LRP1, RAGE and the insulin receptor that are involved in receptor-mediated transport are also expressed at very low levels. Taken together, these data illustrate that BECs lose their unique protein expression pattern outside of their native environment and display a more generic endothelial cell phenotype. A collection of key genes that seems to be highly regulated by the local

  12. In vitro model of production of antibodies; a new approach to reveal the presence of key bacteria in polymicrobial environments.

    Science.gov (United States)

    Wu, Chongcong; Nakka, Sravya; Mansouri, Sepahdar; Bengtsson, Torbjörn; Nayeri, Tayeb; Nayeri, Fariba

    2016-09-09

    There is a rapid emergence of multiple resistant gram-negative bacteria due to overuse of antibiotics in the treatment of infections. Biofilms consist of polymicrobial communities that survive the host's defense system. The key bacteria in biofilms are slow growing and support an attachment and rapid growth of other microorganisms. Current antimicrobial strategies often fail due to poor diagnosis of key pathogens in biofilms. The study aims to develop anti-bacterial human antibodies in vitro from patients who had recently undergone a systemic infection by pathogenic bacteria and to use these antibodies as a tool for detecting bacteria in biofilms. Lymphocytes were separated from whole blood of patients (n = 10) and stimulated with heat-killed bacteria to produce antibodies in vitro. The specificity of antibodies in recognizing the bacteria against which they were directed was evaluated by surface plasmon resonance system (SPR) and electron microscopy. The ulcer secretions from patients with chronic and acute leg ulcers and healthy controls were analyzed by the SPR system and the results were compared with culture studies. The produced antibodies recognized bacteria with high sensitivity (SPR). The antibodies against Enterococcus fecalis bound specifically to the microorganism in a bacterial co-culture that was visualized by electron microscopy. In the present work, a method for producing specific antibodies against bacteria is introduced to recognize bacterial components in body fluids of patients suffering from pathogenic biofilms. This diagnostic technique may be most useful in clinical microbiology and in the choice of antibiotics in the treatment of serious infections.

  13. Transcriptome Analysis of Ullrich Congenital Muscular Dystrophy Fibroblasts Reveals a Disease Extracellular Matrix Signature and Key Molecular Regulators.

    Directory of Open Access Journals (Sweden)

    Sonia Paco

    Full Text Available Collagen VI related myopathies encompass a range of phenotypes with involvement of skeletal muscle, skin and other connective tissues. They represent a severe and relatively common form of congenital disease for which there is no treatment. Collagen VI in skeletal muscle and skin is produced by fibroblasts.In order to gain insight into the consequences of collagen VI mutations and identify key disease pathways we performed global gene expression analysis of dermal fibroblasts from patients with Ullrich Congenital Muscular Dystrophy with and without vitamin C treatment. The expression data were integrated using a range of systems biology tools. Results were validated by real-time PCR, western blotting and functional assays.We found significant changes in the expression levels of almost 600 genes between collagen VI deficient and control fibroblasts. Highly regulated genes included extracellular matrix components and surface receptors, including integrins, indicating a shift in the interaction between the cell and its environment. This was accompanied by a significant increase in fibroblasts adhesion to laminin. The observed changes in gene expression profiling may be under the control of two miRNAs, miR-30c and miR-181a, which we found elevated in tissue and serum from patients and which could represent novel biomarkers for muscular dystrophy. Finally, the response to vitamin C of collagen VI mutated fibroblasts significantly differed from healthy fibroblasts. Vitamin C treatment was able to revert the expression of some key genes to levels found in control cells raising the possibility of a beneficial effect of vitamin C as a modulator of some of the pathological aspects of collagen VI related diseases.

  14. Genome-wide functional analysis of plasmodium protein phosphatases reveals key regulators of parasite development and differentiation

    KAUST Repository

    Guttery, David S.

    2014-07-09

    Reversible protein phosphorylation regulated by kinases and phosphatases controls many cellular processes. Although essential functions for the malaria parasite kinome have been reported, the roles of most protein phosphatases (PPs) during Plasmodium development are unknown. We report a functional analysis of the Plasmodium berghei protein phosphatome, which exhibits high conservation with the P. falciparum phosphatome and comprises 30 predicted PPs with differential and distinct expression patterns during various stages of the life cycle. Gene disruption analysis of P. berghei PPs reveals that half of the genes are likely essential for asexual blood stage development, whereas six are required for sexual development/sporogony in mosquitoes. Phenotypic screening coupled with transcriptome sequencing unveiled morphological changes and altered gene expression in deletion mutants of two N-myristoylated PPs. These findings provide systematic functional analyses of PPs in Plasmodium, identify how phosphatases regulate parasite development and differentiation, and can inform the identification of drug targets for malaria. © 2014 The Authors.

  15. Genome-wide functional analysis of plasmodium protein phosphatases reveals key regulators of parasite development and differentiation

    KAUST Repository

    Guttery, David  S.; Poulin, Benoit; Ramaprasad, Abhinay; Wall, Richard  J.; Ferguson, David  J.P.; Brady, Declan; Patzewitz, Eva-Maria; Whipple, Sarah; Straschil, Ursula; Wright, Megan  H.; Mohamed, Alyaa  M.A.H.; Radhakrishnan, Anand; Arold, Stefan T.; Tate, Edward  W.; Holder, Anthony  A.; Wickstead, Bill; Pain, Arnab; Tewari, Rita

    2014-01-01

    Reversible protein phosphorylation regulated by kinases and phosphatases controls many cellular processes. Although essential functions for the malaria parasite kinome have been reported, the roles of most protein phosphatases (PPs) during Plasmodium development are unknown. We report a functional analysis of the Plasmodium berghei protein phosphatome, which exhibits high conservation with the P. falciparum phosphatome and comprises 30 predicted PPs with differential and distinct expression patterns during various stages of the life cycle. Gene disruption analysis of P. berghei PPs reveals that half of the genes are likely essential for asexual blood stage development, whereas six are required for sexual development/sporogony in mosquitoes. Phenotypic screening coupled with transcriptome sequencing unveiled morphological changes and altered gene expression in deletion mutants of two N-myristoylated PPs. These findings provide systematic functional analyses of PPs in Plasmodium, identify how phosphatases regulate parasite development and differentiation, and can inform the identification of drug targets for malaria. © 2014 The Authors.

  16. Development of a novel in vitro assay for the evaluation of integron DNA integrase activity

    Directory of Open Access Journals (Sweden)

    Fatemeh Tohidi

    2016-05-01

    Full Text Available Integrons play an important role in multidrug resistance. The integron platform codes for integrase (intI that is required for gene cassette integration through site-specific recombination. The recombination crossover occurs between the G and TT nucleotides in non-palindromic attI and palindromic attC sites. The aim of this study was to establish an efficient in vitro assay for integrase purification and activity detection. To this end, the intI gene was cloned into the pET-22b plasmid. Then, the resulting recombinant plasmid was transformed into Escherichia coli Origami™ strain. The recombinant protein expression was confirmed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE and western blot assays. The recombinant intI protein was purified by nickel–nitrilotriacetic acid (Ni–NTA affinity chromatography, and its activity was measured by a newly introduced assay. Briefly, specific primers for each side of attI and attC were used, thereby, a polymerase chain reaction would be performed, if a fused plasmid containing both attI and attC sites was created upon recombination. SDS-PAGE and western blotting confirmed the presence of a 38-kDa recombinant protein. Optimum conditions were established for the measurement of the integrase activity and a new model assay was conducted to analyse the recombination activity in vitro. Although the electrophoretic mobility shift assay is an efficient and reliable method, the newly introduced assay provided new or enhanced capability to determine the integrase activity, suggesting that there is no need for expensive and advanced equipment.

  17. Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors

    Directory of Open Access Journals (Sweden)

    Neamati Nouri

    2009-04-01

    Full Text Available Abstract Correction to Erik Serrao, Srinivas Odde, Kavya Ramkumar and Nouri Neamati: Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors. Retrovirology 2009, 6:25. Since the recent publication of our article (Neamati, Retrovirology 2009, 6:25, we have noticed an error which we would like to correct and we would like to apologise to the readers for this mistake.

  18. Comparative transcriptome analysis reveals key genes potentially related to soluble sugar and organic acid accumulation in watermelon.

    Directory of Open Access Journals (Sweden)

    Lei Gao

    Full Text Available Soluble sugars and organic acids are important components of fruit flavor and have a strong impact on the overall organoleptic quality of watermelon (Citrullus lanatus fruit. Several studies have analyzed the expression levels of the genes related to soluble sugar accumulation and the dynamic changes in their content during watermelon fruit development and ripening. Nevertheless, to date, there have been no reports on the organic acid content in watermelon or the genes regulating their synthesis. In this study, the soluble sugars and organic acids in watermelon were measured and a comparative transcriptome analysis was performed to identify the key genes involved in the accumulation of these substances during fruit development and ripening. The watermelon cultivar '203Z' and its near-isogenic line (NIL 'SW' (in the '203Z' background were used as experimental materials. The results suggested that soluble sugar consist of fructose, glucose and sucrose while malic-, citric-, and oxalic acids are the primary organic acids in watermelon fruit. Several differentially expressed genes (DEGs related to soluble sugar- and organic acid accumulation and metabolism were identified. These include the DEGs encoding raffinose synthase, sucrose synthase (SuSy, sucrose-phosphate synthase (SPSs, insoluble acid invertases (IAI, NAD-dependent malate dehydrogenase (NAD-cyt MDH, aluminum-activated malate transporter (ALMT, and citrate synthase (CS. This is the first report addressing comparative transcriptome analysis via NILs materials in watermelon fruit. These findings provide an important basis for understanding the molecular mechanism that leads to soluble sugar and organic acid accumulation and metabolism during watermelon fruit development and ripening.

  19. Comparative transcriptome analysis reveals key genes potentially related to soluble sugar and organic acid accumulation in watermelon.

    Science.gov (United States)

    Gao, Lei; Zhao, Shengjie; Lu, Xuqiang; He, Nan; Zhu, Hongju; Dou, Junling; Liu, Wenge

    2018-01-01

    Soluble sugars and organic acids are important components of fruit flavor and have a strong impact on the overall organoleptic quality of watermelon (Citrullus lanatus) fruit. Several studies have analyzed the expression levels of the genes related to soluble sugar accumulation and the dynamic changes in their content during watermelon fruit development and ripening. Nevertheless, to date, there have been no reports on the organic acid content in watermelon or the genes regulating their synthesis. In this study, the soluble sugars and organic acids in watermelon were measured and a comparative transcriptome analysis was performed to identify the key genes involved in the accumulation of these substances during fruit development and ripening. The watermelon cultivar '203Z' and its near-isogenic line (NIL) 'SW' (in the '203Z' background) were used as experimental materials. The results suggested that soluble sugar consist of fructose, glucose and sucrose while malic-, citric-, and oxalic acids are the primary organic acids in watermelon fruit. Several differentially expressed genes (DEGs) related to soluble sugar- and organic acid accumulation and metabolism were identified. These include the DEGs encoding raffinose synthase, sucrose synthase (SuSy), sucrose-phosphate synthase (SPSs), insoluble acid invertases (IAI), NAD-dependent malate dehydrogenase (NAD-cyt MDH), aluminum-activated malate transporter (ALMT), and citrate synthase (CS). This is the first report addressing comparative transcriptome analysis via NILs materials in watermelon fruit. These findings provide an important basis for understanding the molecular mechanism that leads to soluble sugar and organic acid accumulation and metabolism during watermelon fruit development and ripening.

  20. Comparative transcriptome analysis reveals key genes potentially related to soluble sugar and organic acid accumulation in watermelon

    Science.gov (United States)

    Gao, Lei; Zhao, Shengjie; Lu, Xuqiang; He, Nan; Zhu, Hongju; Dou, Junling

    2018-01-01

    Soluble sugars and organic acids are important components of fruit flavor and have a strong impact on the overall organoleptic quality of watermelon (Citrullus lanatus) fruit. Several studies have analyzed the expression levels of the genes related to soluble sugar accumulation and the dynamic changes in their content during watermelon fruit development and ripening. Nevertheless, to date, there have been no reports on the organic acid content in watermelon or the genes regulating their synthesis. In this study, the soluble sugars and organic acids in watermelon were measured and a comparative transcriptome analysis was performed to identify the key genes involved in the accumulation of these substances during fruit development and ripening. The watermelon cultivar ‘203Z’ and its near-isogenic line (NIL) ‘SW’ (in the ‘203Z’ background) were used as experimental materials. The results suggested that soluble sugar consist of fructose, glucose and sucrose while malic-, citric-, and oxalic acids are the primary organic acids in watermelon fruit. Several differentially expressed genes (DEGs) related to soluble sugar- and organic acid accumulation and metabolism were identified. These include the DEGs encoding raffinose synthase, sucrose synthase (SuSy), sucrose-phosphate synthase (SPSs), insoluble acid invertases (IAI), NAD-dependent malate dehydrogenase (NAD-cyt MDH), aluminum-activated malate transporter (ALMT), and citrate synthase (CS). This is the first report addressing comparative transcriptome analysis via NILs materials in watermelon fruit. These findings provide an important basis for understanding the molecular mechanism that leads to soluble sugar and organic acid accumulation and metabolism during watermelon fruit development and ripening. PMID:29324867

  1. Efficient site-specific integration in Plasmodium falciparum chromosomes mediated by mycobacteriophage Bxb1 integrase.

    Science.gov (United States)

    Nkrumah, Louis J; Muhle, Rebecca A; Moura, Pedro A; Ghosh, Pallavi; Hatfull, Graham F; Jacobs, William R; Fidock, David A

    2006-08-01

    Here we report an efficient, site-specific system of genetic integration into Plasmodium falciparum malaria parasite chromosomes. This is mediated by mycobacteriophage Bxb1 integrase, which catalyzes recombination between an incoming attP and a chromosomal attB site. We developed P. falciparum lines with the attB site integrated into the glutaredoxin-like cg6 gene. Transfection of these attB(+) lines with a dual-plasmid system, expressing a transgene on an attP-containing plasmid together with a drug resistance gene and the integrase on a separate plasmid, produced recombinant parasites within 2 to 4 weeks that were genetically uniform for single-copy plasmid integration. Integrase-mediated recombination resulted in proper targeting of parasite proteins to intra-erythrocytic compartments, including the apicoplast, a plastid-like organelle. Recombinant attB x attP parasites were genetically stable in the absence of drug and were phenotypically homogeneous. This system can be exploited for rapid genetic integration and complementation analyses at any stage of the P. falciparum life cycle, and it illustrates the utility of Bxb1-based integrative recombination for genetic studies of intracellular eukaryotic organisms.

  2. Postexposure protection of macaques from vaginal SHIV infection by topical integrase inhibitors.

    Science.gov (United States)

    Dobard, Charles; Sharma, Sunita; Parikh, Urvi M; West, Rolieria; Taylor, Andrew; Martin, Amy; Pau, Chou-Pong; Hanson, Debra L; Lipscomb, Jonathan; Smith, James; Novembre, Francis; Hazuda, Daria; Garcia-Lerma, J Gerardo; Heneine, Walid

    2014-03-12

    Coitally delivered microbicide gels containing antiretroviral drugs are important for HIV prevention. However, to date, microbicides have contained entry or reverse transcriptase inhibitors that block early steps in virus infection and thus need to be given as a preexposure dose that interferes with sexual practices and may limit compliance. Integrase inhibitors block late steps after virus infection and therefore are more suitable for post-coital dosing. We first determined the kinetics of strand transfer in vitro and confirmed that integration begins about 6 hours after infection. We then used a repeat-challenge macaque model to assess efficacy of vaginal gels containing integrase strand transfer inhibitors when applied before or after simian/human immunodeficiency virus (SHIV) challenge. We showed that gel containing the strand transfer inhibitor L-870812 protected two of three macaques when applied 30 min before SHIV challenge. We next evaluated the efficacy of 1% raltegravir gel and demonstrated its ability to protect macaques when applied 3 hours after SHIV exposure (five of six protected; P infections showed no evidence of drug resistance in plasma or vaginal secretions despite continued gel dosing after infection. We documented rapid vaginal absorption reflecting a short pharmacological lag time and noted that vaginal, but not plasma, virus load was substantially reduced in the breakthrough infection after raltegravir gel treatment. We provide a proof of concept that topically applied integrase inhibitors protect against vaginal SHIV infection when administered shortly before or 3 hours after virus exposure.

  3. Comparative Transcriptome Analysis of Fetal Skin Reveals Key Genes Related to Hair Follicle Morphogenesis in Cashmere Goats.

    Directory of Open Access Journals (Sweden)

    Ye Gao

    Full Text Available Cashmere goat skin contains two types of hair follicles (HF: primary hair follicles (PHF and secondary hair follicles (SHF. Although multiple genetic determinants associated with HF formation have been identified, the molecules that determine the independent morphogenesis of HF in cashmere goats remain elusive. The growth and development of SHF directly influence the quantity and quality of cashmere production. Here, we report the transcriptome profiling analysis of nine skin samples from cashmere goats using 60- and 120-day-old embryos (E60 and E120, respectively, as well as newborns (NB, through RNA-sequencing (RNA-seq. HF morphological changes indicated that PHF were initiated at E60, with maturation from E120, while differentiation of SHF was identified at E120 until formation of cashmere occurred after birth (NB. The RNA-sequencing analysis generated over 20.6 million clean reads from each mRNA library. The number of differentially expressed genes (DEGs in E60 vs. E120, E120 vs. NB, and E60 vs. NB were 1,024, 0 and 1,801, respectively, indicating that no significant differences were found at transcriptomic levels between E120 and NB. Key genes including B4GALT4, TNC, a-integrin, and FGFR1, were up-regulated and expressed in HF initiation from E60 to E120, while regulatory genes such as GPRC5D, PAD3, HOXC13, PRR9, VSIG8, LRRC15, LHX2, MSX-2, and FOXN1 were up-regulated and expressed in HF keratinisation and hair shaft differentiation from E120 and NB to E60. Several genes belonging to the KRT and KRTAP gene families were detected throughout the three HF developmental stages. The transcriptional trajectory analyses of all DEGs indicated that immune privilege, glycosaminoglycan biosynthesis, extracellular matrix receptor interaction, and growth factor receptors all played dominant roles in the epithelial-mesenchymal interface and HF formation. We found that the Wnt, transforming growth factor-beta/bone morphogenetic protein, and Notch family

  4. Comparative Transcriptome Analysis of Fetal Skin Reveals Key Genes Related to Hair Follicle Morphogenesis in Cashmere Goats.

    Science.gov (United States)

    Gao, Ye; Wang, Xiaolong; Yan, Hailong; Zeng, Jie; Ma, Sen; Niu, Yiyuan; Zhou, Guangxian; Jiang, Yu; Chen, Yulin

    2016-01-01

    Cashmere goat skin contains two types of hair follicles (HF): primary hair follicles (PHF) and secondary hair follicles (SHF). Although multiple genetic determinants associated with HF formation have been identified, the molecules that determine the independent morphogenesis of HF in cashmere goats remain elusive. The growth and development of SHF directly influence the quantity and quality of cashmere production. Here, we report the transcriptome profiling analysis of nine skin samples from cashmere goats using 60- and 120-day-old embryos (E60 and E120, respectively), as well as newborns (NB), through RNA-sequencing (RNA-seq). HF morphological changes indicated that PHF were initiated at E60, with maturation from E120, while differentiation of SHF was identified at E120 until formation of cashmere occurred after birth (NB). The RNA-sequencing analysis generated over 20.6 million clean reads from each mRNA library. The number of differentially expressed genes (DEGs) in E60 vs. E120, E120 vs. NB, and E60 vs. NB were 1,024, 0 and 1,801, respectively, indicating that no significant differences were found at transcriptomic levels between E120 and NB. Key genes including B4GALT4, TNC, a-integrin, and FGFR1, were up-regulated and expressed in HF initiation from E60 to E120, while regulatory genes such as GPRC5D, PAD3, HOXC13, PRR9, VSIG8, LRRC15, LHX2, MSX-2, and FOXN1 were up-regulated and expressed in HF keratinisation and hair shaft differentiation from E120 and NB to E60. Several genes belonging to the KRT and KRTAP gene families were detected throughout the three HF developmental stages. The transcriptional trajectory analyses of all DEGs indicated that immune privilege, glycosaminoglycan biosynthesis, extracellular matrix receptor interaction, and growth factor receptors all played dominant roles in the epithelial-mesenchymal interface and HF formation. We found that the Wnt, transforming growth factor-beta/bone morphogenetic protein, and Notch family members

  5. Secondary structure of the rRNA ITS2 region reveals key evolutionary patterns in acroporid corals.

    Science.gov (United States)

    Coleman, Annette W; van Oppen, Madeleine J H

    2008-10-01

    This study investigates the ribosomal RNA transcript secondary structure in corals as confirmed by compensatory base changes in Isopora/Acropora species. These species are unique versus all other corals in the absence of a eukaryote-wide conserved structural component, the helix III in internal transcriber spacer (ITS) 2, and their variability in the 5.8S-LSU helix basal to ITS2, a helix with pairings identical among all other scleractinian corals. Furthermore, Isopora/Acropora individuals display at least two, and as many as three, ITS sequence isotypes in their genome which appear to be capable of function. From consideration of the conserved elements in ITS2 and flanking regions, it appears that there are three major groups within the IsoporaAcropora lineage: the Isopora + Acropora "longi" group, the large group including Caribbean Acropora + the Acropora "carib" types plus the bulk of the Indo-Pacific Acropora species, and the remaining enigmatic "pseudo" group found in the Pacific. Interbreeding is possible among Caribbean A. palmata and A. cervicornis and among some species of Indo-Pacific Acropora. Recombinant ITS sequences are obvious among these latter, such that morphology (as represented by species name) does not correlate with common ITS sequence. The combination of characters revealed by RNA secondary structure analyses suggests a recent past/current history of interbreeding among the Indo-Pacific Acropora species and a shared ancestry of some of these with the Caribbean Acropora. The unusual absence of helix III of ITS2 of Isopora/Acropora species may have some causative role in the equally unusual instability in the 5.8S-LSU helix basal to ITS2 of this species complex.

  6. The transcriptional programme of Salmonella enterica serovar Typhimurium reveals a key role for tryptophan metabolism in biofilms.

    LENUS (Irish Health Repository)

    Hamilton, Shea

    2009-12-11

    exogenous tryptophan or indole. Conclusions Biofilm growth of S. Typhimurium causes distinct changes in gene and protein expression. Our results show that aromatic amino acids make an important contribution to biofilm formation and reveal a link between SPI2 expression and surface-associated growth in S. Typhimurium.

  7. Molecular modeling study on the allosteric inhibition mechanism of HIV-1 integrase by LEDGF/p75 binding site inhibitors.

    Directory of Open Access Journals (Sweden)

    Weiwei Xue

    Full Text Available HIV-1 integrase (IN is essential for the integration of viral DNA into the host genome and an attractive therapeutic target for developing antiretroviral inhibitors. LEDGINs are a class of allosteric inhibitors targeting LEDGF/p75 binding site of HIV-1 IN. Yet, the detailed binding mode and allosteric inhibition mechanism of LEDGINs to HIV-1 IN is only partially understood, which hinders the structure-based design of more potent anti-HIV agents. A molecular modeling study combining molecular docking, molecular dynamics simulation, and binding free energy calculation were performed to investigate the interaction details of HIV-1 IN catalytic core domain (CCD with two recently discovered LEDGINs BI-1001 and CX14442, as well as the LEDGF/p75 protein. Simulation results demonstrated the hydrophobic domain of BI-1001 and CX14442 engages one subunit of HIV-1 IN CCD dimer through hydrophobic interactions, and the hydrophilic group forms hydrogen bonds with HIV-1 IN CCD residues from other subunit. CX14442 has a larger tert-butyl group than the methyl of BI-1001, and forms better interactions with the highly hydrophobic binding pocket of HIV-1 IN CCD dimer interface, which can explain the stronger affinity of CX14442 than BI-1001. Analysis of the binding mode of LEDGF/p75 with HIV-1 IN CCD reveals that the LEDGF/p75 integrase binding domain residues Ile365, Asp366, Phe406 and Val408 have significant contributions to the binding of the LEDGF/p75 to HIV1-IN. Remarkably, we found that binding of BI-1001 and CX14442 to HIV-1 IN CCD induced the structural rearrangements of the 140 s loop and oration displacements of the side chains of the three conserved catalytic residues Asp64, Asp116, and Glu152 located at the active site. These results we obtained will be valuable not only for understanding the allosteric inhibition mechanism of LEDGINs but also for the rational design of allosteric inhibitors of HIV-1 IN targeting LEDGF/p75 binding site.

  8. Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV.

    Directory of Open Access Journals (Sweden)

    Anneleen Hombrouck

    2007-03-01

    Full Text Available Retroviruses by definition insert their viral genome into the host cell chromosome. Although the key player of retroviral integration is viral integrase, a role for cellular cofactors has been proposed. Lentiviral integrases use the cellular protein LEDGF/p75 to tether the preintegration complex to the chromosome, although the existence of alternative host proteins substituting for the function of LEDGF/p75 in integration has been proposed. Truncation mutants of LEDGF/p75 lacking the chromosome attachment site strongly inhibit HIV replication by competition for the interaction with integrase. In an attempt to select HIV strains that can overcome the inhibition, we now have used T-cell lines that stably express a C-terminal fragment of LEDGF/p75. Despite resistance development, the affinity of integrase for LEDGF/p75 is reduced and replication kinetics in human primary T cells is impaired. Detection of the integrase mutations A128T and E170G at key positions in the LEDGF/p75-integrase interface provides in vivo evidence for previously reported crystallographic data. Moreover, the complementary inhibition by LEDGF/p75 knockdown and mutagenesis at the integrase-LEDGF/p75 interface points to the incapability of HIV to circumvent LEDGF/p75 function during proviral integration. Altogether, the data provide a striking example of the power of viral molecular evolution. The results underline the importance of the LEDGF/p75 HIV-1 interplay as target for innovative antiviral therapy. Moreover, the role of LEDGF/p75 in targeting integration will stimulate research on strategies to direct gene therapy vectors into safe landing sites.

  9. Lack of integrase inhibitors associated resistance mutations among HIV-1C isolates.

    Science.gov (United States)

    Mulu, Andargachew; Maier, Melanie; Liebert, Uwe Gerd

    2015-12-01

    Although biochemical analysis of HIV-1 integrase enzyme suggested the use of integrase inhibitors (INIs) against HIV-1C, different viral subtypes may favor different mutational pathways potentially leading to varying levels of drug resistance. Thus, the aim of this study was to search for the occurrence and natural evolution of integrase polymorphisms and/or resistance mutations in HIV-1C Ethiopian clinical isolates prior to the introduction of INIs. Plasma samples from chronically infected drug naïve patients (N = 45), of whom the PR and RT sequence was determined previously, were used to generate population based sequences of HIV-1 integrase. HIV-1 subtype was determined using the REGA HIV-1 subtyping tool. Resistance mutations were interpreted according to the Stanford HIV drug resistance database ( http://hivdb.stanford.edu ) and the updated International Antiviral Society (IAS)-USA mutation lists. Moreover, rates of polymorphisms in the current isolates were compared with South African and global HIV-1C isolates. All subjects were infected with HIV-1C concordant to the protease (PR) and reverse transcriptase (RT) regions. Neither major resistance-associated IN mutations (T66I/A/K, E92Q/G, T97A, Y143HCR, S147G, Q148H/R/K, and N155H) nor silent mutations known to change the genetic barrier were observed. Moreover, the DDE-catalytic motif (D64G/D116G/E152 K) and signature HHCC zinc-binding motifs at codon 12, 16, 40 and 43 were found to be highly conserved. However, compared to other South African subtype C isolates, the rate of polymorphism was variable at various positions. Although the sample size is small, the findings suggest that this drug class could be effective in Ethiopia and other southern African countries where HIV-1C is predominantly circulating. The data will contribute to define the importance of integrase polymorphism and to improve resistance interpretation algorithms in HIV-1C isolates.

  10. Mutations in the catalytic core or the C-terminus of murine leukemia virus (MLV) integrase disrupt virion infectivity and exert diverse effects on reverse transcription

    International Nuclear Information System (INIS)

    Steinrigl, Adolf; Nosek, Dagmara; Ertl, Reinhard; Guenzburg, Walter H.; Salmons, Brian; Klein, Dieter

    2007-01-01

    Understanding of the structures and functions of the retroviral integrase (IN), a key enzyme in the viral replication cycle, is essential for developing antiretroviral treatments and facilitating the development of safer gene therapy vehicles. Thus, four MLV IN-mutants were constructed in the context of a retroviral vector system, harbouring either a substitution in the catalytic centre, deletions in the C-terminus, or combinations of both modifications. IN-mutants were tested for their performance in different stages of the viral replication cycle: RNA-packaging; RT-activity; transient and stable infection efficiency; dynamics of reverse transcription and nuclear entry. All mutant vectors packaged viral RNA with wild-type efficiencies and displayed only slight reductions in RT-activity. Deletion of either the IN C-terminus alone, or in addition to part of the catalytic domain exerted contrasting effects on intracellular viral DNA levels, implying that IN influences reverse transcription in more than one direction

  11. Four-tiered π interaction at the dimeric interface of HIV-1 integrase critical for DNA integration and viral infectivity

    International Nuclear Information System (INIS)

    Al-Mawsawi, Laith Q.; Hombrouck, Anneleen; Dayam, Raveendra; Debyser, Zeger; Neamati, Nouri

    2008-01-01

    HIV-1 integrase (IN) is an essential enzyme for viral infection. Here, we report an extensive π electron orbital interaction between four amino acids, W132, M178, F181 and F185, located at the dimeric interface of IN that is critical for the strand transfer activity alone. Catalysis of nine different mutant IN proteins at these positions were evaluated. Whereas the 3'-processing activity is predominantly strong, the strand transfer activity of each enzyme was completely dependent on an intact π electron orbital interaction at the dimeric interface. Four representative IN mutants were constructed in the context of the infectious NL4.3 HIV-1 viral clone. Whereas viruses with an intact π electron orbital interaction at the IN dimeric interface replicated comparable to wild type, viruses containing an abolished π interaction were non-infectious. Q-PCR analysis of viral DNA forms during viral replication revealed pleiotropic effects of most mutations. We hypothesize that the π interaction is a critical contact point for the assembly of functional IN multimeric complexes, and that IN multimerization is required for a functional pre-integration complex. The rational design of small molecule inhibitors targeting the disruption of this π-π interaction should lead to powerful anti-retroviral drugs

  12. Primary resistance to integrase strand-transfer inhibitors in Europe

    DEFF Research Database (Denmark)

    Casadellà, M; van Ham, P M; Noguera-Julian, M

    2015-01-01

    the introduction of InSTIs. However, polymorphisms contributing to InSTI resistance were not rare. As InSTI use becomes more widespread, continuous surveillance of primary InSTI resistance is warranted. These data will be key to modelling the kinetics of InSTI resistance transmission in Europe in the coming years....

  13. Epigenomic Co-localization and Co-evolution Reveal a Key Role for 5hmC as a Communication Hub in the Chromatin Network of ESCs

    Directory of Open Access Journals (Sweden)

    David Juan

    2016-02-01

    Full Text Available Summary: Epigenetic communication through histone and cytosine modifications is essential for gene regulation and cell identity. Here, we propose a framework that is based on a chromatin communication model to get insight on the function of epigenetic modifications in ESCs. The epigenetic communication network was inferred from genome-wide location data plus extensive manual annotation. Notably, we found that 5-hydroxymethylcytosine (5hmC is the most-influential hub of this network, connecting DNA demethylation to nucleosome remodeling complexes and to key transcription factors of pluripotency. Moreover, an evolutionary analysis revealed a central role of 5hmC in the co-evolution of chromatin-related proteins. Further analysis of regions where 5hmC co-localizes with specific interactors shows that each interaction points to chromatin remodeling, stemness, differentiation, or metabolism. Our results highlight the importance of cytosine modifications in the epigenetic communication of ESCs. : 5-hydroxymethylcytosine (5hmC plays a key role in the epigenomic communication network of embryonic stem cells. Juan et al. build a communication network based in co-localization of epigenomic data and literature. The analysis of the network and its components reveals that proteins reading and editing 5hmC co-evolve and serve as links between diverse molecular processes.

  14. The allosteric HIV-1 integrase inhibitor BI-D affects virion maturation but does not influence packaging of a functional RNA genome

    NARCIS (Netherlands)

    van Bel, Nikki; van der Velden, Yme; Bonnard, Damien; Le Rouzic, Erwann; Das, Atze T.; Benarous, Richard; Berkhout, Ben

    2014-01-01

    The viral integrase (IN) is an essential protein for HIV-1 replication. IN inserts the viral dsDNA into the host chromosome, thereby aided by the cellular co-factor LEDGF/p75. Recently a new class of integrase inhibitors was described: allosteric IN inhibitors (ALLINIs). Although designed to

  15. Structure of Rhodococcus equi virulence-associated protein B (VapB) reveals an eight-stranded antiparallel β-barrel consisting of two Greek-key motifs

    International Nuclear Information System (INIS)

    Geerds, Christina; Wohlmann, Jens; Haas, Albert; Niemann, Hartmut H.

    2014-01-01

    The structure of VapB, a member of the Vap protein family that is involved in virulence of the bacterial pathogen R. equi, was determined by SAD phasing and reveals an eight-stranded antiparallel β-barrel similar to avidin, suggestive of a binding function. Made up of two Greek-key motifs, the topology of VapB is unusual or even unique. Members of the virulence-associated protein (Vap) family from the pathogen Rhodococcus equi regulate virulence in an unknown manner. They do not share recognizable sequence homology with any protein of known structure. VapB and VapA are normally associated with isolates from pigs and horses, respectively. To contribute to a molecular understanding of Vap function, the crystal structure of a protease-resistant VapB fragment was determined at 1.4 Å resolution. The structure was solved by SAD phasing employing the anomalous signal of one endogenous S atom and two bound Co ions with low occupancy. VapB is an eight-stranded antiparallel β-barrel with a single helix. Structural similarity to avidins suggests a potential binding function. Unlike other eight- or ten-stranded β-barrels found in avidins, bacterial outer membrane proteins, fatty-acid-binding proteins and lysozyme inhibitors, Vaps do not have a next-neighbour arrangement but consist of two Greek-key motifs with strand order 41238567, suggesting an unusual or even unique topology

  16. Structure of Rhodococcus equi virulence-associated protein B (VapB) reveals an eight-stranded antiparallel β-barrel consisting of two Greek-key motifs

    Energy Technology Data Exchange (ETDEWEB)

    Geerds, Christina [Bielefeld University, Universitaetsstrasse 25, 33615 Bielefeld (Germany); Wohlmann, Jens; Haas, Albert [University of Bonn, Ulrich-Haberland Strasse 61a, 53121 Bonn (Germany); Niemann, Hartmut H., E-mail: hartmut.niemann@uni-bielefeld.de [Bielefeld University, Universitaetsstrasse 25, 33615 Bielefeld (Germany)

    2014-06-18

    The structure of VapB, a member of the Vap protein family that is involved in virulence of the bacterial pathogen R. equi, was determined by SAD phasing and reveals an eight-stranded antiparallel β-barrel similar to avidin, suggestive of a binding function. Made up of two Greek-key motifs, the topology of VapB is unusual or even unique. Members of the virulence-associated protein (Vap) family from the pathogen Rhodococcus equi regulate virulence in an unknown manner. They do not share recognizable sequence homology with any protein of known structure. VapB and VapA are normally associated with isolates from pigs and horses, respectively. To contribute to a molecular understanding of Vap function, the crystal structure of a protease-resistant VapB fragment was determined at 1.4 Å resolution. The structure was solved by SAD phasing employing the anomalous signal of one endogenous S atom and two bound Co ions with low occupancy. VapB is an eight-stranded antiparallel β-barrel with a single helix. Structural similarity to avidins suggests a potential binding function. Unlike other eight- or ten-stranded β-barrels found in avidins, bacterial outer membrane proteins, fatty-acid-binding proteins and lysozyme inhibitors, Vaps do not have a next-neighbour arrangement but consist of two Greek-key motifs with strand order 41238567, suggesting an unusual or even unique topology.

  17. Lead Screening for HIV-1 Integrase (IN Inhibited by Traditional Chinese Medicine

    Directory of Open Access Journals (Sweden)

    Tzu-Chieh Hung

    2014-01-01

    Full Text Available Human immunodeficiency virus causes the acquired immunodeficiency syndrome (AIDS and becomes a serious world-wide problem because of this disease's rapid propagation and incurability. Integrase strand transfer inhibitors (INSTIs supports HIV have rapid drug resistance for antitreatment. Screening the traditional Chinese medicine (TCM database by simulating molecular docking and molecular dynamics may select molecular compounds to inhibit INSTIs against HIV drug resistance. (S-cathinone and (1S,2S-norpseudoephedrine are selected based on structure and ligand-based drugs are designed and then get higher bioactivity predicted score from SVM than Raltegravir and other TCM compounds. The molecular dynamics are helpful in the analysis and detection of protein-ligand interactions. According to the docking poses, hydrophobic interactions and hydrogen bond variations define the main regions of important amino acids in integrase. In addition to the detection of TCM compound efficacy, we suggest (1S,2S-norpseudoephedrine is better than the others based on the analysis of interaction and the effect on the structural variation.

  18. Fragment Based Strategies for Discovery of Novel HIV-1 Reverse Transcriptase and Integrase Inhibitors.

    Science.gov (United States)

    Latham, Catherine F; La, Jennifer; Tinetti, Ricky N; Chalmers, David K; Tachedjian, Gilda

    2016-01-01

    Human immunodeficiency virus (HIV) remains a global health problem. While combined antiretroviral therapy has been successful in controlling the virus in patients, HIV can develop resistance to drugs used for treatment, rendering available drugs less effective and limiting treatment options. Initiatives to find novel drugs for HIV treatment are ongoing, although traditional drug design approaches often focus on known binding sites for inhibition of established drug targets like reverse transcriptase and integrase. These approaches tend towards generating more inhibitors in the same drug classes already used in the clinic. Lack of diversity in antiretroviral drug classes can result in limited treatment options, as cross-resistance can emerge to a whole drug class in patients treated with only one drug from that class. A fresh approach in the search for new HIV-1 drugs is fragment-based drug discovery (FBDD), a validated strategy for drug discovery based on using smaller libraries of low molecular weight molecules (FBDD is aimed at not only finding novel drug scaffolds, but also probing the target protein to find new, often allosteric, inhibitory binding sites. Several fragment-based strategies have been successful in identifying novel inhibitory sites or scaffolds for two proven drug targets for HIV-1, reverse transcriptase and integrase. While any FBDD-generated HIV-1 drugs have yet to enter the clinic, recent FBDD initiatives against these two well-characterised HIV-1 targets have reinvigorated antiretroviral drug discovery and the search for novel classes of HIV-1 drugs.

  19. Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV.

    Science.gov (United States)

    Schreier, John D; Embrey, Mark W; Raheem, Izzat T; Barbe, Guillaume; Campeau, Louis-Charles; Dubost, David; McCabe Dunn, Jamie; Grobler, Jay; Hartingh, Timothy J; Hazuda, Daria J; Klein, Daniel; Miller, Michael D; Moore, Keith P; Nguyen, Natalie; Pajkovic, Natasa; Powell, David A; Rada, Vanessa; Sanders, John M; Sisko, John; Steele, Thomas G; Wai, John; Walji, Abbas; Xu, Min; Coleman, Paul J

    2017-05-01

    HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Nanobody-based chimeric receptor gene integration in Jurkat cells mediated by PhiC31 integrase

    International Nuclear Information System (INIS)

    Iri-Sofla, Farnoush Jafari; Rahbarizadeh, Fatemeh; Ahmadvand, Davoud; Rasaee, Mohammad J.

    2011-01-01

    The crucial role of T lymphocytes in anti-tumor immunity has led to the development of novel strategies that can target and activate T cells against tumor cells. Recombinant DNA technology has been used to generate non-MHC-restricted chimeric antigen receptors (CARs). Here, we constructed a panel of recombinant CAR that harbors the anti-MUC1 nanobody and the signaling and co-signaling moieties (CD3ζ/CD28) with different spacer regions derived from human IgG3 with one or two repeats of the hinge sequence or the hinge region of FcγRII. The PhiC31 integrase system was employed to investigate if the recombination efficiency could be recruited for high and stable expression of T cell chimeric receptor genes. The effect of nuclear localization signal (NLS) and two different promoters (CMV and CAG) on efficacy of PhiC31 integrase in human T cell lines was evaluated. The presence of integrase in combination with NLS, mediated up to 7.6 and 8.5 fold increases in CAR expression in ZCHN-attB and ZCHHN-attB cassette integrated T cells, respectively. Our results showed that highly efficient and stable transduction of the Jurkat cell line by PhiC31 integrase is a feasible modality for generating anti-cancer chimeric T cells for use in cancer immunotherapy.

  1. Nanobody-based chimeric receptor gene integration in Jurkat cells mediated by PhiC31 integrase

    Energy Technology Data Exchange (ETDEWEB)

    Iri-Sofla, Farnoush Jafari [Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran (Iran, Islamic Republic of); Rahbarizadeh, Fatemeh, E-mail: rahbarif@modares.ac.ir [Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran (Iran, Islamic Republic of); Ahmadvand, Davoud [Center of Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmaceutics and Analytical Chemistry, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen O (Denmark); Rasaee, Mohammad J. [Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran (Iran, Islamic Republic of)

    2011-11-01

    The crucial role of T lymphocytes in anti-tumor immunity has led to the development of novel strategies that can target and activate T cells against tumor cells. Recombinant DNA technology has been used to generate non-MHC-restricted chimeric antigen receptors (CARs). Here, we constructed a panel of recombinant CAR that harbors the anti-MUC1 nanobody and the signaling and co-signaling moieties (CD3{zeta}/CD28) with different spacer regions derived from human IgG3 with one or two repeats of the hinge sequence or the hinge region of Fc{gamma}RII. The PhiC31 integrase system was employed to investigate if the recombination efficiency could be recruited for high and stable expression of T cell chimeric receptor genes. The effect of nuclear localization signal (NLS) and two different promoters (CMV and CAG) on efficacy of PhiC31 integrase in human T cell lines was evaluated. The presence of integrase in combination with NLS, mediated up to 7.6 and 8.5 fold increases in CAR expression in ZCHN-attB and ZCHHN-attB cassette integrated T cells, respectively. Our results showed that highly efficient and stable transduction of the Jurkat cell line by PhiC31 integrase is a feasible modality for generating anti-cancer chimeric T cells for use in cancer immunotherapy.

  2. Novel Bifunctional Quinolonyl Diketo Acid Derivatives as HIV-1 Integrase Inhibitors: Design, Synthesis, Biological Activities and Mechanism of Action

    Science.gov (United States)

    Di Santo, Roberto; Costi, Roberta; Roux, Alessandra; Artico, Marino; Lavecchia, Antonio; Marinelli, Luciana; Novellino, Ettore; Palmisano, Lucia; Andreotti, Mauro; Amici, Roberta; Galluzzo, Clementina Maria; Nencioni, Lucia; Palamara, Anna Teresa; Pommier, Yves; Marchand, Christophe

    2008-01-01

    The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the β-diketo acids (DKAs) represent a major lead for anti-HIV-1drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3′-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-crosslinking experiments. PMID:16539381

  3. Primary resistance to integrase strand transfer inhibitors in patients infected with diverse HIV-1 subtypes in sub-Saharan Africa

    NARCIS (Netherlands)

    Inzaule, Seth C.; Hamers, Raph L.; Noguera-Julian, Marc; Casadellà, Maria; Parera, Mariona; Rinke de Wit, Tobias F.; Paredes, Roger

    2018-01-01

    To investigate the prevalence and patterns of major and accessory resistance mutations associated with integrase strand transfer inhibitors (INSTIs), across diverse HIV-1 subtypes in sub-Saharan Africa. pol gene sequences were obtained using Illumina next-generation sequencing from 425 INSTI-naive

  4. Contribution of HIV minority variants to drug resistance in an integrase strand transfer inhibitor-based therapy

    Czech Academy of Sciences Publication Activity Database

    Weber, Jan; Gibson, R. M.; Meyer, A. M.; Winner, D.; Robertson, D. L.; Miller, M. D.; Quinones-Mateu, M. E.

    2013-01-01

    Roč. 18, Suppl. 1 (2013), A66-A66 ISSN 1359-6535. [International Workshop on HIV & Hepatitis Virus Drug Resistance Curative Strategies. 04.06.2013-08.06.2013, Toronto] Institutional support: RVO:61388963 Keywords : HIV minority variants * integrase inhibitor * replicative fitness Subject RIV: CE - Biochemistry

  5. [Isolation, idetification and anti-HIV-1 integrase activity of culturable endophytic fungi from Tibetan medicinal plant Phlomis younghusbandii Mukerjee].

    Science.gov (United States)

    Zhang, Da-Wei; Zhao, Ming-Ming; Chen, Juan; Li, Chao; Guo, Shun-Xing

    2013-05-01

    A total of 52 endophytic fungi were isolated from roots and stems of Tibetan medicinal plant Phlomis younghusbandii Mukerjee. These fungal isolates were molecularly identified based on ITS sequnces and 28S sequences distributed to 12 genera, including Phoma, Chaetosphaeronema, Fusarium and Leptosphaeria, etc. Among them, the dominant genus was Phoma. Extracts of all strains were evaluated for anti-HIV-1 integrase activity by using soluable integrase expressed in E. coli BL21 (DE3). The results showed that seven samples from five fungal endophytes PHY-24, PHY-38, PHY-40, PHY-51, PHY-53, which belonged to genus Chaetosphaeronema, inhibited strand transfer reaction catalyzed by HIV-1 integrase with IC50 values, of 6.60, 5.20, 2.86, 7.86, 4.47, 4.56 and 3.23 microg x mL(-1) respectively. In conclusion, the endophytic fungi of Phlomis younghusbandii Mukerjee are valuable for further screening anti-HIV-1 integrase agents.

  6. Novel 3′-Processing Integrase Activity Assay by Real-Time PCR for Screening and Identification of HIV-1 Integrase Inhibitors

    Directory of Open Access Journals (Sweden)

    Supachai Sakkhachornphop

    2015-01-01

    Full Text Available The 3′-end processing (3′P of each viral long terminal repeat (LTR during human immunodeficiency virus type-1 (HIV-1 integration is a vital step in the HIV life cycle. Blocking the 3′P using 3′P inhibitor has recently become an attractive strategy for HIV-1 therapeutic intervention. Recently, we have developed a novel real-time PCR based assay for the detection of 3′P activity in vitro. The methodology usually involves biotinylated HIV-1 LTR, HIV-1 integrase (IN, and specific primers and probe. In this novel assay, we designed the HIV-1 LTR substrate based on a sequence with a homology to HIV-1 LTR labeled at its 3′ end with biotin on the sense strand. Two nucleotides at the 3′ end were subsequently removed by IN activity. Only two nucleotides labeled biotin were captured on an avidin-coated tube; therefore, inhibiting the binding of primers and probe results in late signals in the real-time PCR. This novel assay has successfully detected both the 3′P activity of HIV-1 IN and the anti-IN activity by Raltegravir and sodium azide agent. This real-time PCR assay has been shown to be effective and inexpensive for a high-throughput screening of novel IN inhibitors.

  7. Population Genetics of Two Key Mosquito Vectors of Rift Valley Fever Virus Reveals New Insights into the Changing Disease Outbreak Patterns in Kenya

    Science.gov (United States)

    Tchouassi, David P.; Bastos, Armanda D. S.; Sole, Catherine L.; Diallo, Mawlouth; Lutomiah, Joel; Mutisya, James; Mulwa, Francis; Borgemeister, Christian; Sang, Rosemary; Torto, Baldwyn

    2014-01-01

    Rift Valley fever (RVF) outbreaks in Kenya have increased in frequency and range to include northeastern Kenya where viruses are increasingly being isolated from known (Aedes mcintoshi) and newly-associated (Ae. ochraceus) vectors. The factors contributing to these changing outbreak patterns are unclear and the population genetic structure of key vectors and/or specific virus-vector associations, in particular, are under-studied. By conducting mitochondrial and nuclear DNA analyses on >220 Kenyan specimens of Ae. mcintoshi and Ae. ochraceus, we uncovered high levels of vector complexity which may partly explain the disease outbreak pattern. Results indicate that Ae. mcintoshi consists of a species complex with one of the member species being unique to the newly-established RVF outbreak-prone northeastern region of Kenya, whereas Ae. ochraceus is a homogeneous population that appears to be undergoing expansion. Characterization of specimens from a RVF-prone site in Senegal, where Ae. ochraceus is a primary vector, revealed direct genetic links between the two Ae. ochraceus populations from both countries. Our data strongly suggest that unlike Ae. mcintoshi, Ae. ochraceus appears to be a relatively recent, single 'introduction' into Kenya. These results, together with increasing isolations from this vector, indicate that Ae. ochraceus will likely be of greater epidemiological importance in future RVF outbreaks in Kenya. Furthermore, the overall vector complexity calls into question the feasibility of mosquito population control approaches reliant on genetic modification. PMID:25474018

  8. Population genetics of two key mosquito vectors of Rift Valley Fever virus reveals new insights into the changing disease outbreak patterns in Kenya.

    Directory of Open Access Journals (Sweden)

    David P Tchouassi

    2014-12-01

    Full Text Available Rift Valley fever (RVF outbreaks in Kenya have increased in frequency and range to include northeastern Kenya where viruses are increasingly being isolated from known (Aedes mcintoshi and newly-associated (Ae. ochraceus vectors. The factors contributing to these changing outbreak patterns are unclear and the population genetic structure of key vectors and/or specific virus-vector associations, in particular, are under-studied. By conducting mitochondrial and nuclear DNA analyses on >220 Kenyan specimens of Ae. mcintoshi and Ae. ochraceus, we uncovered high levels of vector complexity which may partly explain the disease outbreak pattern. Results indicate that Ae. mcintoshi consists of a species complex with one of the member species being unique to the newly-established RVF outbreak-prone northeastern region of Kenya, whereas Ae. ochraceus is a homogeneous population that appears to be undergoing expansion. Characterization of specimens from a RVF-prone site in Senegal, where Ae. ochraceus is a primary vector, revealed direct genetic links between the two Ae. ochraceus populations from both countries. Our data strongly suggest that unlike Ae. mcintoshi, Ae. ochraceus appears to be a relatively recent, single 'introduction' into Kenya. These results, together with increasing isolations from this vector, indicate that Ae. ochraceus will likely be of greater epidemiological importance in future RVF outbreaks in Kenya. Furthermore, the overall vector complexity calls into question the feasibility of mosquito population control approaches reliant on genetic modification.

  9. Anti-HIV-1 integrase activity of medicinal plants used as self medication by AIDS patients

    Directory of Open Access Journals (Sweden)

    Sopa Kummee

    2006-07-01

    Full Text Available The extracts of selected medicinal plants used as self medication by AIDS patients were investigated for their inhibitory activities against HIV-1 integrase (HIV-1 IN using the multiplate integration assay (MIA. Of these, the water extract of Eclipta prostrata (whole plant exhibited the most potent inhibitory activity with an IC50 value of 4.8 μg/ml, followed by the methanol extract of Eclipta prostrata (whole plant, IC50 = 21.1 μg/ ml, the water extract of Barleria lupulina (stem, IC50 = 26.4 μg/ml, the chloroform extract of Barleria lupulina (stem, IC50 = 33.0 μg/ml, the methanol extract of Barleria lupulina (stem, IC50 = 38.2 μg/ml and the chloroform extract of Piper betle (leaf, IC50 = 39.3 μg/ml, respectively.

  10. Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors

    Directory of Open Access Journals (Sweden)

    Neamati Nouri

    2009-03-01

    Full Text Available Abstract Merck's MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 integrase (IN inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compound's interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN inhibitors.

  11. Proteomic analyses reveal the key roles of BrlA and AbaA in biogenesis of gliotoxin in Aspergillus fumigatus

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Kwang-Soo, E-mail: shinks@dju.kr [Division of Life Science, Daejeon University, Daejeon, 300-716 (Korea, Republic of); Kim, Young Hwan [Biomedical Omics Team, Korea Basic Science Institute (KBSI), Ohcang, 368-883 (Korea, Republic of); Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764 (Korea, Republic of); Department of Bio-Analytical Science, University of Science and Technology, Daejeon, 305-333 (Korea, Republic of); Yu, Jae-Hyuk, E-mail: jyu1@wisc.edu [Departments of Bacteriology and Genetics, The University of Wisconsin–Madison, Madison, WI, 53706 (United States)

    2015-07-31

    The opportunistic human pathogenic fungus Aspergillus fumigatus primarily reproduces by forming a large number of asexual spores (conidia). Sequential activation of the central regulators BrlA, AbaA and WetA is necessary for the fungus to undergo asexual development. In this study, to address the presumed roles of these key developmental regulators during proliferation of the fungus, we analyzed and compared the proteomes of vegetative cells of wild type (WT) and individual mutant strains. Approximately 1300 protein spots were detectable from 2-D electrophoresis gels. Among these, 13 proteins exhibiting significantly altered accumulation levels were further identified by ESI-MS/MS. Markedly, we found that the GliM and GliT proteins associated with gliotoxin (GT) biosynthesis and self-protection of the fungus from GT were significantly down-regulated in the ΔabaA and ΔbrlA mutants. Moreover, mRNA levels of other GT biosynthetic genes including gliM, gliP, gliT, and gliZ were significantly reduced in both mutant strains, and no and low levels of GT were detectable in the ΔbrlA and ΔabaA mutant strains, respectively. As GliT is required for the protection of the fungus from GT, growth of the ΔbrlA mutant with reduced levels of GliT was severely impaired by exogenous GT. Our studies demonstrate that AbaA and BrlA positively regulate expression of the GT biosynthetic gene cluster in actively growing vegetative cells, and likely bridge morphological and chemical development during the life-cycle of A. fumigatus. - Highlights: • Proteome analyses of WT and mutants reveal 13 differentially expressed proteins. • The GliT and GliM proteins are significantly down-regulated by ΔabaA and ΔbrlA. • Expression of other gliotoxin biosynthetic genes is lowered by ΔabaA and ΔbrlA. • Growth of ΔbrlA strain lacking GliT is completely inhibited by exogenous gliotoxin. • BrlA and AbaA play key roles in biogenesis of gliotoxin in Aspergillus fumigatus.

  12. Proteomic analyses reveal the key roles of BrlA and AbaA in biogenesis of gliotoxin in Aspergillus fumigatus

    International Nuclear Information System (INIS)

    Shin, Kwang-Soo; Kim, Young Hwan; Yu, Jae-Hyuk

    2015-01-01

    The opportunistic human pathogenic fungus Aspergillus fumigatus primarily reproduces by forming a large number of asexual spores (conidia). Sequential activation of the central regulators BrlA, AbaA and WetA is necessary for the fungus to undergo asexual development. In this study, to address the presumed roles of these key developmental regulators during proliferation of the fungus, we analyzed and compared the proteomes of vegetative cells of wild type (WT) and individual mutant strains. Approximately 1300 protein spots were detectable from 2-D electrophoresis gels. Among these, 13 proteins exhibiting significantly altered accumulation levels were further identified by ESI-MS/MS. Markedly, we found that the GliM and GliT proteins associated with gliotoxin (GT) biosynthesis and self-protection of the fungus from GT were significantly down-regulated in the ΔabaA and ΔbrlA mutants. Moreover, mRNA levels of other GT biosynthetic genes including gliM, gliP, gliT, and gliZ were significantly reduced in both mutant strains, and no and low levels of GT were detectable in the ΔbrlA and ΔabaA mutant strains, respectively. As GliT is required for the protection of the fungus from GT, growth of the ΔbrlA mutant with reduced levels of GliT was severely impaired by exogenous GT. Our studies demonstrate that AbaA and BrlA positively regulate expression of the GT biosynthetic gene cluster in actively growing vegetative cells, and likely bridge morphological and chemical development during the life-cycle of A. fumigatus. - Highlights: • Proteome analyses of WT and mutants reveal 13 differentially expressed proteins. • The GliT and GliM proteins are significantly down-regulated by ΔabaA and ΔbrlA. • Expression of other gliotoxin biosynthetic genes is lowered by ΔabaA and ΔbrlA. • Growth of ΔbrlA strain lacking GliT is completely inhibited by exogenous gliotoxin. • BrlA and AbaA play key roles in biogenesis of gliotoxin in Aspergillus fumigatus

  13. Partitioning of the net CO2 exchange using an automated chamber system reveals plant phenology as key control of production and respiration fluxes in a boreal peatland.

    Science.gov (United States)

    Järveoja, Järvi; Nilsson, Mats B; Gažovič, Michal; Crill, Patrick M; Peichl, Matthias

    2018-04-30

    The net ecosystem CO 2 exchange (NEE) drives the carbon (C) sink-source strength of northern peatlands. Since NEE represents a balance between various production and respiration fluxes, accurate predictions of its response to global changes require an in depth understanding of these underlying processes. Currently, however, detailed information of the temporal dynamics as well as the separate biotic and abiotic controls of the NEE component fluxes is lacking in peatland ecosystems. In this study, we address this knowledge gap by using an automated chamber system established across natural and trenching-/vegetation removal plots to partition NEE into its production (i.e. gross and net primary production; GPP and NPP) and respiration (i.e. ecosystem, heterotrophic and autotrophic respiration; ER, Rh and Ra) fluxes in a boreal peatland in northern Sweden. Our results showed that daily NEE patterns were driven by GPP while variations in ER were governed by Ra rather than Rh. Moreover, we observed pronounced seasonal shifts in the Ra/Rh and above-/belowground NPP ratios throughout the main phenological phases. Generalized linear model analysis revealed that the greenness index derived from digital images (as a proxy for plant phenology) was the strongest control of NEE, GPP and NPP while explaining considerable fractions also in the variations of ER and Ra. In addition, our data exposed greater temperature sensitivity of NPP compared to Rh resulting in enhanced C sequestration with increasing temperature. Overall, our study suggests that the temporal patterns in NEE and its component fluxes are tightly coupled to vegetation dynamics in boreal peatlands and thus challenges previous studies that commonly identify abiotic factors as key drivers. These findings further emphasize the need for integrating detailed information on plant phenology into process-based models to improve predictions of global change impacts on the peatland C cycle. This article is protected by

  14. An effective HIV-1 integrase inhibitor screening platform: Rationality validation of drug screening, conformational mobility and molecular recognition analysis for PFV integrase complex with viral DNA.

    Science.gov (United States)

    Du, Wenyi; Zuo, Ke; Sun, Xin; Liu, Wei; Yan, Xiao; Liang, Li; Wan, Hua; Chen, Fengzheng; Hu, Jianping

    2017-11-01

    As an important target for the development of novel anti-AIDS drugs, HIV-1 integrase (IN) has been widely concerned. However, the lack of a complete accurate crystal structure of HIV-1 IN greatly blocks the discovery of novel inhibitors. In this work, an effective HIV-1 IN inhibitor screening platform, namely PFV IN, was filtered from all species of INs. Next, the 40.8% similarity with HIV-1 IN, as well as the high efficiency of virtual screening and the good agreement between calculated binding free energies and experimental ones all proved PFV IN is a promising screening platform for HIV-1 IN inhibitors. Then, the molecular recognition mechanism of PFV IN by its substrate viral DNA and six naphthyridine derivatives (NRDs) inhibitors was investigated through molecular docking, molecular dynamics simulations and water-mediated interactions analyses. The functional partition of NRDs IN inhibitors could be divided into hydrophobic and hydrophilic ones, and the Mg 2+ ions, water molecules and conserved DDE motif residues all interacted with the hydrophilic partition, while the bases in viral DNA and residues like Tyr212, Pro214 interacted with the hydrophobic one. Finally, the free energy landscape (FEL) and cluster analyses were performed to explore the molecular motion of PFV IN-DNA system. It is found that the association with NRDs inhibitors would obviously decrease the motion amplitude of PFV IN-DNA, which may be one of the most potential mechanisms of IN inhibitors. This work will provide a theoretical basis for the inhibitor design based on the structure of HIV-1 IN. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. In vivo and in vitro characterization of site-specific recombination of a novel serine integrase from the temperate phage EFC-1

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    Yoon, Bohyun; Kim, Inki; Nam, Ja-Ae [Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, 86 Asanbyeoungwon-gil, Songpa-gu, Seoul 138-736 (Korea, Republic of); Chang, Hyo-Ihl [College of Life Sciences & Biotechnology, Korea University, 5-1 Anam-dong, Seongbuk-gu, Seoul 136-701 (Korea, Republic of); Ha, Chang Hoon, E-mail: chhoonha@amc.seoul.kr [Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, 86 Asanbyeoungwon-gil, Songpa-gu, Seoul 138-736 (Korea, Republic of)

    2016-04-22

    EFC-1 integrase is a site-specific recombinase that belongs to the large family of serine recombinase. In previously study, we isolated the temperate phage EFC-1, and characterized its genomic sequence. Within its genome, Orf28 was predicted encode a 464 amino acid of a putative integrase gene. In this study, EFC-1 integrase was characterized in vitro and in vivo. In vitro assay was performed using purified His-tag fusion integrase. Also, to identify which serine is involved in the catalytic domain, we used site-directed mutagenesis and analyzed by a recombination assay in vitro. In vivo assay involved PCR and confocal microscopy in HEK293 cells, and determined the minimal lengths of attP and attB sites. According to our results, the EFC-1 integrase-mediated recombination was site-specific and unidirectional system in vitro and in vivo. Serine 21 of EFC-1 integrase plays a major role in the catalytic domain, and minimal sizes of attB and attP was defined 48 and 54 bp. Our finding may help develop a useful tool for gene therapy and gene delivery system. - Highlights: • EFC-1 integrase-mediated recombination was site-specific and unidirectional system. • Serine 21 of EFC-1 integrase plays a major role in the catalytic domain. • The functional minimal sizes of attB and attP was defined 48 and 54 bp.

  16. In vivo and in vitro characterization of site-specific recombination of a novel serine integrase from the temperate phage EFC-1

    International Nuclear Information System (INIS)

    Yoon, Bohyun; Kim, Inki; Nam, Ja-Ae; Chang, Hyo-Ihl; Ha, Chang Hoon

    2016-01-01

    EFC-1 integrase is a site-specific recombinase that belongs to the large family of serine recombinase. In previously study, we isolated the temperate phage EFC-1, and characterized its genomic sequence. Within its genome, Orf28 was predicted encode a 464 amino acid of a putative integrase gene. In this study, EFC-1 integrase was characterized in vitro and in vivo. In vitro assay was performed using purified His-tag fusion integrase. Also, to identify which serine is involved in the catalytic domain, we used site-directed mutagenesis and analyzed by a recombination assay in vitro. In vivo assay involved PCR and confocal microscopy in HEK293 cells, and determined the minimal lengths of attP and attB sites. According to our results, the EFC-1 integrase-mediated recombination was site-specific and unidirectional system in vitro and in vivo. Serine 21 of EFC-1 integrase plays a major role in the catalytic domain, and minimal sizes of attB and attP was defined 48 and 54 bp. Our finding may help develop a useful tool for gene therapy and gene delivery system. - Highlights: • EFC-1 integrase-mediated recombination was site-specific and unidirectional system. • Serine 21 of EFC-1 integrase plays a major role in the catalytic domain. • The functional minimal sizes of attB and attP was defined 48 and 54 bp.

  17. Real-time monitoring of disintegration activity of catalytic core domain of HIV-1 integrase using molecular beacon.

    Science.gov (United States)

    Zhang, Da-wei; Zhao, Ming-ming; He, Hong-qiu; Guo, Shun-xing

    2013-09-15

    HIV-1 integrase, an essential enzyme for retroviral replication, is a validated target for anti-HIV therapy development. The catalytic core domain of integrase (IN-CCD) is capable of catalyzing disintegration reaction. In this work, a hairpin-shaped disintegration substrate was designed and validated by enzyme-linked immunosorbent assay; a molecular beacon-based assay was developed for disintegration reaction of IN-CCD. Results showed that the disintegration substrate could be recognized and catalyzed by IN-CCD, and the disintegration reaction can be monitored according to the increase of fluorescent signal. The assay can be applied to real-time detection of disintegration with advantages of simplicity, high sensitivity, and excellent specificity. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Cloning, purification and structure determination of the HIV integrase-binding domain of lens epithelium-derived growth factor.

    Science.gov (United States)

    Hannon, Clare; Cruz-Migoni, Abimael; Platonova, Olga; Owen, Robin L; Nettleship, Joanne E; Miller, Ami; Carr, Stephen B; Harris, Gemma; Rabbitts, Terence H; Phillips, Simon E V

    2018-03-01

    Lens epithelium-derived growth factor (LEDGF)/p75 is the dominant binding partner of HIV-1 integrase in human cells. The crystal structure of the HIV integrase-binding domain (IBD) of LEDGF has been determined in the absence of ligand. IBD was overexpressed in Escherichia coli, purified and crystallized by sitting-drop vapour diffusion. X-ray diffraction data were collected at Diamond Light Source to a resolution of 2.05 Å. The crystals belonged to space group P2 1 , with eight polypeptide chains in the asymmetric unit arranged as an unusual octamer composed of four domain-swapped IBD dimers. IBD exists as a mixture of monomers and dimers in concentrated solutions, but the dimers are unlikely to be biologically relevant.

  19. Contribution of the C-terminal region within the catalytic core domain of HIV-1 integrase to yeast lethality, chromatin binding and viral replication

    Directory of Open Access Journals (Sweden)

    Belhumeur Pierre

    2008-11-01

    Full Text Available Abstract Background HIV-1 integrase (IN is a key viral enzymatic molecule required for the integration of the viral cDNA into the genome. Additionally, HIV-1 IN has been shown to play important roles in several other steps during the viral life cycle, including reverse transcription, nuclear import and chromatin targeting. Interestingly, previous studies have demonstrated that the expression of HIV-1 IN induces the lethal phenotype in some strains of Saccharomyces cerevisiae. In this study, we performed mutagenic analyses of the C-terminal region of the catalytic core domain of HIV-1 IN in order to delineate the critical amino acid(s and/or motif(s required for the induction of the lethal phenotype in the yeast strain HP16, and to further elucidate the molecular mechanism which causes this phenotype. Results Our study identified three HIV-1 IN mutants, V165A, A179P and KR186,7AA, located in the C-terminal region of the catalytic core domain of IN that do not induce the lethal phenotype in yeast. Chromatin binding assays in yeast and mammalian cells demonstrated that these IN mutants were impaired for the ability to bind chromatin. Additionally, we determined that while these IN mutants failed to interact with LEDGF/p75, they retained the ability to bind Integrase interactor 1. Furthermore, we observed that VSV-G-pseudotyped HIV-1 containing these IN mutants was unable to replicate in the C8166 T cell line and this defect was partially rescued by complementation with the catalytically inactive D64E IN mutant. Conclusion Overall, this study demonstrates that three mutations located in the C-terminal region of the catalytic core domain of HIV-1 IN inhibit the IN-induced lethal phenotype in yeast by inhibiting the binding of IN to the host chromatin. These results demonstrate that the C-terminal region of the catalytic core domain of HIV-1 IN is important for binding to host chromatin and is crucial for both viral replication and the promotion of

  20. HIV-2 integrase polymorphisms and longitudinal genotypic analysis of HIV-2 infected patients failing a raltegravir-containing regimen.

    Science.gov (United States)

    Cavaco-Silva, Joana; Abecasis, Ana; Miranda, Ana Cláudia; Poças, José; Narciso, Jorge; Águas, Maria João; Maltez, Fernando; Almeida, Isabel; Germano, Isabel; Diniz, António; Gonçalves, Maria de Fátima; Gomes, Perpétua; Cunha, Celso; Camacho, Ricardo Jorge

    2014-01-01

    To characterize the HIV-2 integrase gene polymorphisms and the pathways to resistance of HIV-2 patients failing a raltegravir-containing regimen, we studied 63 integrase strand transfer inhibitors (INSTI)-naïve patients, and 10 heavily pretreated patients exhibiting virological failure while receiving a salvage raltegravir-containing regimen. All patients were infected by HIV-2 group A. 61.4% of the integrase residues were conserved, including the catalytic motif residues. No INSTI-major resistance mutations were detected in the virus population from naïve patients, but two amino acids that are secondary resistance mutations to INSTIs in HIV-1 were observed. The 10 raltegravir-experienced patients exhibited resistance mutations via three main genetic pathways: N155H, Q148R, and eventually E92Q - T97A. The 155 pathway was preferentially used (7/10 patients). Other mutations associated to raltegravir resistance in HIV-1 were also observed in our HIV-2 population (V151I and D232N), along with several novel mutations previously unreported. Data retrieved from this study should help build a more robust HIV-2-specific algorithm for the genotypic interpretation of raltegravir resistance, and contribute to improve the clinical monitoring of HIV-2-infected patients.

  1. Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication in vitro and provide a rationale to redesign antiretroviral treatment for feline AIDS

    Directory of Open Access Journals (Sweden)

    Ciervo Alessandra

    2007-10-01

    Full Text Available Abstract Background Treatment of feline immunodeficiency virus (FIV infection has been hampered by the absence of a specific combination antiretroviral treatment (ART. Integrase strand transfer inhibitors (INSTIs are emerging as a promising new drug class for HIV-1 treatment, and we evaluated the possibility of inhibiting FIV replication using INSTIs. Methods Phylogenetic analysis of lentiviral integrase (IN sequences was carried out using the PAUP* software. A theoretical three-dimensional structure of the FIV IN catalytic core domain (CCD was obtained by homology modeling based on a crystal structure of HIV-1 IN CCD. The interaction of the transferred strand of viral DNA with the catalytic cavity of FIV IN was deduced from a crystal structure of a structurally similar transposase complexed with transposable DNA. Molecular docking simulations were conducted using a genetic algorithm (GOLD. Antiviral activity was tested in feline lymphoblastoid MBM cells acutely infected with the FIV Petaluma strain. Circular and total proviral DNA was quantified by real-time PCR. Results The calculated INSTI-binding sites were found to be nearly identical in FIV and HIV-1 IN CCDs. The close similarity of primate and feline lentivirus IN CCDs was also supported by phylogenetic analysis. In line with these bioinformatic analyses, FIV replication was efficiently inhibited in acutely infected cell cultures by three investigational INSTIs, designed for HIV-1 and belonging to different classes. Of note, the naphthyridine carboxamide INSTI, L-870,810 displayed an EC50 in the low nanomolar range. Inhibition of FIV integration in situ was shown by real-time PCR experiments that revealed accumulation of circular forms of FIV DNA within cells treated with L-870,810. Conclusion We report a drug class (other than nucleosidic reverse transcriptase inhibitors that is capable of inhibiting FIV replication in vitro. The present study helped establish L-870,810, a compound

  2. Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication in vitro and provide a rationale to redesign antiretroviral treatment for feline AIDS

    Science.gov (United States)

    Savarino, Andrea; Pistello, Mauro; D'Ostilio, Daniela; Zabogli, Elisa; Taglia, Fabiana; Mancini, Fabiola; Ferro, Stefania; Matteucci, Donatella; De Luca, Laura; Barreca, Maria Letizia; Ciervo, Alessandra; Chimirri, Alba; Ciccozzi, Massimo; Bendinelli, Mauro

    2007-01-01

    Background Treatment of feline immunodeficiency virus (FIV) infection has been hampered by the absence of a specific combination antiretroviral treatment (ART). Integrase strand transfer inhibitors (INSTIs) are emerging as a promising new drug class for HIV-1 treatment, and we evaluated the possibility of inhibiting FIV replication using INSTIs. Methods Phylogenetic analysis of lentiviral integrase (IN) sequences was carried out using the PAUP* software. A theoretical three-dimensional structure of the FIV IN catalytic core domain (CCD) was obtained by homology modeling based on a crystal structure of HIV-1 IN CCD. The interaction of the transferred strand of viral DNA with the catalytic cavity of FIV IN was deduced from a crystal structure of a structurally similar transposase complexed with transposable DNA. Molecular docking simulations were conducted using a genetic algorithm (GOLD). Antiviral activity was tested in feline lymphoblastoid MBM cells acutely infected with the FIV Petaluma strain. Circular and total proviral DNA was quantified by real-time PCR. Results The calculated INSTI-binding sites were found to be nearly identical in FIV and HIV-1 IN CCDs. The close similarity of primate and feline lentivirus IN CCDs was also supported by phylogenetic analysis. In line with these bioinformatic analyses, FIV replication was efficiently inhibited in acutely infected cell cultures by three investigational INSTIs, designed for HIV-1 and belonging to different classes. Of note, the naphthyridine carboxamide INSTI, L-870,810 displayed an EC50 in the low nanomolar range. Inhibition of FIV integration in situ was shown by real-time PCR experiments that revealed accumulation of circular forms of FIV DNA within cells treated with L-870,810. Conclusion We report a drug class (other than nucleosidic reverse transcriptase inhibitors) that is capable of inhibiting FIV replication in vitro. The present study helped establish L-870,810, a compound successfully tested in

  3. Impact of hydrodynamic injection and phiC31 integrase on tumor latency in a mouse model of MYC-induced hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Lauren E Woodard

    2010-06-01

    Full Text Available Hydrodynamic injection is an effective method for DNA delivery in mouse liver and is being translated to larger animals for possible clinical use. Similarly, phiC31 integrase has proven effective in mediating long-term gene therapy in mice when delivered by hydrodynamic injection and is being considered for clinical gene therapy applications. However, chromosomal aberrations have been associated with phiC31 integrase expression in tissue culture, leading to questions about safety.To study whether hydrodynamic delivery alone, or in conjunction with delivery of phiC31 integrase for long-term transgene expression, could facilitate tumor formation, we used a transgenic mouse model in which sustained induction of the human C-MYC oncogene in the liver was followed by hydrodynamic injection. Without injection, mice had a median tumor latency of 154 days. With hydrodynamic injection of saline alone, the median tumor latency was significantly reduced, to 105 days. The median tumor latency was similar, 106 days, when a luciferase donor plasmid and backbone plasmid without integrase were administered. In contrast, when active or inactive phiC31 integrase and donor plasmid were supplied to the mouse liver, the median tumor latency was 153 days, similar to mice receiving no injection.Our data suggest that phiC31 integrase does not facilitate tumor formation in this C-MYC transgenic mouse model. However, in groups lacking phiC31 integrase, hydrodynamic injection appeared to contribute to C-MYC-induced hepatocellular carcinoma in adult mice. Although it remains to be seen to what extent these findings may be extrapolated to catheter-mediated hydrodynamic delivery in larger species, they suggest that caution should be used during translation of hydrodynamic injection to clinical applications.

  4. The Microbiota and Abundance of the Class 1 Integron-Integrase Gene in Tropical Sewage Treatment Plant Influent and Activated Sludge.

    Directory of Open Access Journals (Sweden)

    Magna C Paiva

    Full Text Available Bacteria are assumed to efficiently remove organic pollutants from sewage in sewage treatment plants, where antibiotic-resistance genes can move between species via mobile genetic elements known as integrons. Nevertheless, few studies have addressed bacterial diversity and class 1 integron abundance in tropical sewage. Here, we describe the extant microbiota, using V6 tag sequencing, and quantify the class 1 integron-integrase gene (intI1 in raw sewage (RS and activated sludge (AS. The analysis of 1,174,486 quality-filtered reads obtained from RS and AS samples revealed complex and distinct bacterial diversity in these samples. The RS sample, with 3,074 operational taxonomic units, exhibited the highest alpha-diversity indices. Among the 25 phyla, Proteobacteria, Bacteroidetes and Firmicutes represented 85% (AS and 92% (RS of all reads. Increased relative abundance of Micrococcales, Myxococcales, and Sphingobacteriales and reduced pathogen abundance were noted in AS. At the genus level, differences were observed for the dominant genera Simplicispira and Diaphorobacter (AS as well as for Enhydrobacter (RS. The activated sludge process decreased (55% the amount of bacteria harboring the intI1 gene in the RS sample. Altogether, our results emphasize the importance of biological treatment for diminishing pathogenic bacteria and those bearing the intI1 gene that arrive at a sewage treatment plant.

  5. Architecture and Assembly of HIV Integrase Multimers in the Absence of DNA Substrates*

    Science.gov (United States)

    Bojja, Ravi Shankar; Andrake, Mark D.; Merkel, George; Weigand, Steven; Dunbrack, Roland L.; Skalka, Anna Marie

    2013-01-01

    We have applied small angle x-ray scattering and protein cross-linking coupled with mass spectrometry to determine the architectures of full-length HIV integrase (IN) dimers in solution. By blocking interactions that stabilize either a core-core domain interface or N-terminal domain intermolecular contacts, we show that full-length HIV IN can form two dimer types. One is an expected dimer, characterized by interactions between two catalytic core domains. The other dimer is stabilized by interactions of the N-terminal domain of one monomer with the C-terminal domain and catalytic core domain of the second monomer as well as direct interactions between the two C-terminal domains. This organization is similar to the “reaching dimer” previously described for wild type ASV apoIN and resembles the inner, substrate binding dimer in the crystal structure of the PFV intasome. Results from our small angle x-ray scattering and modeling studies indicate that in the absence of its DNA substrate, the HIV IN tetramer assembles as two stacked reaching dimers that are stabilized by core-core interactions. These models of full-length HIV IN provide new insight into multimer assembly and suggest additional approaches for enzyme inhibition. PMID:23322775

  6. Investigating on the fermentation behavior of six lactic acid bacteria strains in barley malt wort reveals limitation in key amino acids and buffer capacity.

    Science.gov (United States)

    Nsogning, Sorelle Dongmo; Fischer, Susann; Becker, Thomas

    2018-08-01

    Understanding lactic acid bacteria (LAB) fermentation behavior in malt wort is a milestone towards flavor improvement of lactic acid fermented malt beverages. Therefore, this study aims to outline deficiencies that may exist in malt wort fermentation. First, based on six LAB strains, cell viability and vitality were evaluated. Second, sugars, organic acids, amino acids, pH value and buffering capacity (BC) were monitored. Finally, the implication of key amino acids, fructose and wort BC on LAB growth was determined. Short growth phase coupled with prompt cell death and a decrease in metabolic activity was observed. Low wort BC caused rapid pH drop with lactic acid accumulation, which conversely increased the BC leading to less pH change at late-stage fermentation. Lactic acid content (≤3.9 g/L) was higher than the reported inhibitory concentration (1.8 g/L). Furthermore, sugars were still available but fructose and key amino acids lysine, arginine and glutamic acid were considerably exhausted (≤98%). Wort supplementations improved cell growth and viability leading to conclude that key amino acid depletion coupled with low BC limits LAB growth in malt wort. Then, a further increase in organic acid reduces LAB viability. This knowledge opens doors for LAB fermentation process optimization in malt wort. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Prediction of the binding mode and resistance profile for a dual-target pyrrolyl diketo acid scaffold against HIV-1 integrase and reverse-transcriptase-associated ribonuclease H.

    Science.gov (United States)

    Yang, Fengyuan; Zheng, Guoxun; Fu, Tingting; Li, Xiaofeng; Tu, Gao; Li, Ying Hong; Yao, Xiaojun; Xue, Weiwei; Zhu, Feng

    2018-06-27

    The rapid emergence of drug-resistant variants is one of the most common causes of highly active antiretroviral therapeutic (HAART) failure in patients infected with HIV-1. Compared with the existing HAART, the recently developed pyrrolyl diketo acid scaffold targeting both HIV-1 integrase (IN) and reverse transcriptase-associated ribonuclease H (RNase H) is an efficient approach to counteract the failure of anti-HIV treatment due to drug resistance. However, the binding mode and potential resistance profile of these inhibitors with important mechanistic principles remain poorly understood. To address this issue, an integrated computational method was employed to investigate the binding mode of inhibitor JMC6F with HIV-1 IN and RNase H. By using per-residue binding free energy decomposition analysis, the following residues: Asp64, Thr66, Leu68, Asp116, Tyr143, Gln148 and Glu152 in IN, Asp443, Glu478, Trp536, Lys541 and Asp549 in RNase H were identified as key residues for JMC6F binding. And then computational alanine scanning was carried to further verify the key residues. Moreover, the resistance profile of the currently known major mutations in HIV-1 IN and 2 mutations in RNase H against JMC6F was predicted by in silico mutagenesis studies. The results demonstrated that only three mutations in HIV-1 IN (Y143C, Q148R and N155H) and two mutations in HIV-1 RNase H (Y501R and Y501W) resulted in a reduction of JMC6F potency, thus indicating their potential role in providing resistance to JMC6F. These data provided important insights into the binding mode and resistance profile of the inhibitors with a pyrrolyl diketo acid scaffold in HIV-1 IN and RNase H, which would be helpful for the development of more effective dual HIV-1 IN and RNase H inhibitors.

  8. HIV-1 integrase inhibitors are substrates for the multidrug transporter MDR1-P-glycoprotein

    Directory of Open Access Journals (Sweden)

    Cara Andrea

    2007-03-01

    Full Text Available Abstract Background The discovery of diketoacid-containing derivatives as inhibitors of HIV-1 Integrase (IN (IN inhibitors, IINs has played a major role in validating this enzyme as an important target for antiretroviral therapy. Since the in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether the IINs are recognized by the multidrug transporter MDR1-P-glycoprotein (P-gp thereby reducing their intracellular accumulation. To address the effect of IINs on drug transport, nine quinolonyl diketo acid (DKA derivatives active on the HIV-1 IN strand transfer (ST step and with EC50 ranging from 1.83 to >50 μm in cell-based assays were tested for their in vitro interaction with P-gp in the CEM-MDR cell system. IINs were investigated for the inhibition and induction of the P-gp function and expression as well as for multidrug resistance (MDR reversing ability. Results The HIV-1 IINs act as genuine P-gp substrates by inhibiting doxorubicin efflux and inducing P-gp functional conformation changes as evaluated by the modulation of UIC2 mAb epitope. Further, IINs chemosensitize MDR cells to vinblastine and induce P-gp expression in drug sensitive revertants of CEM-MDR cells. Conclusion To our knowledge, this is the first demonstration that HIV-1 IINs are P-gp substrates. This biological property may influence the absorption, distribution and elimination of these novels anti HIV-1 compounds.

  9. Mechanism of inhibition of HIV-1 integrase by G-tetrad-forming oligonucleotides in Vitro.

    Science.gov (United States)

    Jing, N; Marchand, C; Liu, J; Mitra, R; Hogan, M E; Pommier, Y

    2000-07-14

    The G-tetrad-forming oligonucleotides and have been identified as potent inhibitors of human immunodeficiency virus type 1 integrase (HIV-1 IN) activity (Rando, R. F., Ojwang, J., Elbaggari, A., Reyes, G. R., Tinder, R., McGrath, M. S., and Hogan, M. E. (1995) J. Biol. Chem. 270, 1754-1760; Mazumder, A., Neamati, N., Ojwang, J. O., Sunder, S., Rando, R. F., and Pommier, Y. (1996) Biochemistry 35, 13762-13771; Jing, N., and Hogan, M. E. (1998) J. Biol. Chem. 273, 34992-34999). To understand the inhibition of HIV-1 IN activity by the G-quartet inhibitors, we have designed the oligonucleotides and, composed of three and four G-quartets with stem lengths of 19 and 24 A, respectively. The fact that increasing the G-quartet stem length from 15 to 24 A kept inhibition of HIV-1 IN activity unchanged suggests that the binding interaction occurs between a GTGT loop domain of the G-quartet inhibitors and a catalytic site of HIV-1 IN, referred to as a face-to-face interaction. Docking the NMR structure of (Jing and Hogan (1998)) into the x-ray structure of the core domain of HIV-1 IN, HIV-1 IN-(51-209) (Maignan, S., Guilloteau, J.-P. , Qing, Z.-L., Clement-Mella, C., and Mikol, V. (1998) J. Mol. Biol. 282, 359-368), was performed using the GRAMM program. The statistical distributions of hydrogen bonding between HIV-1 IN and were obtained from the analyses of 1000 random docking structures. The docking results show a high probability of interaction between the GTGT loop residues of the G-quartet inhibitors and the catalytic site of HIV-1 IN, in agreement with the experimental observation.

  10. BF integrase genes of HIV-1 circulating in São Paulo, Brazil, with a recurrent recombination region.

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    Atila Iamarino

    Full Text Available Although some studies have shown diversity in HIV integrase (IN genes, none has focused particularly on the gene evolving in epidemics in the context of recombination. The IN gene in 157 HIV-1 integrase inhibitor-naïve patients from the São Paulo State, Brazil, were sequenced tallying 128 of subtype B (23 of which were found in non-B genomes, 17 of subtype F (8 of which were found in recombinant genomes, 11 integrases were BF recombinants, and 1 from subtype C. Crucially, we found that 4 BF recombinant viruses shared a recurrent recombination breakpoint region between positions 4900 and 4924 (relative to the HXB2 that includes 2 gRNA loops, where the RT may stutter. Since these recombinants had independent phylogenetic origin, we argue that these results suggest a possible recombination hotspot not observed so far in BF CRF in particular, or in any other HIV-1 CRF in general. Additionally, 40% of the drug-naïve and 45% of the drug-treated patients had at least 1 raltegravir (RAL or elvitegravir (EVG resistance-associated amino acid change, but no major resistance mutations were found, in line with other studies. Importantly, V151I was the most common minor resistance mutation among B, F, and BF IN genes. Most codon sites of the IN genes had higher rates of synonymous substitutions (dS indicative of a strong negative selection. Nevertheless, several codon sites mainly in the subtype B were found under positive selection. Consequently, we observed a higher genetic diversity in the B portions of the mosaics, possibly due to the more recent introduction of subtype F on top of an ongoing subtype B epidemics and a fast spread of subtype F alleles among the B population.

  11. The origins of enhanced activity in factor VIIa analogs and the interplay between key allosteric sites revealed by hydrogen exchange mass spectrometry

    DEFF Research Database (Denmark)

    Rand, Kasper D; Andersen, Mette D; Olsen, Ole H

    2008-01-01

    Factor VIIa (FVIIa) circulates in the blood in a zymogen-like state. Only upon association with membrane-bound tissue factor (TF) at the site of vascular injury does FVIIa become active and able to initiate blood coagulation. Here we used hydrogen exchange monitored by mass spectrometry to invest......Factor VIIa (FVIIa) circulates in the blood in a zymogen-like state. Only upon association with membrane-bound tissue factor (TF) at the site of vascular injury does FVIIa become active and able to initiate blood coagulation. Here we used hydrogen exchange monitored by mass spectrometry...... to investigate the conformational effects of site-directed mutagenesis at key positions in FVIIa and the origins of enhanced intrinsic activity of FVIIa analogs. The differences in hydrogen exchange of two highly active variants, FVIIa(DVQ) and FVIIa(VEAY), imply that enhanced catalytic efficiency was attained...

  12. High-throughput sequencing reveals key genes and immune homeostatic pathways activated in myeloid dendritic cells by Porphyromonas gingivalis 381 and its fimbrial mutants.

    Science.gov (United States)

    Arjunan, P; El-Awady, A; Dannebaum, R O; Kunde-Ramamoorthy, G; Cutler, C W

    2016-02-01

    The human microbiome consists of highly diverse microbial communities that colonize our skin and mucosal surfaces, aiding in maintenance of immune homeostasis. The keystone pathogen Porphyromonas gingivalis induces a dysbiosis and disrupts immune homeostasis through as yet unclear mechanisms. The fimbrial adhesins of P. gingivalis facilitate biofilm formation, invasion of and dissemination by blood dendritic cells; hence, fimbriae may be key factors in disruption of immune homeostasis. In this study we employed RNA-sequencing transcriptome profiling to identify differentially expressed genes (DEGs) in human monocyte-derived dendritic cells (MoDCs) in response to in vitro infection/exposure by Pg381 or its isogenic mutant strains that solely express minor-Mfa1 fimbriae (DPG3), major-FimA fimbriae (MFI) or are deficient in both fimbriae (MFB) relative to uninfected control. Our results yielded a total of 479 DEGs that were at least two-fold upregulated and downregulated in MoDCs significantly (P ≤ 0.05) by all four strains and certain DEGs that were strain-specific. Interestingly, the gene ontology biological and functional analysis shows that the upregulated genes in DPG3-induced MoDCs were more significant than other strains and associated with inflammation, immune response, anti-apoptosis, cell proliferation, and other homeostatic functions. Both transcriptome and quantitative polymerase chain reaction results show that DPG3, which solely expresses Mfa1, increased ZNF366, CD209, LOX1, IDO1, IL-10, CCL2, SOCS3, STAT3 and FOXO1 gene expression. In conclusion, we have identified key DC-mediated immune homeostatic pathways that could contribute to dysbiosis in periodontal infection with P. gingivalis. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Docking studies on a new human immunodeficiency virus integrase-Mg-DNA complex: phenyl ring exploration and synthesis of 1H-benzylindole derivatives through fluorine substitutions.

    Science.gov (United States)

    Ferro, Stefania; De Luca, Laura; Barreca, Maria Letizia; Iraci, Nunzio; De Grazia, Sara; Christ, Frauke; Witvrouw, Myriam; Debyser, Zeger; Chimirri, Alba

    2009-01-22

    A new model of HIV-1 integrase-Mg-DNA complex that is useful for docking experiments has been built. It was used to study the binding mode of integrase strand transfer inhibitor 1 (CHI-1043) and other fluorine analogues. Molecular modeling results prompted us to synthesize the designed derivatives which showed potent enzymatic inhibition at nanomolar concentration, high antiviral activity, and low toxicity. Microwave assisted organic synthesis (MAOS) was employed in several steps of the synthetic pathway, thus reducing reaction times and improving yields.

  14. A molecular mechanism for the origin of a key evolutionary innovation, the bird beak and palate, revealed by an integrative approach to major transitions in vertebrate history.

    Science.gov (United States)

    Bhullar, Bhart-Anjan S; Morris, Zachary S; Sefton, Elizabeth M; Tok, Atalay; Tokita, Masayoshi; Namkoong, Bumjin; Camacho, Jasmin; Burnham, David A; Abzhanov, Arhat

    2015-07-01

    The avian beak is a key evolutionary innovation whose flexibility has permitted birds to diversify into a range of disparate ecological niches. We approached the problem of the mechanism behind this innovation using an approach bridging paleontology, comparative anatomy, and experimental developmental biology. First, we used fossil and extant data to show the beak is distinctive in consisting of fused premaxillae that are geometrically distinct from those of ancestral archosaurs. To elucidate underlying developmental mechanisms, we examined candidate gene expression domains in the embryonic face: the earlier frontonasal ectodermal zone (FEZ) and the later midfacial WNT-responsive region, in birds and several reptiles. This permitted the identification of an autapomorphic median gene expression region in Aves. To test the mechanism, we used inhibitors of both pathways to replicate in chicken the ancestral amniote expression. Altering the FEZ altered later WNT responsiveness to the ancestral pattern. Skeletal phenotypes from both types of experiments had premaxillae that clustered geometrically with ancestral fossil forms instead of beaked birds. The palatal region was also altered to a more ancestral phenotype. This is consistent with the fossil record and with the tight functional association of avian premaxillae and palate in forming a kinetic beak. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

  15. In Vivo Loss of Function Screening Reveals Carbonic Anhydrase IX as a Key Modulator of Tumor Initiating Potential in Primary Pancreatic Tumors

    Directory of Open Access Journals (Sweden)

    Nabendu Pore

    2015-06-01

    Full Text Available Reprogramming of energy metabolism is one of the emerging hallmarks of cancer. Up-regulation of energy metabolism pathways fuels cell growth and division, a key characteristic of neoplastic disease, and can lead to dependency on specific metabolic pathways. Thus, targeting energy metabolism pathways might offer the opportunity for novel therapeutics. Here, we describe the application of a novel in vivo screening approach for the identification of genes involved in cancer metabolism using a patient-derived pancreatic xenograft model. Lentiviruses expressing short hairpin RNAs (shRNAs targeting 12 different cell surface protein transporters were separately transduced into the primary pancreatic tumor cells. Transduced cells were pooled and implanted into mice. Tumors were harvested at different times, and the frequency of each shRNA was determined as a measure of which ones prevented tumor growth. Several targets including carbonic anhydrase IX (CAIX, monocarboxylate transporter 4, and anionic amino acid transporter light chain, xc- system (xCT were identified in these studies and shown to be required for tumor initiation and growth. Interestingly, CAIX was overexpressed in the tumor initiating cell population. CAIX expression alone correlated with a highly tumorigenic subpopulation of cells. Furthermore, CAIX expression was essential for tumor initiation because shRNA knockdown eliminated the ability of cells to grow in vivo. To the best of our knowledge, this is the first parallel in vivo assessment of multiple novel oncology target genes using a patient-derived pancreatic tumor model.

  16. In Situ Analysis of Metabolic Characteristics Reveals the Key Yeast in the Spontaneous and Solid-State Fermentation Process of Chinese Light-Style Liquor

    Science.gov (United States)

    Kong, Yu; Wu, Qun; Zhang, Yan

    2014-01-01

    The in situ metabolic characteristics of the yeasts involved in spontaneous fermentation process of Chinese light-style liquor are poorly understood. The covariation between metabolic profiles and yeast communities in Chinese light-style liquor was modeled using the partial least square (PLS) regression method. The diversity of yeast species was evaluated by sequence analysis of the 26S ribosomal DNA (rDNA) D1/D2 domains of cultivable yeasts, and the volatile compounds in fermented grains were analyzed by gas chromatography (GC)-mass spectrometry (MS). Eight yeast species and 58 volatile compounds were identified, respectively. The modulation of 16 of these volatile compounds was associated with variations in the yeast population (goodness of prediction [Q2] > 20%). The results showed that Pichia anomala was responsible for the characteristic aroma of Chinese liquor, through the regulation of several important volatile compounds, such as ethyl lactate, octanoic acid, and ethyl tetradecanoate. Correspondingly, almost all of the compounds associated with P. anomala were detected in a pure culture of this yeast. In contrast to the PLS regression results, however, ethyl lactate and ethyl isobutyrate were not detected in the same pure culture, which indicated that some metabolites could be generated by P. anomala only when it existed in a community with other yeast species. Furthermore, different yeast communities provided different volatile patterns in the fermented grains, which resulted in distinct flavor profiles in the resulting liquors. This study could help identify the key yeast species involved in spontaneous fermentation and provide a deeper understanding of the role of individual yeast species in the community. PMID:24727269

  17. Proteomic analyses reveal the key roles of BrlA and AbaA in biogenesis of gliotoxin in Aspergillus fumigatus.

    Science.gov (United States)

    Shin, Kwang-Soo; Kim, Young Hwan; Yu, Jae-Hyuk

    2015-07-31

    The opportunistic human pathogenic fungus Aspergillus fumigatus primarily reproduces by forming a large number of asexual spores (conidia). Sequential activation of the central regulators BrlA, AbaA and WetA is necessary for the fungus to undergo asexual development. In this study, to address the presumed roles of these key developmental regulators during proliferation of the fungus, we analyzed and compared the proteomes of vegetative cells of wild type (WT) and individual mutant strains. Approximately 1300 protein spots were detectable from 2-D electrophoresis gels. Among these, 13 proteins exhibiting significantly altered accumulation levels were further identified by ESI-MS/MS. Markedly, we found that the GliM and GliT proteins associated with gliotoxin (GT) biosynthesis and self-protection of the fungus from GT were significantly down-regulated in the ΔabaA and ΔbrlA mutants. Moreover, mRNA levels of other GT biosynthetic genes including gliM, gliP, gliT, and gliZ were significantly reduced in both mutant strains, and no and low levels of GT were detectable in the ΔbrlA and ΔabaA mutant strains, respectively. As GliT is required for the protection of the fungus from GT, growth of the ΔbrlA mutant with reduced levels of GliT was severely impaired by exogenous GT. Our studies demonstrate that AbaA and BrlA positively regulate expression of the GT biosynthetic gene cluster in actively growing vegetative cells, and likely bridge morphological and chemical development during the life-cycle of A. fumigatus. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Comprehensive analysis of miRNAs expression profiles revealed potential key miRNA/mRNAs regulating colorectal cancer stem cell self-renewal.

    Science.gov (United States)

    Xu, Peng; Wang, Junhua; Sun, Bo; Xiao, Zhongdang

    2018-05-20

    Self-renewal is essential for the malignant biological behaviors of colorectal cancer stem cells. While the self-renewal molecular mechanisms of colorectal cancer stem cells are not yet fully understood. Recently, miRNAs are reported to be relevant to the self-renewal ability of cancer stem cells. In this study, we first isolated colorectal cancer stem cell from colorectal cancer cell line HCT-116 by 1% low serum culture. Then we conducted a comprehensive analysis based on the miRNAs profiles data of both colorectal cancer stem cells and normal cultured colorectal cancer cells. Pathway analysis revealed multiple pathways including Jak-STAT, TGF-beta, PI3K-Akt and MAPK signaling pathway that are correlated to colorectal cancer. Further, we constructed a miRNA-mRNA network, based on which, several miRNA/mRNA pairs were ranked according to their impact index to the self-renewal of colorectal cancer stem cells. Further biological experiment showed that up-regulation of miR-92a-3p led to cell cycle arrest and reduced colony formation. This work provides clues to find the new potential biomarkers for colorectal cancer stem cell diagnosis and select effective miRNAs for targeted therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

  19. Plasmid integration in a wide range of bacteria mediated by the integrase of Lactobacillus delbrueckii bacteriophage mv4.

    Science.gov (United States)

    Auvray, F; Coddeville, M; Ritzenthaler, P; Dupont, L

    1997-01-01

    Bacteriophage mv4 is a temperate phage infecting Lactobacillus delbrueckii subsp. bulgaricus. During lysogenization, the phage integrates its genome into the host chromosome at the 3' end of a tRNA(Ser) gene through a site-specific recombination process (L. Dupont et al., J. Bacteriol., 177:586-595, 1995). A nonreplicative vector (pMC1) based on the mv4 integrative elements (attP site and integrase-coding int gene) is able to integrate into the chromosome of a wide range of bacterial hosts, including Lactobacillus plantarum, Lactobacillus casei (two strains), Lactococcus lactis subsp. cremoris, Enterococcus faecalis, and Streptococcus pneumoniae. Integrative recombination of pMC1 into the chromosomes of all of these species is dependent on the int gene product and occurs specifically at the pMC1 attP site. The isolation and sequencing of pMC1 integration sites from these bacteria showed that in lactobacilli, pMC1 integrated into the conserved tRNA(Ser) gene. In the other bacterial species where this tRNA gene is less or not conserved; secondary integration sites either in potential protein-coding regions or in intergenic DNA were used. A consensus sequence was deduced from the analysis of the different integration sites. The comparison of these sequences demonstrated the flexibility of the integrase for the bacterial integration site and suggested the importance of the trinucleotide CCT at the 5' end of the core in the strand exchange reaction. PMID:9068626

  20. Site-Directed Mutagenesis Study Revealed Three Important Residues in Hc-DAF-22, a Key Enzyme Regulating Diapause of Haemonchus contortus

    Directory of Open Access Journals (Sweden)

    Yan Huang

    2017-11-01

    Full Text Available Haemonchus contortus (H. contortus is one of the most important parasites of small ruminants, especially goats and sheep. The complex life cycle of this nematode is a main obstacle for the control and prevention of haemonchosis. So far, a special form of arrested development called diapause different from the dauer stage in Caenorhabditis elegans (C. elegans has been found in many parasitic nematodes. In our previous study, we have characterized a novel gene Hc-daf-22 from H. contortus sharing high homology with Ce-daf-22 and functional analysis showed this gene has similar biological function with Ce-daf-22. In this study, Hc-daf-22 mutants were constructed using site-directed mutagenesis, and carried out rescue experiments, RNA interference (RNAi experiments and in vitro enzyme activity analysis with the mutants to further explore the precise function site of Hc-DAF-22. The results showed that Hc-daf-22 mutants could be expressed in the rescued ok693 worms and the expression positions were mainly in the intestine which was identical with that of Hc-daf-22 rescued worms. Through lipid staining we found that Hc-daf-22 could rescue daf-22 mutant (ok693 from the fatty acid metabolism deficiency while Hc-daf-22 mutants failed. Brood size and body length analyses in rescue experiment along with body length and life span analyses in RNAi experiment elucidated that Hc-daf-22 resembled Ce-daf-22 in effecting the development and capacity of C. elegans and mutants impaired the function of Hc-daf-22. Together with the protease activity assay, this research revealed three important active resides 84C/299H/349H in Hc-DAF-22 by site-directed mutagenesis.

  1. RNA-Seq reveals dynamic changes of gene expression in key stages of intestine regeneration in the sea cucumber Apostichopus japonicus. [corrected].

    Directory of Open Access Journals (Sweden)

    Lina Sun

    Full Text Available BACKGROUND: Sea cucumbers (Holothuroidea; Echinodermata have the capacity to regenerate lost tissues and organs. Although the histological and cytological aspects of intestine regeneration have been extensively studied, little is known of the genetic mechanisms involved. There has, however, been a renewed effort to develop a database of Expressed Sequence Tags (ESTs in Apostichopus japonicus, an economically-important species that occurs in China. This is important for studies on genetic breeding, molecular markers and special physiological phenomena. We have also constructed a library of ESTs obtained from the regenerative body wall and intestine of A. japonicus. The database has increased to ~30000 ESTs. RESULTS: We used RNA-Seq to determine gene expression profiles associated with intestinal regeneration in A. japonicus at 3, 7, 14 and 21 days post evisceration (dpe. This was compared to profiles obtained from a normally-functioning intestine. Approximately 5 million (M reads were sequenced in every library. Over 2400 up-regulated genes (>10% and over 1000 down-regulated genes (~5% were observed at 3 and 7dpe (log2Ratio ≥ 1, FDR ≤ 0.001. Specific "Go terms" revealed that the DEGs (Differentially Expressed Genes performed an important function at every regeneration stage. Besides some expected pathways (for example, Ribosome and Spliceosome pathway term, the "Notch signaling pathway," the "ECM-receptor interaction" and the "Cytokine-cytokine receptor interaction" were significantly enriched. We also investigated the expression profiles of developmental genes, ECM-associated genes and Cytoskeletal genes. Twenty of the most important differentially expressed genes (DEGs were verified by Real-time PCR, which resulted in a trend concordance of almost 100% between the two techniques. CONCLUSION: Our studies demonstrated dynamic changes in global gene expression during intestine regeneration and presented a series of candidate genes and enriched

  2. Transcriptomic studies reveal a key metabolic pathway contributing to a well-maintained photosynthetic system under drought stress in foxtail millet (Setaria italica L.

    Directory of Open Access Journals (Sweden)

    Weiping Shi

    2018-05-01

    Full Text Available Drought stress is one of the most important abiotic factors limiting crop productivity. A better understanding of the effects of drought on millet (Setaria italica L. production, a model crop for studying drought tolerance, and the underlying molecular mechanisms responsible for drought stress responses is vital to improvement of agricultural production. In this study, we exposed the drought resistant F1 hybrid, M79, and its parental lines E1 and H1 to drought stress. Subsequent physiological analysis demonstrated that M79 showed higher photosynthetic energy conversion efficiency and drought tolerance than its parents. A transcriptomic study using leaves collected six days after drought treatment, when the soil water content was about ∼20%, identified 3066, 1895, and 2148 differentially expressed genes (DEGs in M79, E1 and H1 compared to the respective untreated controls, respectively. Further analysis revealed 17 Gene Ontology (GO enrichments and 14 Kyoto Encyclopedia of Genes and Genomes (KEGG pathways in M79, including photosystem II (PSII oxygen-evolving complex, peroxidase (POD activity, plant hormone signal transduction, and chlorophyll biosynthesis. Co-regulation analysis suggested that these DEGs in M79 contributed to the formation of a regulatory network involving multiple biological processes and pathways including photosynthesis, signal transduction, transcriptional regulation, redox regulation, hormonal signaling, and osmotic regulation. RNA-seq analysis also showed that some photosynthesis-related DEGs were highly expressed in M79 compared to its parental lines under drought stress. These results indicate that various molecular pathways, including photosynthesis, respond to drought stress in M79, and provide abundant molecular information for further analysis of the underlying mechanism responding to this stress.

  3. Transcriptomic studies reveal a key metabolic pathway contributing to a well-maintained photosynthetic system under drought stress in foxtail millet (Setaria italica L.).

    Science.gov (United States)

    Shi, Weiping; Cheng, Jingye; Wen, Xiaojie; Wang, Jixiang; Shi, Guanyan; Yao, Jiayan; Hou, Liyuan; Sun, Qian; Xiang, Peng; Yuan, Xiangyang; Dong, Shuqi; Guo, Pingyi; Guo, Jie

    2018-01-01

    Drought stress is one of the most important abiotic factors limiting crop productivity. A better understanding of the effects of drought on millet ( Setaria italica L.) production, a model crop for studying drought tolerance, and the underlying molecular mechanisms responsible for drought stress responses is vital to improvement of agricultural production. In this study, we exposed the drought resistant F 1 hybrid, M79, and its parental lines E1 and H1 to drought stress. Subsequent physiological analysis demonstrated that M79 showed higher photosynthetic energy conversion efficiency and drought tolerance than its parents. A transcriptomic study using leaves collected six days after drought treatment, when the soil water content was about ∼20%, identified 3066, 1895, and 2148 differentially expressed genes (DEGs) in M79, E1 and H1 compared to the respective untreated controls, respectively. Further analysis revealed 17 Gene Ontology (GO) enrichments and 14 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in M79, including photosystem II (PSII) oxygen-evolving complex, peroxidase (POD) activity, plant hormone signal transduction, and chlorophyll biosynthesis. Co-regulation analysis suggested that these DEGs in M79 contributed to the formation of a regulatory network involving multiple biological processes and pathways including photosynthesis, signal transduction, transcriptional regulation, redox regulation, hormonal signaling, and osmotic regulation. RNA-seq analysis also showed that some photosynthesis-related DEGs were highly expressed in M79 compared to its parental lines under drought stress. These results indicate that various molecular pathways, including photosynthesis, respond to drought stress in M79, and provide abundant molecular information for further analysis of the underlying mechanism responding to this stress.

  4. Site-Directed Mutagenesis Study Revealed Three Important Residues in Hc-DAF-22, a Key Enzyme Regulating Diapause of Haemonchus contortus.

    Science.gov (United States)

    Huang, Yan; Zheng, Xiuping; Zhang, Hongli; Ding, Haojie; Guo, Xiaolu; Yang, Yi; Chen, Xueqiu; Zhou, Qianjin; Du, Aifang

    2017-01-01

    Haemonchus contortus ( H. contortus ) is one of the most important parasites of small ruminants, especially goats and sheep. The complex life cycle of this nematode is a main obstacle for the control and prevention of haemonchosis. So far, a special form of arrested development called diapause different from the dauer stage in Caenorhabditis elegans ( C. elegans ) has been found in many parasitic nematodes. In our previous study, we have characterized a novel gene Hc-daf-22 from H. contortus sharing high homology with Ce-daf-22 and functional analysis showed this gene has similar biological function with Ce-daf-22 . In this study, Hc-daf-22 mutants were constructed using site-directed mutagenesis, and carried out rescue experiments, RNA interference (RNAi) experiments and in vitro enzyme activity analysis with the mutants to further explore the precise function site of Hc-DAF-22. The results showed that Hc-daf-22 mutants could be expressed in the rescued ok693 worms and the expression positions were mainly in the intestine which was identical with that of Hc-daf-22 rescued worms. Through lipid staining we found that Hc-daf-22 could rescue daf-22 mutant ( ok693 ) from the fatty acid metabolism deficiency while Hc-daf-22 mutants failed. Brood size and body length analyses in rescue experiment along with body length and life span analyses in RNAi experiment elucidated that Hc-daf-22 resembled Ce-daf-22 in effecting the development and capacity of C. elegans and mutants impaired the function of Hc-daf-22 . Together with the protease activity assay, this research revealed three important active resides 84C/299H/349H in Hc-DAF-22 by site-directed mutagenesis.

  5. Integrase inhibitors in late pregnancy and rapid HIV viral load reduction.

    Science.gov (United States)

    Rahangdale, Lisa; Cates, Jordan; Potter, JoNell; Badell, Martina L; Seidman, Dominika; Miller, Emilly S; Coleman, Jenell S; Lazenby, Gweneth B; Levison, Judy; Short, William R; Yawetz, Sigal; Ciaranello, Andrea; Livingston, Elizabeth; Duthely, Lunthita; Rimawi, Bassam H; Anderson, Jean R; Stringer, Elizabeth M

    2016-03-01

    Minimizing time to HIV viral suppression is critical in pregnancy. Integrase strand transfer inhibitors (INSTIs), like raltegravir, are known to rapidly suppress plasma HIV RNA in nonpregnant adults. There are limited data in pregnant women. We describe time to clinically relevant reduction in HIV RNA in pregnant women using INSTI-containing and non-INSTI-containing antiretroviral therapy (ART) options. We conducted a retrospective cohort study of pregnant HIV-infected women in the United States from 2009 through 2015. We included women who initiated ART, intensified their regimen, or switched to a new regimen due to detectable viremia (HIV RNA >40 copies/mL) at ≥20 weeks gestation. Among women with a baseline HIV RNA permitting 1-log reduction, we estimated time to 1-log RNA reduction using the Kaplan-Meier estimator comparing women starting/adding an INSTI in their regimen vs other ART. To compare groups with similar follow-up time, we also conducted a subgroup analysis limited to women with ≤14 days between baseline and follow-up RNA data. This study describes 101 HIV-infected pregnant women from 11 US clinics. In all, 75% (76/101) of women were not taking ART at baseline; 24 were taking non-INSTI containing ART, and 1 received zidovudine monotherapy. In all, 39% (39/101) of women started an INSTI-containing regimen or added an INSTI to their ART regimen. Among 90 women with a baseline HIV RNA permitting 1-log reduction, the median time to 1-log RNA reduction was 8 days (interquartile range [IQR], 7-14) in the INSTI group vs 35 days (IQR, 20-53) in the non-INSTI ART group (P pregnancy. Inclusion of an INSTI may play a role in optimal reduction of HIV RNA for HIV-infected pregnant women presenting late to care or failing initial therapy. Larger studies are urgently needed to assess the safety and effectiveness of this approach. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. In vivo approaches reveal a key role for DCs in CD4+ T cell activation and parasite clearance during the acute phase of experimental blood-stage malaria.

    Directory of Open Access Journals (Sweden)

    Henrique Borges da Silva

    2015-02-01

    Full Text Available Dendritic cells (DCs are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip, with Plasmodium chabaudi AS (Pc parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection.

  7. In vivo approaches reveal a key role for DCs in CD4+ T cell activation and parasite clearance during the acute phase of experimental blood-stage malaria.

    Science.gov (United States)

    Borges da Silva, Henrique; Fonseca, Raíssa; Cassado, Alexandra Dos Anjos; Machado de Salles, Érika; de Menezes, Maria Nogueira; Langhorne, Jean; Perez, Katia Regina; Cuccovia, Iolanda Midea; Ryffel, Bernhard; Barreto, Vasco M; Marinho, Cláudio Romero Farias; Boscardin, Silvia Beatriz; Álvarez, José Maria; D'Império-Lima, Maria Regina; Tadokoro, Carlos Eduardo

    2015-02-01

    Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin)-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip), with Plasmodium chabaudi AS (Pc) parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs) by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection.

  8. A quantitative structure–activity relationship study on HIV-1 integrase inhibitors using genetic algorithm, artificial neural networks and different statistical methods

    Directory of Open Access Journals (Sweden)

    Ghasem Ghasemi

    2016-09-01

    Full Text Available In this work, quantitative structure–activity relationship (QSAR study has been done on tricyclic phthalimide analogues acting as HIV-1 integrase inhibitors. Forty compounds were used in this study. Genetic algorithm (GA, artificial neural network (ANN and multiple linear regressions (MLR were utilized to construct the non-linear and linear QSAR models. It revealed that the GA–ANN model was much better than other models. For this purpose, ab initio geometry optimization performed at B3LYP level with a known basis set 6–31G (d. Hyperchem, ChemOffice and Gaussian 98W softwares were used for geometry optimization of the molecules and calculation of the quantum chemical descriptors. To include some of the correlation energy, the calculation was done with the density functional theory (DFT with the same basis set and Becke’s three parameter hybrid functional using the LYP correlation functional (B3LYP/6–31G (d. For the calculations in solution phase, the polarized continuum model (PCM was used and also included optimizations at gas-phase B3LYP/6–31G (d level for comparison. In the aqueous phase, the root–mean–square errors of the training set and the test set for GA–ANN model using jack–knife method, were 0.1409, 0.1804, respectively. In the gas phase, the root–mean–square errors of the training set and the test set for GA–ANN model were 0.1408, 0.3103, respectively. Also, the R2 values in the aqueous and the gas phase were obtained as 0.91, 0.82, respectively.

  9. Removal of bacterial cells, antibiotic resistance genes and integrase genes by on-site hospital wastewater treatment plants: surveillance of treated hospital effluent quality

    KAUST Repository

    Timraz, Kenda Hussain Hassan; Xiong, Yanghui; Al Qarni, Hamed; Hong, Pei-Ying

    2016-01-01

    This study aims to evaluate the removal efficiency of microbial contaminants, including total cell counts, antibiotic-resistant bacteria (ARB), antibiotic resistance genes (ARGs, e.g. tetO, tetZ, sul1 and sul2) and integrase genes (e.g. intl1

  10. The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity

    NARCIS (Netherlands)

    Amadori, Céline; Ubeles van der Velden, Yme; Bonnard, Damien; Orlov, Igor; van Bel, Nikki; Le Rouzic, Erwann; Miralles, Laia; Brias, Julie; Chevreuil, Francis; Spehner, Daniele; Chasset, Sophie; Ledoussal, Benoit; Mayr, Luzia; Moreau, François; García, Felipe; Gatell, José; Zamborlini, Alessia; Emiliani, Stéphane; Ruff, Marc; Klaholz, Bruno P.; Moog, Christiane; Berkhout, Ben; Plana, Montserrat; Benarous, Richard

    2017-01-01

    HIV-1 Integrase (IN) interacts with the cellular co-factor LEDGF/p75 and tethers the HIV preintegration complex to the host genome enabling integration. Recently a new class of IN inhibitors was described, the IN-LEDGF allosteric inhibitors (INLAIs). Designed to interfere with the IN-LEDGF

  11. Next-generation site-directed transgenesis in the malaria vector mosquito Anopheles gambiae: self-docking strains expressing germline-specific phiC31 integrase.

    Directory of Open Access Journals (Sweden)

    Janet M Meredith

    Full Text Available Diseases transmitted by mosquitoes have a devastating impact on global health and the situation is complicated due to difficulties with both existing control measures and the impact of climate change. Genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the delivery of novel control strategies. The Streptomyces phage phiC31 integrase system has been successfully adapted for site-directed transgene integration in a range of insects, thus overcoming many limitations due to size constraints and random integration associated with transposon-mediated transformation. Using this technology, we previously published the first site-directed transformation of Anopheles gambiae, the principal vector of human malaria. Mosquitoes were initially engineered to incorporate the phiC31 docking site at a defined genomic location. A second phase of genetic modification then achieved site-directed integration of an anti-malarial effector gene. In the current publication we report improved efficiency and utility of the phiC31 integrase system following the generation of Anopheles gambiae self-docking strains. Four independent strains, with docking sites at known locations on three different chromosome arms, were engineered to express integrase under control of the regulatory regions of the nanos gene from Anopheles gambiae. The resulting protein accumulates in the posterior oocyte to provide integrase activity at the site of germline development. Two self-docking strains, exhibiting significantly different levels of integrase expression, were assessed for site-directed transgene integration and found to demonstrate greatly improved survival and efficiency of transformation. In the fight against malaria, it is imperative to establish a broad repertoire of both anti-malarial effector genes and tissue-specific promoters to regulate their expression, enabling those offering maximum effect with minimum fitness

  12. Design and Synthesis of Bis-amide and Hydrazide-containing Derivatives of Malonic Acid as Potential HIV-1 Integrase Inhibitors

    Directory of Open Access Journals (Sweden)

    Nouri Neamati

    2008-10-01

    Full Text Available HIV-1 integrase (IN is an attractive and validated target for the development of novel therapeutics against AIDS. In the search for new IN inhibitors, we designed and synthesized three series of bis-amide and hydrazide-containing derivatives of malonic acid. We performed a docking study to investigate the potential interactions of the title compounds with essential amino acids on the IN active site.

  13. D77, one benzoic acid derivative, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular LEDGF/p75

    International Nuclear Information System (INIS)

    Du Li; Zhao Yaxue; Chen, Jing; Yang Liumeng; Zheng Yongtang; Tang Yun; Shen Xu; Jiang Hualiang

    2008-01-01

    Integration of viral-DNA into host chromosome mediated by the viral protein HIV-1 integrase (IN) is an essential step in the HIV-1 life cycle. In this process, Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration. Since LEDGF/p75 plays an important role in HIV integration, disruption of the LEDGF/p75 interaction with IN has provided a special interest for anti-HIV agent discovery. In this work, we reported that a benzoic acid derivative, 4-[(5-bromo-4-{[2,4-dioxo-3-(2-oxo-2-phenylethyl) -1,3-thiazolidin-5-ylidene]methyl}-2-ethoxyphenoxy)methyl]benzoic acid (D77) could potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution thus exhibiting antiretroviral activity. Molecular docking with site-directed mutagenesis analysis and surface plasmon resonance (SPR) binding assays has clarified possible binding mode of D77 against HIV-1 integrase. As the firstly discovered small molecular compound targeting HIV-1 integrase interaction with LEDGF/p75, D77 might supply useful structural information for further anti-HIV agent discovery

  14. Metagenomic exploration reveals a marked change in the river resistome and mobilome after treated wastewater discharges.

    Science.gov (United States)

    Lekunberri, Itziar; Balcázar, José Luis; Borrego, Carles M

    2018-03-01

    Mobile genetic elements (MGEs) are key agents in the spread of antibiotic resistance genes (ARGs) across environments. Here we used metagenomics to compare the river resistome (collection of all ARGs) and mobilome (e.g., integrases, transposases, integron integrases and insertion sequence common region "ISCR" elements) between samples collected upstream (n = 6) and downstream (n = 6) of an urban wastewater treatment plant (UWWTP). In comparison to upstream metagenomes, downstream metagenomes showed a drastic increase in the abundance of ARGs, as well as markers of MGEs, particularly integron integrases and ISCR elements. These changes were accompanied by a concomitant prevalence of 16S rRNA gene signatures of bacteria affiliated to families encompassing well-known human and animal pathogens. Our results confirm that chronic discharges of treated wastewater severely impact the river resistome affecting not only the abundance and diversity of ARGs but also their potential spread by enriching the river mobilome in a wide variety of MGEs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Contribution of the C-terminal tri-lysine regions of human immunodeficiency virus type 1 integrase for efficient reverse transcription and viral DNA nuclear import

    Directory of Open Access Journals (Sweden)

    Fowke Keith R

    2005-10-01

    Full Text Available Abstract Background In addition to mediating the integration process, HIV-1 integrase (IN has also been implicated in different steps during viral life cycle including reverse transcription and viral DNA nuclear import. Although the karyophilic property of HIV-1 IN has been well demonstrated using a variety of experimental approaches, the definition of domain(s and/or motif(s within the protein that mediate viral DNA nuclear import and its mechanism are still disputed and controversial. In this study, we performed mutagenic analyses to investigate the contribution of different regions in the C-terminal domain of HIV-1 IN to protein nuclear localization as well as their effects on virus infection. Results Our analysis showed that replacing lysine residues in two highly conserved tri-lysine regions, which are located within previously described Region C (235WKGPAKLLWKGEGAVV and sequence Q (211KELQKQITK in the C-terminal domain of HIV-1 IN, impaired protein nuclear accumulation, while mutations for RK263,4 had no significant effect. Analysis of their effects on viral infection in a VSV-G pseudotyped RT/IN trans-complemented HIV-1 single cycle replication system revealed that all three C-terminal mutant viruses (KK215,9AA, KK240,4AE and RK263,4AA exhibited more severe defect of induction of β-Gal positive cells and luciferase activity than an IN class 1 mutant D64E in HeLa-CD4-CCR5-β-Gal cells, and in dividing as well as non-dividing C8166 T cells, suggesting that some viral defects are occurring prior to viral integration. Furthermore, by analyzing viral DNA synthesis and the nucleus-associated viral DNA level, the results clearly showed that, although all three C-terminal mutants inhibited viral reverse transcription to different extents, the KK240,4AE mutant exhibited most profound effect on this step, whereas KK215,9AA significantly impaired viral DNA nuclear import. In addition, our analysis could not detect viral DNA integration in each C

  16. Integrase-independent HIV-1 infection is augmented under conditions of DNA damage and produces a viral reservoir

    Energy Technology Data Exchange (ETDEWEB)

    Ebina, Hirotaka, E-mail: hebina@virus.kyoto-u.ac.jp; Kanemura, Yuka; Suzuki, Yasutsugu; Urata, Kozue; Misawa, Naoko; Koyanagi, Yoshio

    2012-05-25

    HIV-1 possesses a viral protein, integrase (IN), which is necessary for its efficient integration in target cells. However, it has been reported that an IN-defective HIV strain is still capable of integration. Here, we assessed the ability of wild type (WT) HIV-1 to establish infection in the presence of IN inhibitors. We observed a low, yet clear infection of inhibitor-incubated cells infected with WT HIV which was identical to cells infected with IN-deficient HIV, D64A. Furthermore, the IN-independent integration could be enhanced by the pretreatment of cells with DNA-damaging agents suggesting that integration is mediated by a DNA repair system. Moreover, significantly faster viral replication kinetics with augmented viral DNA integration was observed after infection in irradiated cells treated with IN inhibitor compared to nonirradiated cells. Altogether, our results suggest that HIV DNA has integration potential in the presence of an IN inhibitor and may serve as a virus reservoir.

  17. Adeno-associated virus Rep-mediated targeting of integrase-defective retroviral vector DNA circles into human chromosome 19

    International Nuclear Information System (INIS)

    Huang, Shuohao; Kawabe, Yoshinori; Ito, Akira; Kamihira, Masamichi

    2012-01-01

    Highlights: ► Adeno-associated virus (AAV) is capable of targeted integration in human cells. ► Integrase-defective retroviral vector (IDRV) enables a circular DNA delivery. ► A targeted integration system of IDRV DNA using the AAV integration mechanism. ► Targeted IDRV integration ameliorates the safety concerns for retroviral vectors. -- Abstract: Retroviral vectors have been employed in clinical trials for gene therapy owing to their relative large packaging capacity, alterable cell tropism, and chromosomal integration for stable transgene expression. However, uncontrollable integrations of transgenes are likely to cause safety issues, such as insertional mutagenesis. A targeted transgene integration system for retroviral vectors, therefore, is a straightforward way to address the insertional mutagenesis issue. Adeno-associated virus (AAV) is the only known virus capable of targeted integration in human cells. In the presence of AAV Rep proteins, plasmids possessing the p5 integration efficiency element (p5IEE) can be integrated into the AAV integration site (AAVS1) in the human genome. In this report, we describe a system that can target the circular DNA derived from non-integrating retroviral vectors to the AAVS1 site by utilizing the Rep/p5IEE integration mechanism. Our results showed that after G418 selection 30% of collected clones had retroviral DNA targeted at the AAVS1 site.

  18. Resistance Analyses of Integrase Strand Transfer Inhibitors within Phase 3 Clinical Trials of Treatment-Naive Patients

    Directory of Open Access Journals (Sweden)

    Kirsten L. White

    2014-07-01

    Full Text Available The integrase (IN strand transfer inhibitors (INSTIs, raltegravir (RAL, elvitegravir (EVG and dolutegravir (DTG, comprise the newest drug class approved for the treatment of HIV-1 infection, which joins the existing classes of reverse transcriptase, protease and binding/entry inhibitors. The efficacy of first-line regimens has attained remarkably high levels, reaching undetectable viral loads in 90% of patients by Week 48; however, there remain patients who require a change in regimen due to adverse events, virologic failure with emergent resistance or other issues of patient management. Large, randomized clinical trials conducted in antiretroviral treatment-naive individuals are required for drug approval in this population in the US, EU and other countries, with the primary endpoint for virologic success at Week 48. However, there are differences in the definition of virologic failure and the evaluation of drug resistance among the trials. This review focuses on the methodology and tabulation of resistance to INSTIs in phase 3 clinical trials of first-line regimens and discusses case studies of resistance.

  19. Integrase-independent HIV-1 infection is augmented under conditions of DNA damage and produces a viral reservoir

    International Nuclear Information System (INIS)

    Ebina, Hirotaka; Kanemura, Yuka; Suzuki, Yasutsugu; Urata, Kozue; Misawa, Naoko; Koyanagi, Yoshio

    2012-01-01

    HIV-1 possesses a viral protein, integrase (IN), which is necessary for its efficient integration in target cells. However, it has been reported that an IN-defective HIV strain is still capable of integration. Here, we assessed the ability of wild type (WT) HIV-1 to establish infection in the presence of IN inhibitors. We observed a low, yet clear infection of inhibitor-incubated cells infected with WT HIV which was identical to cells infected with IN-deficient HIV, D64A. Furthermore, the IN-independent integration could be enhanced by the pretreatment of cells with DNA-damaging agents suggesting that integration is mediated by a DNA repair system. Moreover, significantly faster viral replication kinetics with augmented viral DNA integration was observed after infection in irradiated cells treated with IN inhibitor compared to nonirradiated cells. Altogether, our results suggest that HIV DNA has integration potential in the presence of an IN inhibitor and may serve as a virus reservoir.

  20. The S230R Integrase Substitution Associated with Viral Rebound during DTG Monotherapy Confers Low Levels INSTI Drug Resistance.

    Science.gov (United States)

    Pham, Hanh T; Labrie, Lydia; Wijting, Ingeborg E A; Hassounah, Said; Lok, Ka Yee; Portna, Inna; Goring, Mark; Han, Yingshan; Lungu, Cynthia; van der Ende, Marchina E; Brenner, Bluma G; Boucher, Charles A; Rijnders, Bart J A; van Kampen, Jeroen J A; Mesplède, Thibault; Wainberg, Mark A

    2018-03-29

    Dolutegravir (DTG) is an integrase strand-transfer inhibitor (INSTI) used for treatment of HIV-infected individuals. Due to its high genetic barrier to resistance, DTG has been clinically investigated as maintenance monotherapy to maintain viral suppression and to reduce complication and healthcare costs. Our study aims to explain the underlying mechanism related to the emergence of a S230R substitution in patients who experienced virological failure while using DTG monotherapy. We evaluated the effect of S230R substitution in regard to IN enzyme activity, viral infectivity, replicative capacity and susceptibility to different INSTIs by biochemical and cell-based assays. S230R substitution conferred 63% reduction in enzyme efficiency. The S230R virus was 1.29-fold less infectious than wildtype (WT), but could replicate in PM1 cells without significant delay. Resistance levels against DTG, CAB, RAL and EVG in tissue culture were 3.85-, 3.72-, 1.52-, and 1.21-fold, respectively. Our data indicate that the S230R substitution is comparable to the previously reported R263K in some respects. Virological failure under DTG monotherapy can occur through the development of such S230R or R263K mutations without the need for high levels DTG resistance.

  1. A QSAR study of integrase strand transfer inhibitors based on a large set of pyrimidine, pyrimidone, and pyridopyrazine carboxamide derivatives

    Science.gov (United States)

    de Campos, Luana Janaína; de Melo, Eduardo Borges

    2017-08-01

    In the present study, 199 compounds derived from pyrimidine, pyrimidone and pyridopyrazine carboxamides with inhibitory activity against HIV-1 integrase were modeled. Subsequently, a multivariate QSAR study was conducted with 54 molecules employed by Ordered Predictors Selection (OPS) and Partial Least Squares (PLS) for the selection of variables and model construction, respectively. Topological, electrotopological, geometric, and molecular descriptors were used. The selected real model was robust and free from chance correlation; in addition, it demonstrated favorable internal and external statistical quality. Once statistically validated, the training model was used to predict the activity of a second data set (n = 145). The root mean square deviation (RMSD) between observed and predicted values was 0.698. Although it is a value outside of the standards, only 15 (10.34%) of the samples exhibited higher residual values than 1 log unit, a result considered acceptable. Results of Williams and Euclidean applicability domains relative to the prediction showed that the predictions did not occur by extrapolation and that the model is representative of the chemical space of test compounds.

  2. X-ray crystal structure of the N-terminal region of Moloney murine leukemia virus integrase and its implications for viral DNA recognition: N-Terminal Region of M-MuLV Integrase

    Energy Technology Data Exchange (ETDEWEB)

    Guan, Rongjin [Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Aiyer, Sriram [Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Cote, Marie L. [Department of Biochemistry, Robert Wood Johnson Medical School, UMDNJ, Piscataway New Jersey 08854; Xiao, Rong [Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Jiang, Mei [Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Acton, Thomas B. [Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Roth, Monica J. [Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Montelione, Gaetano T. [Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Department of Biochemistry, Robert Wood Johnson Medical School, UMDNJ, Piscataway New Jersey 08854

    2017-02-03

    The retroviral integrase (IN) carries out the integration of a dsDNA copy of the viral genome into the host DNA, an essential step for viral replication. All IN proteins have three general domains, the N-terminal domain (NTD), the catalytic core domain, and the C-terminal domain. The NTD includes an HHCC zinc finger-like motif, which is conserved in all retroviral IN proteins. Two crystal structures of Moloney murine leukemia virus (M-MuLV) IN N-terminal region (NTR) constructs that both include an N-terminal extension domain (NED, residues 1–44) and an HHCC zinc-finger NTD (residues 45–105), in two crystal forms are reported. The structures of IN NTR constructs encoding residues 1–105 (NTR1–105) and 8–105 (NTR8–105) were determined at 2.7 and 2.15 Å resolution, respectively and belong to different space groups. While both crystal forms have similar protomer structures, NTR1–105 packs as a dimer and NTR8–105 packs as a tetramer in the asymmetric unit. The structure of the NED consists of three anti-parallel β-strands and an α-helix, similar to the NED of prototype foamy virus (PFV) IN. These three β-strands form an extended β-sheet with another β-strand in the HHCC Zn2+ binding domain, which is a unique structural feature for the M-MuLV IN. The HHCC Zn2+ binding domain structure is similar to that in HIV and PFV INs, with variations within the loop regions. Differences between the PFV and MLV IN NEDs localize at regions identified to interact with the PFV LTR and are compared with established biochemical and virological data for M-MuLV. Proteins 2017; 85:647–656.

  3. A long-acting integrase inhibitor protects female macaques from repeated high-dose intravaginal SHIV challenge.

    Science.gov (United States)

    Andrews, Chasity D; Yueh, Yun Lan; Spreen, William R; St Bernard, Leslie; Boente-Carrera, Mar; Rodriguez, Kristina; Gettie, Agegnehu; Russell-Lodrigue, Kasi; Blanchard, James; Ford, Susan; Mohri, Hiroshi; Cheng-Mayer, Cecilia; Hong, Zhi; Ho, David D; Markowitz, Martin

    2015-01-14

    Long-acting GSK1265744 (GSK744 LA) is a strand transfer inhibitor of the HIV/SIV (simian immunodeficiency virus) integrase and was shown to be an effective preexposure prophylaxis (PrEP) agent in a low-dose intrarectal SHIV (simian-human immunodeficiency virus) rhesus macaque challenge model. We examined the pharmacokinetics and efficacy of GSK744 LA as PrEP against repeat high-dose intravaginal SHIV challenge in female rhesus macaques treated with Depo-Provera (depot medroxyprogesterone acetate), which promotes viral transmission vaginally. When Depo-Provera-treated female rhesus macaques were dosed with GSK744 LA (50 mg/kg) monthly, systemic and tissue drug concentrations were lower than previously observed in male rhesus macaques. GSK744 concentrations were fivefold lower on average in cervical tissues than in rectal tissues. Eight female rhesus macaques were treated with GSK744 LA at week 0, and four female rhesus macaques served as controls. All animals received a high-dose challenge of SHIV162P3 at week 1. No infection was detected in GSK744 LA-treated rhesus macaques, whereas viremia was detected 1 to 2 weeks after SHIV challenge in all control animals. The GSK744 LA-treated rhesus macaques were given a second administration of drug at week 4 and further challenged at weeks 5 and 7. GSK744 LA treatment protected six of eight female rhesus macaques against three high-dose SHIV challenges, whereas all control animals became infected after the first challenge (P = 0.0003, log-rank test). These results support further clinical development of GSK744 LA for PrEP. Copyright © 2015, American Association for the Advancement of Science.

  4. Mutational analyses of the core domain of Avian Leukemia and Sarcoma Viruses integrase: critical residues for concerted integration and multimerization

    International Nuclear Information System (INIS)

    Moreau, Karen; Faure, Claudine; Violot, Sebastien; Gouet, Patrice; Verdier, Gerard; Ronfort, Corinne

    2004-01-01

    During replicative cycle of retroviruses, the reverse-transcribed viral DNA is integrated into the cell DNA by the viral integrase (IN) enzyme. The central core domain of IN contains the catalytic site of the enzyme and is involved in binding viral ends and cell DNA as well as dimerization. We previously performed single amino acid substitutions in the core domain of an Avian Leukemia and Sarcoma Virus (ALSV) IN [Arch. Virol. 147 (2002) 1761]. Here, we modeled the resulting IN mutants and analyzed the ability of these mutants to mediate concerted DNA integration in an in vitro assay, and to form dimers by protein-protein cross-linking and size exclusion chromatography. The N197C mutation resulted in the inability of the mutant to perform concerted integration that was concomitant with a loss of IN dimerization. Surprisingly, mutations Q102G and A106V at the dimer interface resulted in mutants with higher efficiencies than the wild-type IN in performing two-ended concerted integration of viral DNA ends. The G139D and A195V mutants had a trend to perform one-ended DNA integration of viral ends instead of two-ended integration. More drastically, the I88L and L135G mutants preferentially mediated nonconcerted DNA integration although the proteins form dimers. Therefore, these mutations may alter the formation of IN complexes of higher molecular size than a dimer that would be required for concerted integration. This study points to the important role of core domain residues in the concerted integration of viral DNA ends as well as in the oligomerization of the enzyme

  5. Key issues

    International Nuclear Information System (INIS)

    Cook, N.G.W.

    1980-01-01

    Successful modeling of the thermo-mechanical and hydrochemical behavior of radioactive waste repositories in hard rock is possible in principle. Because such predictions lie outside the realm of experience, their adequacy depends entirely upon a thorough understanding of three fundamental questions: an understanding of the chemical and physical processess that determine the behavior of rock and all its complexities; accurate and realistic numerical models of the geologic media within which a repository may be built; and sufficient in-situ data covering the entire geologic region affected by, or effecting the behavior of a repository. At present sufficient is known to be able to identify most of those areas which require further attention. These areas extend all the way from a complete understanding of the chemical and physical processes determining the behavior of rock through to the exploration mapping and testing that must be done during the development of any potential repository. Many of the techniques, laboratory equipment, field instrumentation, and numerical methods needed to accomplish this do not exist at present. Therefore it is necessary to accept that a major investment in scientific research is required to generate this information over the next few years. The spectrum of scientific and engineering activities is wide extending from laboratory measurements through the development of numerical models to the measurement of data in-situ, but there is every prospect that sufficient can be done to resolve these key issues. However, to do so requires overt recognition of the many gaps which exist in our knowledge and abilities today, and of the need to bridge these gaps and of the significant costs involved in doing so

  6. Evidence for the horizontal transfer of an integrase gene from a fusellovirus to a pRN-like plasmid within a single strain of Sulfolobus and the implications for plasmid survival

    DEFF Research Database (Denmark)

    Peng, Xu

    2008-01-01

    of the integrase gene occurs in the viral attachment site (attP), which corresponds to the anticodon region of the targeted tRNA gene in the host chromosome. This point mutation confers on pXZ1 the ability to integrate into the tRNA(Glu)[CUC] gene, which differs from the integration site of SSV4, t......RNA(Glu)[UUC]. SSV4 and pXZ1 were also shown experimentally to integrate into separate sites on the host chromosome. This is believed to be the first report of a pRN plasmid sharing its natural host with a fusellovirus and carrying a highly similar integrase gene....

  7. Study of Structure-active Relationship for Inhibitors of HIV-1 Integrase LEDGF/p75 Interaction by Machine Learning Methods.

    Science.gov (United States)

    Li, Yang; Wu, Yanbin; Yan, Aixia

    2017-07-01

    HIV-1 integrase (IN) is a promising target for anti-AIDS therapy, and LEDGF/p75 is proved to enhance the HIV-1 integrase strand transfer activity in vitro. Blocking the interaction between IN and LEDGF/p75 is an effective way to inhibit HIV replication infection. In this work, 274 LEDGF/p75-IN inhibitors were collected as the dataset. Support Vector Machine (SVM), Decision Tree (DT), Function Tree (FT) and Random Forest (RF) were applied to build several computational models for predicting whether a compound is an active or weakly active LEDGF/p75-IN inhibitor. Each compound is represented by MACCS fingerprints and CORINA Symphony descriptors. The prediction accuracies for the test sets of all the models are over 70 %. The best model Model 3B built by FT obtained a prediction accuracy and a Matthews Correlation Coefficient (MCC) of 81.08 % and 0.62 on test set, respectively. We found that the hydrogen bond and hydrophobic interactions are important for the bioactivity of an inhibitor. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Ultrasensitive liquid chromatography-tandem mass spectrometric methodologies for quantification of five HIV-1 integrase inhibitors in plasma for a microdose clinical trial.

    Science.gov (United States)

    Sun, Li; Li, Hankun; Willson, Kenneth; Breidinger, Sheila; Rizk, Matthew L; Wenning, Larissa; Woolf, Eric J

    2012-10-16

    HIV-1 integrase strand transfer inhibitors are an important class of compounds targeted for the treatment of HIV-1 infection. Microdosing has emerged as an attractive tool to assist in drug candidate screening for clinical development, but necessitates extremely sensitive bioanalytical assays, typically in the pg/mL concentration range. Currently, accelerator mass spectrometry is the predominant tool for microdosing support, which requires a specialized facility and synthesis of radiolabeled compounds. There have been few studies attempted to comprehensively assess a liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach in the context of microdosing applications. Herein, we describe the development of automated LC-MS/MS methods to quantify five integrase inhibitors in plasma with the limits of quantification at 1 pg/mL for raltegravir and 2 pg/mL for four proprietary compounds. The assays involved double extractions followed by UPLC coupled with negative ion electrospray MS/MS analysis. All methods were fully validated to the rigor of regulated bioanalysis requirements, with intraday precision between 1.20 and 14.1% and accuracy between 93.8 and 107% at the standard curve concentration range. These methods were successfully applied to a human microdose study and demonstrated to be accurate, reproducible, and cost-effective. Results of the study indicate that raltegravir displayed linear pharmacokinetics between a microdose and a pharmacologically active dose.

  9. Targeted transgene insertion into the CHO cell genome using Cre recombinase-incorporating integrase-defective retroviral vectors.

    Science.gov (United States)

    Kawabe, Yoshinori; Shimomura, Takuya; Huang, Shuohao; Imanishi, Suguru; Ito, Akira; Kamihira, Masamichi

    2016-07-01

    Retroviral vectors have served as efficient gene delivery tools in various biotechnology fields. However, viral DNA is randomly inserted into the genome, which can cause problems, such as insertional mutagenesis and gene silencing. Previously, we reported a site-specific gene integration system, in which a transgene is integrated into a predetermined chromosomal locus of Chinese hamster ovary (CHO) cells using integrase-defective retroviral vectors (IDRVs) and Cre recombinase. In this system, a Cre expression plasmid is transfected into founder cells before retroviral transduction. In practical applications of site-specific gene modification such as for hard-to-transfect cells or for in vivo gene delivery, both the transgene and the Cre protein into retroviral virions should be encapsulate. Here, we generated novel hybrid IDRVs in which viral genome and enzymatically active Cre can be delivered (Cre-IDRVs). Cre-IDRVs encoding marker genes, neomycin resistance and enhanced green fluorescent protein (EGFP), flanked by wild-type and mutated loxP sites were produced using an expression plasmid for a chimeric protein of Cre and retroviral gag-pol. After analyzing the incorporation of the Cre protein into retroviral virions by Western blotting, the Cre-IDRV was infected into founder CHO cells, in which marker genes (hygromycin resistance and red fluorescent protein) flanked with corresponding loxP sites are introduced into the genome. G418-resistant colonies expressing GFP appeared and the site-specific integration of the transgene into the expected chromosomal site was confirmed by PCR and sequencing of amplicons. Moreover, when Cre-IDRV carried a gene expression unit for a recombinant antibody, the recombinant cells in which the antibody expression cassette was integrated in a site-specific manner were generated and the cells produced the recombinant antibody. This method may provide a promising tool to perform site-specific gene modification according to Cre

  10. Geometrically and conformationally restrained cinnamoyl compounds as inhibitors of HIV-1 integrase: synthesis, biological evaluation, and molecular modeling.

    Science.gov (United States)

    Artico, M; Di Santo, R; Costi, R; Novellino, E; Greco, G; Massa, S; Tramontano, E; Marongiu, M E; De Montis, A; La Colla, P

    1998-10-08

    Various cinnammoyl-based structures were synthesized and tested in enzyme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrained analogues of caffeic acid phenethyl ester (CAPE) and were characterized by a syn disposition of the carbonyl group with respect to the vinylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn disposition could favor anti-HIV-1 activity in cell-based assays. Geometrical and conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambridge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclopentanone, cyclohexanone, 1,3-diacetylbenzene, 2, 4-dihydroxyacetophenone, 2,3-dihydro-1-indanone, 2,3-dihydro-1, 3-indandione, and others. While active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multiplication in acutely infected MT-4 cells. Nevertheless, they specifically inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellular (RNA polymerase II) nucleic acid-processing enzymes. On the other hand, title compounds were endowed with remarkable antiproliferative activity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoisomerases. The SARs developed for our compounds led to novel findings concerning the molecular determinants of IN inhibitory activity within the class of cinnamoyl-based structures. We hypothesize that these compounds bind to IN featuring the

  11. Mode of inhibition of HIV-1 Integrase by a C-terminal domain-specific monoclonal antibody*

    Directory of Open Access Journals (Sweden)

    Merkel George

    2006-06-01

    Full Text Available Abstract Background To further our understanding of the structure and function of HIV-1 integrase (IN we developed and characterized a library of monoclonal antibodies (mAbs directed against this protein. One of these antibodies, mAb33, which is specific for the C-terminal domain, was found to inhibit HIV-1 IN processing activity in vitro; a corresponding Fv fragment was able to inhibit HIV-1 integration in vivo. Our subsequent studies, using heteronuclear nuclear magnetic resonance spectroscopy, identified six solvent accessible residues on the surface of the C-terminal domain that were immobilized upon binding of the antibody, which were proposed to comprise the epitope. Here we test this hypothesis by measuring the affinity of mAb33 to HIV-1 proteins that contain Ala substitutions in each of these positions. To gain additional insight into the mode of inhibition we also measured the DNA binding capacity and enzymatic activities of the Ala substituted proteins. Results We found that Ala substitution of any one of five of the putative epitope residues, F223, R224, Y226, I267, and I268, caused a decrease in the affinity of the mAb33 for HIV-1 IN, confirming the prediction from NMR data. Although IN derivatives with Ala substitutions in or near the mAb33 epitope exhibited decreased enzymatic activity, none of the epitope substitutions compromised DNA binding to full length HIV-1 IN, as measured by surface plasmon resonance spectroscopy. Two of these derivatives, IN (I276A and IN (I267A/I268A, exhibited both increased DNA binding affinity and uncharacteristic dissociation kinetics; these proteins also exhibited non-specific nuclease activity. Results from these investigations are discussed in the context of current models for how the C-terminal domain interacts with substrate DNA. Conclusion It is unlikely that inhibition of HIV-1 IN activity by mAb33 is caused by direct interaction with residues that are essential for substrate binding. Rather

  12. Development of elvitegravir resistance and linkage of integrase inhibitor mutations with protease and reverse transcriptase resistance mutations.

    Directory of Open Access Journals (Sweden)

    Mark A Winters

    Full Text Available Failure of antiretroviral regimens containing elvitegravir (EVG and raltegravir (RAL can result in the appearance of integrase inhibitor (INI drug-resistance mutations (DRMs. While several INI DRMs have been identified, the evolution of EVG DRMs and the linkage of these DRMs with protease inhibitor (PI and reverse transcriptase inhibitor (RTI DRMs have not been studied at the clonal level. We examined the development of INI DRMs in 10 patients failing EVG-containing regimens over time, and the linkage of INI DRMs with PI and RTI DRMs in these patients plus 6 RAL-treated patients. A one-step RT-nested PCR protocol was used to generate a 2.7 kB amplicon that included the PR, RT, and IN coding region, and standard cloning and sequencing techniques were used to determine DRMs in 1,277 clones (mean 21 clones per time point. Results showed all patients had multiple PI, NRTI, and/or NNRTI DRMs at baseline, but no primary INI DRM. EVG-treated patients developed from 2 to 6 strains with different primary INI DRMs as early as 2 weeks after initiation of treatment, predominantly as single mutations. The prevalence of these strains fluctuated and new strains, and/or strains with new combinations of INI DRMs, developed over time. Final failure samples (weeks 14 to 48 typically showed a dominant strain with multiple mutations or N155H alone. Single N155H or multiple mutations were also observed in RAL-treated patients at virologic failure. All patient strains showed evidence of INI DRM co-located with single or multiple PI and/or RTI DRMs on the same viral strand. Our study shows that EVG treatment can select for a number of distinct INI-resistant strains whose prevalence fluctuates over time. Continued appearance of new INI DRMs after initial INI failure suggests a potent, highly dynamic selection of INI resistant strains that is unaffected by co-location with PI and RTI DRMs.

  13. Clinical Improvement by Switching to an Integrase Strand Transfer Inhibitor in Hemophiliac Patients with HIV: The Japan Cohort Study of HIV Patients Infected through Blood Products.

    Science.gov (United States)

    Kawado, Miyuki; Hashimoto, Shuji; Oka, Shin-Ichi; Fukutake, Katsuyuki; Higasa, Satoshi; Yatsuhashi, Hiroshi; Ogane, Miwa; Okamoto, Manabu; Shirasaka, Takuma

    2017-01-01

    This study aimed to determine improvement in HIV RNA levels and the CD4 cell count by switching to an antiretroviral regimen with an integrase strand transfer inhibitor (INSTI) in patients with HIV. This study was conducted on Japanese patients with HIV who were infected by blood products in the 1980s. Data were collected between 2007 and 2014. Data of 564 male hemophiliac patients with HIV from the Japan Cohort Study of HIV Patients Infected through Blood Products were available. Changes in antiretroviral regimen use, HIV RNA levels, and the CD4 cell count between 2007 and 2014 were examined. From 2007 to 2014, the proportion of use of a regimen with an INSTI increased from 0.0% to 41.0%. For patients with HIV who used a regimen, including an INSTI, the proportion of HIV RNA levels products. This suggests that performing this switch in clinical practice will lead to favorable effects.

  14. Semantic Keys and Reading

    Directory of Open Access Journals (Sweden)

    Zev bar-Lev

    2016-12-01

    Full Text Available Semantic Keys are elements (word-parts of written language that give an iconic, general representation of the whole word’s meaning. In written Sino-Japanese the “radical” or semantic components play this role. For example, the character meaning ‘woman, female’ is the Semantic Key of the character for Ma ‘Mama’ (alongside the phonetic component Ma, which means ‘horse’ as a separate character. The theory of semantic Keys in both graphic and phonemic aspects is called qTheory or nanosemantics. The most innovative aspect of the present article is the hypothesis that, in languages using alphabetic writing systems, the role of Semantic Key is played by consonants, more specifically the first consonant. Thus, L meaning ‘LIFT’ is the Semantic Key of English Lift, Ladle, Lofty, aLps, eLevator, oLympus; Spanish Leva, Lecantarse, aLto, Lengua; Arabic aLLah, and Hebrew① ªeL-ºaL ‘upto-above’ (the Israeli airline, Polish Lot ‘flight’ (the Polish airline; Hebrew ªeL, ªeLohim ‘God’, and haLLeluyah ‘praise-ye God’ (using Parallels, ‘Lift up God’. Evidence for the universality of the theory is shown by many examples drawn from various languages, including Indo-European Semitic, Chinese and Japanese. The theory reveals hundreds of relationships within and between languages, related and unrelated, that have been “Hiding in Plain Sight”, to mention just one example: the Parallel between Spanish Pan ‘bread’ and Mandarin Fan ‘rice’.

  15. Integrase-Deficient Lentiviral Vector as an All-in-One Platform for Highly Efficient CRISPR/Cas9-Mediated Gene Editing

    Directory of Open Access Journals (Sweden)

    Pavel I. Ortinski

    2017-06-01

    Full Text Available The CRISPR/Cas9 systems have revolutionized the field of genome editing by providing unprecedented control over gene sequences and gene expression in many species, including humans. Lentiviral vectors (LVs are one of the primary delivery platforms for the CRISPR/Cas9 system due to their ability to accommodate large DNA payloads and sustain robust expression in a wide range of dividing and non-dividing cells. However, long-term expression of LV-delivered Cas9/guide RNA may lead to undesirable off-target effects characterized by non-specific RNA-DNA interactions and off-target DNA cleavages. Integrase-deficient lentiviral vectors (IDLVs present an attractive means for delivery of CRISPR/Cas9 components because: (1 they are capable of transducing a broad range of cells and tissues, (2 have superior packaging capacity compared to other vectors (e.g., adeno-associated viral vectors, and (3 they are expressed transiently and demonstrate very weak integration capability. In this manuscript, we aimed to establish IDLVs as a means for safe and efficient delivery of CRISPR/Cas9. To this end, we developed an all-in-one vector cassette with increased production efficacy and demonstrated that CRISPR/Cas9 delivered by the improved IDLV vectors can mediate rapid and robust gene editing in human embryonic kidney (HEK293T cells and post-mitotic brain neurons in vivo, via transient expression and with higher gene-targeting specificity than the corresponding integrase-competent vectors.

  16. The allosteric HIV-1 integrase inhibitor BI-D affects virion maturation but does not influence packaging of a functional RNA genome.

    Directory of Open Access Journals (Sweden)

    Nikki van Bel

    Full Text Available The viral integrase (IN is an essential protein for HIV-1 replication. IN inserts the viral dsDNA into the host chromosome, thereby aided by the cellular co-factor LEDGF/p75. Recently a new class of integrase inhibitors was described: allosteric IN inhibitors (ALLINIs. Although designed to interfere with the IN-LEDGF/p75 interaction to block HIV DNA integration during the early phase of HIV-1 replication, the major impact was surprisingly found on the process of virus maturation during the late phase, causing a reverse transcription defect upon infection of target cells. Virus particles produced in the presence of an ALLINI are misformed with the ribonucleoprotein located outside the virus core. Virus assembly and maturation are highly orchestrated and regulated processes in which several viral proteins and RNA molecules closely interact. It is therefore of interest to study whether ALLINIs have unpredicted pleiotropic effects on these RNA-related processes. We confirm that the ALLINI BI-D inhibits virus replication and that the produced virus is non-infectious. Furthermore, we show that the wild-type level of HIV-1 genomic RNA is packaged in virions and these genomes are in a dimeric state. The tRNAlys3 primer for reverse transcription was properly placed on this genomic RNA and could be extended ex vivo. In addition, the packaged reverse transcriptase enzyme was fully active when extracted from virions. As the RNA and enzyme components for reverse transcription are properly present in virions produced in the presence of BI-D, the inhibition of reverse transcription is likely to reflect the mislocalization of the components in the aberrant virus particle.

  17. The allosteric HIV-1 integrase inhibitor BI-D affects virion maturation but does not influence packaging of a functional RNA genome.

    Science.gov (United States)

    van Bel, Nikki; van der Velden, Yme; Bonnard, Damien; Le Rouzic, Erwann; Das, Atze T; Benarous, Richard; Berkhout, Ben

    2014-01-01

    The viral integrase (IN) is an essential protein for HIV-1 replication. IN inserts the viral dsDNA into the host chromosome, thereby aided by the cellular co-factor LEDGF/p75. Recently a new class of integrase inhibitors was described: allosteric IN inhibitors (ALLINIs). Although designed to interfere with the IN-LEDGF/p75 interaction to block HIV DNA integration during the early phase of HIV-1 replication, the major impact was surprisingly found on the process of virus maturation during the late phase, causing a reverse transcription defect upon infection of target cells. Virus particles produced in the presence of an ALLINI are misformed with the ribonucleoprotein located outside the virus core. Virus assembly and maturation are highly orchestrated and regulated processes in which several viral proteins and RNA molecules closely interact. It is therefore of interest to study whether ALLINIs have unpredicted pleiotropic effects on these RNA-related processes. We confirm that the ALLINI BI-D inhibits virus replication and that the produced virus is non-infectious. Furthermore, we show that the wild-type level of HIV-1 genomic RNA is packaged in virions and these genomes are in a dimeric state. The tRNAlys3 primer for reverse transcription was properly placed on this genomic RNA and could be extended ex vivo. In addition, the packaged reverse transcriptase enzyme was fully active when extracted from virions. As the RNA and enzyme components for reverse transcription are properly present in virions produced in the presence of BI-D, the inhibition of reverse transcription is likely to reflect the mislocalization of the components in the aberrant virus particle.

  18. ФC31 Integrase-Mediated Isolation and Characterization of Novel Safe Harbors for Transgene Expression in the Pig Genome

    Science.gov (United States)

    Bi, Yanzhen; Hua, Zaidong; Ren, Hongyan; Zhang, Liping; Xiao, Hongwei; Liu, Ximei; Hua, Wenjun; Mei, Shuqi; Molenaar, Adrian; Laible, Götz; Zheng, Xinmin

    2018-01-01

    Programmable nucleases have allowed the rapid development of gene editing and transgenics, but the technology still suffers from the lack of predefined genetic loci for reliable transgene expression and maintenance. To address this issue, we used ФC31 integrase to navigate the porcine genome and identify the pseudo attP sites suitable as safe harbors for sustained transgene expression. The combined ФC31 integrase mRNA and an enhanced green fluorescence protein (EGFP) reporter donor were microinjected into one-cell zygotes for transgene integration. Among the resulting seven EGFP-positive piglets, two had transgene integrations at pseudo attP sites, located in an intergenic region of chromosome 1 (chr1-attP) and the 6th intron of the TRABD2A gene on chromosome 3 (chr3-attP), respectively. The integration structure was determined by TAIL-PCR and Southern blotting. Primary fibroblast cells were isolated from the two piglets and examined using fluorescence-activated cell sorting (FACS) and enzyme-linked immunosorbent assay (ELISA), which demonstrated that the chr1-attP site was more potent than chr3-attP site in supporting the EGFP expression. Both piglets had green feet under the emission of UV light, and pelleted primary fibroblast cells were green-colored under natural light, corroborating that the two pseudo attP sites are beneficial to transgene expression. The discovery of these two novel safe harbors for robust and durable transgene expression will greatly facilitate the use of transgenic pigs for basic, biomedical and agricultural studies and applications. PMID:29300364

  19. Removal of bacterial cells, antibiotic resistance genes and integrase genes by on-site hospital wastewater treatment plants: surveillance of treated hospital effluent quality

    KAUST Repository

    Timraz, Kenda Hussain Hassan

    2016-12-15

    This study aims to evaluate the removal efficiency of microbial contaminants, including total cell counts, antibiotic-resistant bacteria (ARB), antibiotic resistance genes (ARGs, e.g. tetO, tetZ, sul1 and sul2) and integrase genes (e.g. intl1 and intl2), by wastewater treatment plants (WWTPs) operated on-site of two hospitals (i.e., SH WWTP and IH WWTP). Both SH and IH WWTPs utilize the conventional activated sludge process but differences in the removal efficiencies were observed. Over the 2 week sampling period, IH WWTP outperformed SH WWTP, and achieved an approximate 0.388 to 2.49-log log removal values (LRVs) for total cell counts compared to the 0.010 to 0.162-log removal in SH WWTP. Although ARB were present in the hospital influent, the treatment process of both hospitals effectively removed ARB from most of the effluent samples. In instances where ARB were recovered in the effluent, none of the viable isolates were identified to be opportunistic pathogenic species based on 16S rRNA gene sequencing. However, sul1 and intl1 genes remained detectable at up to 105 copies per mL or 8 x 10(-1) copies per 16S rRNA gene in the treated effluent, with an LRV of less than 1.2. When the treated effluent is discharged from hospital WWTPs into the public sewer for further treatment as per requirement in many countries, the detected amount of ARGs and integrase genes in the hospital effluent can become a potential source of horizontal gene dissemination in the municipal WWTP. Proper on-site wastewater treatment and surveillance of the effluent quality for emerging contaminants are therefore highly recommended.

  20. Inorganic and organic fertilizers impact the abundance and proportion of antibiotic resistance and integron-integrase genes in agricultural grassland soil.

    Science.gov (United States)

    Nõlvak, Hiie; Truu, Marika; Kanger, Kärt; Tampere, Mailiis; Espenberg, Mikk; Loit, Evelin; Raave, Henn; Truu, Jaak

    2016-08-15

    Soil fertilization with animal manure or its digestate may facilitate an important antibiotic resistance dissemination route from anthropogenic sources to the environment. This study examines the effect of mineral fertilizer (NH4NO3), cattle slurry and cattle slurry digestate amendment on the abundance and proportion dynamics of five antibiotic resistance genes (ARGs) and two classes of integron-integrase genes (intI1 and intI2) in agricultural grassland soil. Fertilization was performed thrice throughout one vegetation period. The targeted ARGs (sul1, tetA, blaCTX-M, blaOXA2 and qnrS) encode resistance to several major antibiotic classes used in veterinary medicine such as sulfonamides, tetracycline, cephalosporins, penicillin and fluoroquinolones, respectively. The non-fertilized grassland soil contained a stable background of tetA, blaCTX-M and sul1 genes. The type of applied fertilizer significantly affected ARGs and integron-integrase genes abundances and proportions in the bacterial community (porganic fertilizer's application event, but this increase was followed by a stage of decrease, suggesting that microbes possessing these genes were predominantly entrained into soil via cattle slurry or its digestate application and had somewhat limited survival potential in a soil environment. However, the abundance of these three target genes did not decrease to a background level by the end of the study period. TetA was most abundant in mineral fertilizer treated soil and blaCTX-M in cattle slurry digestate amended soil. Despite significantly different abundances, the abundance dynamics of bacteria possessing these genes were similar (p<0.05 in all cases) in different treatments and resembled the dynamics of the whole bacterial community abundance in each soil treatment. Copyright © 2016. Published by Elsevier B.V.

  1. Various Bee Pheromones Binding Affinity, Exclusive Chemosensillar Localization, and Key Amino Acid Sites Reveal the Distinctive Characteristics of Odorant-Binding Protein 11 in the Eastern Honey Bee, Apis cerana.

    Science.gov (United States)

    Song, Xin-Mi; Zhang, Lin-Ya; Fu, Xiao-Bin; Wu, Fan; Tan, Jing; Li, Hong-Liang

    2018-01-01

    Odorant-binding proteins (OBPs) are the critical elements responsible for binding and transporting odors and pheromones in the sensitive olfactory system in insects. Honey bees are representative social insects that have complex odorants and pheromone communication systems relative to solitary insects. Here, we first cloned and characterized OBP11 ( AcerOBP11 ), from the worker bees antennae of Eastern honey bee, Apis cerana . Based on sequence and phylogenetic analysis, most sequences homologous to AcerOBP11 belong to the typical OBPs family. The transcriptional expression profiles showed that AcerOBP11 was expressed throughout the developmental stages and highly specifically expressed in adult antennae. Using immunofluorescence localization, AcerOBP11 in worker bee's antennae was only localized in the sensilla basiconica (SB) near the fringe of each segment. Fluorescence ligand-binding assay showed that AcerOBP11 protein had strong binding affinity with the tested various bee pheromones components, including the main queen mandibular pheromones (QMPs), methyl p-hydroxybenzoate (HOB), and ( E )-9-oxo-2-decanoic acid (9-ODA), alarm pheromone (n-hexanol), and worker pheromone components. AcerOBP11 also had strong binding affinity to plant volatiles, such as 4-Allylveratrole. Based on the docking and site-directed mutagenesis, two key amino acid residues (Ile97 and Ile140) were involved in the binding of AcerOBP11 to various bee pheromones. Taken together, we identified that AcerOBP11 was localized in a single type of antennal chemosensilla and had complex ligand-binding properties, which confer the dual-role with the primary characteristics of sensing various bee pheromones and secondary characteristics of sensing general odorants. This study not only prompts the theoretical basis of OBPs-mediated bee pheromones recognition of honey bee, but also extends the understanding of differences in pheromone communication between social and solitary insects.

  2. Various Bee Pheromones Binding Affinity, Exclusive Chemosensillar Localization, and Key Amino Acid Sites Reveal the Distinctive Characteristics of Odorant-Binding Protein 11 in the Eastern Honey Bee, Apis cerana

    Directory of Open Access Journals (Sweden)

    Xin-Mi Song

    2018-04-01

    Full Text Available Odorant-binding proteins (OBPs are the critical elements responsible for binding and transporting odors and pheromones in the sensitive olfactory system in insects. Honey bees are representative social insects that have complex odorants and pheromone communication systems relative to solitary insects. Here, we first cloned and characterized OBP11 (AcerOBP11, from the worker bees antennae of Eastern honey bee, Apis cerana. Based on sequence and phylogenetic analysis, most sequences homologous to AcerOBP11 belong to the typical OBPs family. The transcriptional expression profiles showed that AcerOBP11 was expressed throughout the developmental stages and highly specifically expressed in adult antennae. Using immunofluorescence localization, AcerOBP11 in worker bee's antennae was only localized in the sensilla basiconica (SB near the fringe of each segment. Fluorescence ligand-binding assay showed that AcerOBP11 protein had strong binding affinity with the tested various bee pheromones components, including the main queen mandibular pheromones (QMPs, methyl p-hydroxybenzoate (HOB, and (E-9-oxo-2-decanoic acid (9-ODA, alarm pheromone (n-hexanol, and worker pheromone components. AcerOBP11 also had strong binding affinity to plant volatiles, such as 4-Allylveratrole. Based on the docking and site-directed mutagenesis, two key amino acid residues (Ile97 and Ile140 were involved in the binding of AcerOBP11 to various bee pheromones. Taken together, we identified that AcerOBP11 was localized in a single type of antennal chemosensilla and had complex ligand-binding properties, which confer the dual-role with the primary characteristics of sensing various bee pheromones and secondary characteristics of sensing general odorants. This study not only prompts the theoretical basis of OBPs-mediated bee pheromones recognition of honey bee, but also extends the understanding of differences in pheromone communication between social and solitary insects.

  3. 6-(1-Benzyl-1H-pyrrol-2-yl)-2,4-dioxo-5-hexenoic acids as dual inhibitors of recombinant HIV-1 integrase and ribonuclease H, synthesized by a parallel synthesis approach.

    Science.gov (United States)

    Costi, Roberta; Métifiot, Mathieu; Esposito, Francesca; Cuzzucoli Crucitti, Giuliana; Pescatori, Luca; Messore, Antonella; Scipione, Luigi; Tortorella, Silvano; Zinzula, Luca; Novellino, Ettore; Pommier, Yves; Tramontano, Enzo; Marchand, Christophe; Di Santo, Roberto

    2013-11-14

    The increasing efficiency of HAART has helped to transform HIV/AIDS into a chronic disease. Still, resistance and drug-drug interactions warrant the development of new anti-HIV agents. We previously discovered hit 6, active against HIV-1 replication and targeting RNase H in vitro. Because of its diketo-acid moiety, we speculated that this chemotype could serve to develop dual inhibitors of both RNase H and integrase. Here, we describe a new series of 1-benzyl-pyrrolyl diketohexenoic derivatives, 7a-y and 8a-y, synthesized following a parallel solution-phase approach. Those 50 analogues have been tested on recombinant enzymes (RNase H and integrase) and in cell-based assays. Approximately half (22) exibited inhibition of HIV replication. Compounds 7b, 7u, and 8g were the most active against the RNase H activity of reverse-transcriptase, with IC50 values of 3, 3, and 2.5 μM, respectively. Compound 8g was also the most potent integrase inhibitor with an IC50 value of 26 nM.

  4. Adaptation of maize to temperate climates: mid-density genome-wide association genetics and diversity patterns reveal key genomic regions, with a major contribution of the Vgt2 (ZCN8 locus.

    Directory of Open Access Journals (Sweden)

    Sophie Bouchet

    Full Text Available The migration of maize from tropical to temperate climates was accompanied by a dramatic evolution in flowering time. To gain insight into the genetic architecture of this adaptive trait, we conducted a 50K SNP-based genome-wide association and diversity investigation on a panel of tropical and temperate American and European representatives. Eighteen genomic regions were associated with flowering time. The number of early alleles cumulated along these regions was highly correlated with flowering time. Polymorphism in the vicinity of the ZCN8 gene, which is the closest maize homologue to Arabidopsis major flowering time (FT gene, had the strongest effect. This polymorphism is in the vicinity of the causal factor of Vgt2 QTL. Diversity was lower, whereas differentiation and LD were higher for associated loci compared to the rest of the genome, which is consistent with selection acting on flowering time during maize migration. Selection tests also revealed supplementary loci that were highly differentiated among groups and not associated with flowering time in our panel, whereas they were in other linkage-based studies. This suggests that allele fixation led to a lack of statistical power when structure and relatedness were taken into account in a linear mixed model. Complementary designs and analysis methods are necessary to unravel the architecture of complex traits. Based on linkage disequilibrium (LD estimates corrected for population structure, we concluded that the number of SNPs genotyped should be at least doubled to capture all QTLs contributing to the genetic architecture of polygenic traits in this panel. These results show that maize flowering time is controlled by numerous QTLs of small additive effect and that strong polygenic selection occurred under cool climatic conditions. They should contribute to more efficient genomic predictions of flowering time and facilitate the dissemination of diverse maize genetic resources under a wide

  5. Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study.

    Science.gov (United States)

    Akil, Bisher; Blick, Gary; Hagins, Debbie P; Ramgopal, Moti N; Richmond, Gary J; Samuel, Rafik M; Givens, Naomi; Vavro, Cindy; Song, Ivy H; Wynne, Brian; Ait-Khaled, Mounir

    2015-01-01

    The Phase III VIKING-3 study demonstrated that dolutegravir (DTG) 50 mg twice daily was efficacious in antiretroviral therapy (ART)-experienced subjects harbouring raltegravir- and/or elvitegravir-resistant HIV-1. VIKING-4 (ING116529) included a placebo-controlled 7-day monotherapy phase to demonstrate that short-term antiviral activity was attributable to DTG. VIKING-4 is a Phase III randomized, double-blind study in therapy-experienced adults with integrase inhibitor (INI)-resistant virus randomized to DTG 50 mg twice daily or placebo while continuing their failing regimen (without raltegravir or elvitegravir) for 7 days (clinicaltrials.gov identifier NCT01568892). At day 8, all subjects switched to open-label DTG 50 mg twice daily and optimized background therapy including ≥1 fully active drug. The primary end point was change from baseline in plasma HIV-1 RNA at day 8. The study population (n=30) was highly ART-experienced with advanced HIV disease. Patients had extensive baseline resistance to all approved antiretroviral classes. Adjusted mean change in HIV-1 RNA at day 8 was 
-1.06 log10 copies/ml for the DTG arm and 0.10 log10 copies/ml for the placebo arm (treatment difference -1.16 log10 copies/ml [-1.52, -0.80]; PVIKING-3 study.

  6. Effect of temperature on the fate of genes encoding tetracycline resistance and the integrase of class 1 integrons within anaerobic and aerobic digesters treating municipal wastewater solids.

    Science.gov (United States)

    Diehl, David L; LaPara, Timothy M

    2010-12-01

    The objective of this research was to investigate the ability of anaerobic and aerobic digesters to reduce the quantity of antibiotic resistant bacteria in wastewater solids. Lab-scale digesters were operated at different temperatures (22 °C, 37 °C, 46 °C, and 55 °C) under both anaerobic and aerobic conditions and fed wastewater solids collected from a full-scale treatment facility. Quantitative PCR was used to track five genes encoding tetracycline resistance (tet(A), tet(L), tet(O), tet(W), and tet(X)) and the gene encoding the integrase (intI1) of class 1 integrons. Statistically significant reductions in the quantities of these genes occurred in the anaerobic reactors at 37 °C, 46 °C, and 55 °C, with the removal rates and removal efficiencies increasing as a function of temperature. The aerobic digesters, in contrast, were generally incapable of significantly decreasing gene quantities, although these digesters were operated at much shorter mean hydraulic residence times. This research suggests that high temperature anaerobic digestion of wastewater solids would be a suitable technology for eliminating various antibiotic resistance genes, an emerging pollutant of concern.

  7. A novel co-crystal structure affords the design of gain-of-function lentiviral integrase mutants in the presence of modified PSIP1/LEDGF/p75.

    Directory of Open Access Journals (Sweden)

    Stephen Hare

    2009-01-01

    Full Text Available Lens epithelium derived growth factor (LEDGF, also known as PC4 and SFRS1 interacting protein 1 (PSIP1 and transcriptional co-activator p75, is the cellular binding partner of lentiviral integrase (IN proteins. LEDGF accounts for the characteristic propensity of Lentivirus to integrate within active transcription units and is required for efficient viral replication. We now present a crystal structure containing the N-terminal and catalytic core domains (NTD and CCD of HIV-2 IN in complex with the IN binding domain (IBD of LEDGF. The structure extends the known IN-LEDGF interface, elucidating primarily charge-charge interactions between the NTD of IN and the IBD. A constellation of acidic residues on the NTD is characteristic of lentiviral INs, and mutations of the positively charged residues on the IBD severely affect interaction with all lentiviral INs tested. We show that the novel NTD-IBD contacts are critical for stimulation of concerted lentiviral DNA integration by LEDGF in vitro and for its function during the early steps of HIV-1 replication. Furthermore, the new structural details enabled us to engineer a mutant of HIV-1 IN that primarily functions only when presented with a complementary LEDGF mutant. These findings provide structural basis for the high affinity lentiviral IN-LEDGF interaction and pave the way for development of LEDGF-based targeting technologies for gene therapy.

  8. L-Chicoric acid inhibits human immunodeficiency virus type 1 integration in vivo and is a noncompetitive but reversible inhibitor of HIV-1 integrase in vitro

    International Nuclear Information System (INIS)

    Reinke, Ryan A.; Lee, Deborah J.; McDougall, Brenda R.; King, Peter J.; Victoria, Joseph; Mao Yingqun; Lei Xiangyang; Reinecke, Manfred G.; Robinson, W. Edward

    2004-01-01

    The human immunodeficiency virus (HIV) integrase (IN) must covalently join the viral cDNA into a host chromosome for productive HIV infection. L-Chicoric acid (L-CA) enters cells poorly but is a potent inhibitor of IN in vitro. Using quantitative real-time polymerase chain reaction (PCR), L-CA inhibits integration at concentrations from 500 nM to 10 μM but also inhibits entry at concentrations above 1 μM. Using recombinant HIV IN, steady-state kinetic analyses with L-CA were consistent with a noncompetitive or irreversible mechanism of inhibition. IN, in the presence or absence of L-CA, was successively washed. Inhibition of IN diminished, demonstrating that L-CA was reversibly bound to the protein. These data demonstrate that L-CA is a noncompetitive but reversible inhibitor of IN in vitro and of HIV integration in vivo. Thus, L-CA likely interacts with amino acids other than those which bind substrate

  9. Robust Public Key Cryptography — A New Cryptosystem Surviving Private Key Compromise

    Science.gov (United States)

    Shaik, Cheman

    A weakness of the present-day public key cryptosystems is that these cryptosystems do not survive private-key compromise attacks resulting from an internal breach of trust. In a competitive business environment, private key compromise is a common incident that voids the strength of public key cryptosystems such as RSA and ECC. Bribing corporate employees to disclose their secret keys and inadvertently disclosing secret information are among a plethora of practical attacks that occur at the implementation level. Once a breach of trust takes place and subsequently the private key is revealed, any public key cryptosystem fails to secure electronic data in Internet communications. The revealed key may be used by an attacker to decipher the intercepted data at an intermediary router. This weakness of public key cryptography calls for an additional security measure that enables encryptions to survive private key compromise attacks.

  10. Quantum key management

    Energy Technology Data Exchange (ETDEWEB)

    Hughes, Richard John; Thrasher, James Thomas; Nordholt, Jane Elizabeth

    2016-11-29

    Innovations for quantum key management harness quantum communications to form a cryptography system within a public key infrastructure framework. In example implementations, the quantum key management innovations combine quantum key distribution and a quantum identification protocol with a Merkle signature scheme (using Winternitz one-time digital signatures or other one-time digital signatures, and Merkle hash trees) to constitute a cryptography system. More generally, the quantum key management innovations combine quantum key distribution and a quantum identification protocol with a hash-based signature scheme. This provides a secure way to identify, authenticate, verify, and exchange secret cryptographic keys. Features of the quantum key management innovations further include secure enrollment of users with a registration authority, as well as credential checking and revocation with a certificate authority, where the registration authority and/or certificate authority can be part of the same system as a trusted authority for quantum key distribution.

  11. NASA's Chandra Reveals Origin of Key Cosmic Explosions

    Science.gov (United States)

    2010-02-01

    WASHINGTON -- New findings from NASA's Chandra X-ray Observatory have provided a major advance in understanding a type of supernova critical for studying the dark energy that astronomers think pervades the universe. The results show mergers of two dense stellar remnants are the likely cause of many of the supernovae that have been used to measure the accelerated expansion of the universe. These supernovae, called Type Ia, serve as cosmic mile markers to measure expansion of the universe because they can be seen at large distances, and they follow a reliable pattern of brightness. However, until now, scientists have been unsure what actually causes the explosions. "These are such critical objects in understanding the universe," said Marat Gilfanov of the Max Planck Institute for Astrophysics in Germany and lead author of the study that appears in the Feb. 18 edition of the journal Nature. "It was a major embarrassment that we did not know how they worked. Now we are beginning to understand what lights the fuse of these explosions." Most scientists agree a Type Ia supernova occurs when a white dwarf star -- a collapsed remnant of an elderly star -- exceeds its weight limit, becomes unstable and explodes. Scientists have identified two main possibilities for pushing the white dwarf over the edge: two white dwarfs merging or accretion, a process in which the white dwarf pulls material from a sun-like companion star until it exceeds its weight limit. "Our results suggest the supernovae in the galaxies we studied almost all come from two white dwarfs merging," said co-author Akos Bogdan, also of Max Planck. "This is probably not what many astronomers would expect." The difference between these two scenarios may have implications for how these supernovae can be used as "standard candles" -- objects of a known brightness -- to track vast cosmic distances. Because white dwarfs can come in a range of masses, the merger of two could result in explosions that vary somewhat in brightness. Because these two scenarios would generate different amounts of X-ray emission, Gilfanov and Bogdan used Chandra to observe five nearby elliptical galaxies and the central region of the Andromeda galaxy. A Type 1a supernova caused by accreting material produces significant X- ray emission prior to the explosion. A supernova from a merger of two white dwarfs, on the other hand, would create significantly less X-ray emission than the accretion scenario. The scientists found the observed X-ray emission was a factor of 30 to 50 times smaller than expected from the accretion scenario, effectively ruling it out. This implies that white dwarf mergers dominate in these galaxies. An open question remains whether these white dwarf mergers are the primary catalyst for Type Ia supernovae in spiral galaxies. Further studies are required to know if supernovae in spiral galaxies are caused by mergers or a mixture of the two processes. Another intriguing consequence of this result is that a pair of white dwarfs is relatively hard to spot, even with the best telescopes. "To many astrophysicists, the merger scenario seemed to be less likely because too few double-white-dwarf systems appeared to exist," said Gilfanov. "Now this path to supernovae will have to be investigated in more detail." In addition to the X-rays observed with Chandra, other data critical for this result came from NASA's Spitzer Space Telescope and the ground-based, infrared Two Micron All Sky Survey. The infrared brightness of the galaxies allowed the team to estimate how many supernovae should occur. NASA's Marshall Space Flight Center in Huntsville, Ala., manages the Chandra program for NASA's Science Mission Directorate in Washington. The Smithsonian Astrophysical Observatory controls Chandra's science and flight operations from Cambridge, Mass. More information, including images and other multimedia, can be found at: http://chandra.harvard.edu and http://chandra.nasa.gov

  12. Key roles for freshwater Actinobacteria revealed by deep metagenomic sequencing.

    Science.gov (United States)

    Ghai, Rohit; Mizuno, Carolina Megumi; Picazo, Antonio; Camacho, Antonio; Rodriguez-Valera, Francisco

    2014-12-01

    Freshwater ecosystems are critical but fragile environments directly affecting society and its welfare. However, our understanding of genuinely freshwater microbial communities, constrained by our capacity to manipulate its prokaryotic participants in axenic cultures, remains very rudimentary. Even the most abundant components, freshwater Actinobacteria, remain largely unknown. Here, applying deep metagenomic sequencing to the microbial community of a freshwater reservoir, we were able to circumvent this traditional bottleneck and reconstruct de novo seven distinct streamlined actinobacterial genomes. These genomes represent three new groups of photoheterotrophic, planktonic Actinobacteria. We describe for the first time genomes of two novel clades, acMicro (Micrococcineae, related to Luna2,) and acAMD (Actinomycetales, related to acTH1). Besides, an aggregate of contigs belonged to a new branch of the Acidimicrobiales. All are estimated to have small genomes (approximately 1.2 Mb), and their GC content varied from 40 to 61%. One of the Micrococcineae genomes encodes a proteorhodopsin, a rhodopsin type reported for the first time in Actinobacteria. The remarkable potential capacity of some of these genomes to transform recalcitrant plant detrital material, particularly lignin-derived compounds, suggests close linkages between the terrestrial and aquatic realms. Moreover, abundances of Actinobacteria correlate inversely to those of Cyanobacteria that are responsible for prolonged and frequently irretrievable damage to freshwater ecosystems. This suggests that they might serve as sentinels of impending ecological catastrophes. © 2014 John Wiley & Sons Ltd.

  13. Group key management

    Energy Technology Data Exchange (ETDEWEB)

    Dunigan, T.; Cao, C.

    1997-08-01

    This report describes an architecture and implementation for doing group key management over a data communications network. The architecture describes a protocol for establishing a shared encryption key among an authenticated and authorized collection of network entities. Group access requires one or more authorization certificates. The implementation includes a simple public key and certificate infrastructure. Multicast is used for some of the key management messages. An application programming interface multiplexes key management and user application messages. An implementation using the new IP security protocols is postulated. The architecture is compared with other group key management proposals, and the performance and the limitations of the implementation are described.

  14. Modular Connector Keying Concept

    Science.gov (United States)

    Ishman, Scott; Dukes, Scott; Warnica, Gary; Conrad, Guy; Senigla, Steven

    2013-01-01

    For panel-mount-type connectors, keying is usually "built-in" to the connector body, necessitating different part numbers for each key arrangement. This is costly for jobs that require small quantities. This invention was driven to provide a cost savings and to reduce documentation of individual parts. The keys are removable and configurable in up to 16 combinations. Since the key parts are separate from the connector body, a common design can be used for the plug, receptacle, and key parts. The keying can then be set at the next higher assembly.

  15. Biometry, the safe key

    Directory of Open Access Journals (Sweden)

    María Fraile-Hurtado

    2010-12-01

    Full Text Available Biometry is the next step in authentication, why do not we take this stepforward in our communication security systems? Keys are the main disadvantage in the cryptography, what if we were our own key?

  16. Financial Key Ratios

    OpenAIRE

    Tănase Alin-Eliodor

    2014-01-01

    This article focuses on computing techniques starting from trial balance data regarding financial key ratios. There are presented activity, liquidity, solvency and profitability financial key ratios. It is presented a computing methodology in three steps based on a trial balance.

  17. Public Key Cryptography.

    Science.gov (United States)

    Tapson, Frank

    1996-01-01

    Describes public key cryptography, also known as RSA, which is a system using two keys, one used to put a message into cipher and another used to decipher the message. Presents examples using small prime numbers. (MKR)

  18. Key Management Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — FUNCTION: Provides a secure environment to research and develop advanced electronic key management and networked key distribution technologies for the Navy and DoD....

  19. Public Key Infrastructure Study

    National Research Council Canada - National Science Library

    Berkovits, Shimshon

    1994-01-01

    The National Institute of Standards and Technology (NIST) has tasked The MITRE Corporation to study the alternatives for automated management of public keys and of the associated public key certificates for the Federal Government...

  20. The Key Lake project

    International Nuclear Information System (INIS)

    1991-01-01

    Key Lake is located in the Athabasca sand stone basin, 640 kilometers north of Saskatoon, Saskatchewan, Canada. The three sources of ore at Key Lake contain 70 100 tonnes of uranium. Features of the Key Lake Project were described under the key headings: work force, mining, mill process, tailings storage, permanent camp, environmental features, worker health and safety, and economic benefits. Appendices covering the historical background, construction projects, comparisons of western world mines, mining statistics, Northern Saskatchewan surface lease, and Key Lake development and regulatory agencies were included

  1. LOCKS AND KEYS SERVICE

    CERN Multimedia

    Locks and Keys Service

    2002-01-01

    The Locks and Keys service (ST/FM) will move from building 55 to building 570 from the 2nd August to the 9th August 2002 included. During this period the service will be closed. Only in case of extreme urgency please call the 164550. Starting from Monday, 12th August, the Locks and Keys Service will continue to follow the activities related to office keys (keys and locks) and will provide the keys for furniture. The service is open from 8h30 to 12h00 and from 13h00 to 17h30. We remind you that your divisional correspondents can help you in the execution of the procedures. We thank you for your comprehension and we remain at your service to help you in solving all the matters related to keys for offices and furniture. Locks and Keys Service - ST Division - FM Group

  2. Antiviral activity of dolutegravir in subjects with failure on an integrase inhibitor-based regimen: week 24 phase 3 results from VIKING-3

    Science.gov (United States)

    Nichols, G; Mills, A; Grossberg, R; Lazzarin, A; Maggiolo, F; Molina, J; Pialoux, G; Wright, D; Ait-Khaled, M; Huang, J; Vavro, C; Wynne, B; Yeo, J

    2012-01-01

    Background VIKING-3 aimed to examine efficacy and safety of dolutegravir (DTG) 50 mg twice daily in patients with resistance to multiple ARV classes, including integrase inhibitors (INI). Methods RAL and/or EVG-resistant (current or historical) adult subjects with screening plasma HIV-1 RNA ≥500 c/mL and resistance to ≥2 other ART classes received open-label DTG 50 mg BID while continuing their failing regimen (without RAL/EVG). At Day 8 the background regimen was optimised and DTG continued. Activity of the optimized background regimen (OBR) was determined by Monogram Net Assessment. Primary endpoints were antiviral efficacy at Day 8 and Week 24. Results 183 subjects enrolled, 124 with INI-resistance at screening and 59 with historical (but no screening) resistance. Population was advanced: at BL, median CD4 140, prior ART 13 yrs, 56% CDC Class C; 79% had >2 NRTI, 75% >1 NNRTI, and 70% >2 PI resistance-associated mutations, and 61% had non-R5 HIV detected. Of the 114 subjects who had the opportunity to complete 24 weeks on study before data cutoff, 72 (63%) had 1 log HIV RNA decline of 2, respectively. Discontinuations due to adverse events were uncommon (6/183, 3%); the most common drug-related AEs were diarrhoea, nausea and headache, each reported in only 5% of subjects. Conclusion A majority of the highly treatment-experienced subjects in VIKING-3 achieved suppression with DTG-based therapy. Responses were associated with Baseline IN genotype but not OSS, highlighting the importance and independence of DTG antiviral activity. DTG had a low rate of discontinuation due to adverse events at 50 mg BID in this advanced patient population.

  3. A Single-Center Retrospective Cohort Analysis of Maternal and Infant Outcomes in HIV-Infected Mothers Treated with Integrase Inhibitors During Pregnancy.

    Science.gov (United States)

    Mounce, Monique L; Pontiggia, Laura; Adams, Jessica L

    2017-12-01

    Integrase strand transfer inhibitors (INSTI) are currently being investigated for the treatment of HIV in pregnancy. The purpose of this study is to evaluate the differences in maternal and infant outcomes in HIV-positive mothers treated with INSTI-containing antiretroviral therapy (ART) during pregnancy compared to protease inhibitor (PI)-containing ART. A retrospective, cohort study of INSTI- and PI-based ART used in pregnancy between 2007 and 2015 was performed. The primary objective was to evaluate the differences in viral load (VL) suppression prior to delivery. Secondary endpoints included time to and duration of VL suppression and safety parameters in both mothers and infants. For the primary analysis, the two arms were matched 1:2 INSTI to PI based on the presence or absence of viremia at the time of pregnancy determination. Additional analysis was performed on the entire matched and unmatched dataset. Twenty-one patients were matched (7 INSTI and 14 PI). There were no significant differences between groups with respect to the proportion of patients with VL suppression prior to delivery (71.4% INSTI vs. 92.9% PI, p = 0.247), and there were no significant differences in any of the secondary endpoints. Patients with documented adherence issues were statistically more likely to not be virologically suppressed prior to delivery (p = 0.002). No differences in efficacy or safety were found between patients treated with INSTIs compared to PIs. This study supports the further investigation of the use of INSTIs during pregnancy to reduce HIV transmission.

  4. Evaluation of the effect of short-term treatment with the integrase inhibitor raltegravir (Isentress) on the course of progressive feline leukemia virus infection.

    Science.gov (United States)

    Boesch, Andrea; Cattori, Valentino; Riond, Barbara; Willi, Barbara; Meli, Marina L; Rentsch, Katharina M; Hosie, Margaret J; Hofmann-Lehmann, Regina; Lutz, Hans

    2015-02-25

    Cats persistently infected with the gammaretrovirus feline leukemia virus (FeLV) are at risk to die within months to years from FeLV-associated disease, such as immunosuppression, anemia or lymphoma/leukemia. The integrase inhibitor raltegravir has been demonstrated to reduce FeLV replication in vitro. The aim of the present study was to investigate raltegravir in vivo for its safety and efficacy to suppress FeLV replication. The safety was tested in three naïve specified pathogen-free (SPF) cats during a 15 weeks treatment period (initially 20mg then 40mg orally b.i.d.). No adverse effects were noted. The efficacy was tested in seven persistently FeLV-infected SPF cats attained from 18 cats experimentally exposed to FeLV-A/Glasgow-1. The seven cats were treated during nine weeks (40mg then 80mg b.i.d.). Raltegravir was well tolerated even at the higher dose. A significant decrease in plasma viral RNA loads (∼5×) was found; however, after treatment termination a rebound effect was observed. Only one cat developed anti-FeLV antibodies and viral RNA loads remained decreased after treatment termination. Of note, one of the untreated FeLV-A infected cats developed fatal FeLV-C associated anemia within 5 weeks of FeLV-A infection. Moreover, progressive FeLV infection was associated with significantly lower enFeLV loads prior to infection supporting that FeLV susceptibility may be related to the genetic background of the cat. Overall, our data demonstrate the ability of raltegravir to reduce viral replication also in vivo. However, no complete control of viremia was achieved. Further investigations are needed to find an optimized treatment against FeLV. (250 words). Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Development of pharmacophore similarity-based quantitative activity hypothesis and its applicability domain: applied on a diverse data-set of HIV-1 integrase inhibitors.

    Science.gov (United States)

    Kumar, Sivakumar Prasanth; Jasrai, Yogesh T; Mehta, Vijay P; Pandya, Himanshu A

    2015-01-01

    Quantitative pharmacophore hypothesis combines the 3D spatial arrangement of pharmacophore features with biological activities of the ligand data-set and predicts the activities of geometrically and/or pharmacophoric similar ligands. Most pharmacophore discovery programs face difficulties in conformational flexibility, molecular alignment, pharmacophore features sampling, and feature selection to score models if the data-set constitutes diverse ligands. Towards this focus, we describe a ligand-based computational procedure to introduce flexibility in aligning the small molecules and generating a pharmacophore hypothesis without geometrical constraints to define pharmacophore space, enriched with chemical features necessary to elucidate common pharmacophore hypotheses (CPHs). Maximal common substructure (MCS)-based alignment method was adopted to guide the alignment of carbon molecules, deciphered the MCS atom connectivity to cluster molecules in bins and subsequently, calculated the pharmacophore similarity matrix with the bin-specific reference molecules. After alignment, the carbon molecules were enriched with original atoms in their respective positions and conventional pharmacophore features were perceived. Distance-based pharmacophoric descriptors were enumerated by computing the interdistance between perceived features and MCS-aligned 'centroid' position. The descriptor set and biological activities were used to develop support vector machine models to predict the activities of the external test set. Finally, fitness score was estimated based on pharmacophore similarity with its bin-specific reference molecules to recognize the best and poor alignments and, also with each reference molecule to predict outliers of the quantitative hypothesis model. We applied this procedure to a diverse data-set of 40 HIV-1 integrase inhibitors and discussed its effectiveness with the reported CPH model.

  6. Key distillation in quantum cryptography

    Science.gov (United States)

    Slutsky, Boris Aron

    1998-11-01

    Quantum cryptography is a technique which permits two parties to communicate over an open channel and establish a shared sequence of bits known only to themselves. This task, provably impossible in classical cryptography, is accomplished by encoding the data on quantum particles and harnessing their unique properties. It is believed that no eavesdropping attack consistent with the laws of quantum theory can compromise the secret data unknowingly to the legitimate users of the channel. Any attempt by a hostile actor to monitor the data carrying particles while in transit reveals itself through transmission errors it must inevitably introduce. Unfortunately, in practice a communication is not free of errors even when no eavesdropping is present. Key distillation is a technique that permits the parties to overcome this difficulty and establish a secret key despite channel defects, under the assumption that every particle is handled independently from other particles by the enemy. In the present work, key distillation is described and its various aspects are studied. A relationship is derived between the average error rate resulting from an eavesdropping attack and the amount of information obtained by the attacker. Formal definition is developed of the security of the final key. The net throughput of secret bits in a quantum cryptosystem employing key distillation is assessed. An overview of quantum cryptographic protocols and related information theoretical results is also given.

  7. Mathematics revealed

    CERN Document Server

    Berman, Elizabeth

    1979-01-01

    Mathematics Revealed focuses on the principles, processes, operations, and exercises in mathematics.The book first offers information on whole numbers, fractions, and decimals and percents. Discussions focus on measuring length, percent, decimals, numbers as products, addition and subtraction of fractions, mixed numbers and ratios, division of fractions, addition, subtraction, multiplication, and division. The text then examines positive and negative numbers and powers and computation. Topics include division and averages, multiplication, ratios, and measurements, scientific notation and estim

  8. Quantum dense key distribution

    International Nuclear Information System (INIS)

    Degiovanni, I.P.; Ruo Berchera, I.; Castelletto, S.; Rastello, M.L.; Bovino, F.A.; Colla, A.M.; Castagnoli, G.

    2004-01-01

    This paper proposes a protocol for quantum dense key distribution. This protocol embeds the benefits of a quantum dense coding and a quantum key distribution and is able to generate shared secret keys four times more efficiently than the Bennet-Brassard 1984 protocol. We hereinafter prove the security of this scheme against individual eavesdropping attacks, and we present preliminary experimental results, showing its feasibility

  9. Key improvements to XTR

    NARCIS (Netherlands)

    Lenstra, A.K.; Verheul, E.R.; Okamoto, T.

    2000-01-01

    This paper describes improved methods for XTR key representation and parameter generation (cf. [4]). If the field characteristic is properly chosen, the size of the XTR public key for signature applications can be reduced by a factor of three at the cost of a small one time computation for the

  10. Fundamental study on the size and inter-key spacing of numeric keys for touch screen.

    Science.gov (United States)

    Harada, H; Katsuura, T; Kikuchi, Y

    1996-12-01

    The purpose of this study was to reveal the optimum size and inter-key spacing of numeric square keys for touch screens. Six male students (22-25 years old) and three female students (21-24 years old) volunteered as subjects for this experiment. Each subject took part in data entry tasks using numeric square keys of touch devices. The sizes of keys were 6, 12, 21, 30 and 39 mm and each the inter-key spacing was 0, 3, 6, 12 and 21 mm. Response times with key sizes of 6 and 12 mm were significantly slower than with key sizes of 21 and 30 mm (p touch screens should be more than 21 mm and optimum inter-key spacing should be from 3 to 6 mm. Optimum key size, however, must be selected with regard to the limitation of screen size.

  11. Emerging contaminants and nutrients synergistically affect the spread of class 1 integron-integrase (intI1) and sul1 genes within stable streambed bacterial communities.

    Science.gov (United States)

    Subirats, Jèssica; Timoner, Xisca; Sànchez-Melsió, Alexandre; Balcázar, José Luis; Acuña, Vicenç; Sabater, Sergi; Borrego, Carles M

    2018-07-01

    Wastewater effluents increase the nutrient load of receiving streams while introducing a myriad of anthropogenic chemical pollutants that challenge the resident aquatic (micro)biota. Disentangling the effects of both kind of stressors and their potential interaction on the dissemination of antibiotic resistance genes in bacterial communities requires highly controlled manipulative experiments. In this work, we investigated the effects of a combined regime of nutrients (at low, medium and high concentrations) and a mixture of emerging contaminants (ciprofloxacin, erythromycin, sulfamethoxazole, diclofenac, and methylparaben) on the bacterial composition, abundance and antibiotic resistance profile of biofilms grown in artificial streams. In particular, we investigated the effect of this combined stress on genes encoding resistance to ciprofloxacin (qnrS), erythromycin (ermB), sulfamethoxazole (sul1 and sul2) as well as the class 1 integron-integrase gene (intI1). Only genes conferring resistance to sulfonamides (sul1 and sul2) and intI1 gene were detected in all treatments during the study period. Besides, bacterial communities exposed to emerging contaminants showed higher copy numbers of sul1 and intI1 genes than those not exposed, whereas nutrient amendments did not affect their abundance. However, bacterial communities exposed to both emerging contaminants and a high nutrient concentration (1, 25 and 1 mg L -1 of phosphate, nitrate and ammonium, respectively) showed the highest increase on the abundance of sul1 and intI1 genes thus suggesting a factors synergistic effect of both stressors. Since none of the treatments caused a significant change on the composition of bacterial communities, the enrichment of sul1 and intI1 genes within the community was caused by their dissemination under the combined pressure exerted by nutrients and emerging contaminants. To the best of our knowledge, this is the first study demonstrating the contribution of nutrients on

  12. Key Facts about Tularemia

    Science.gov (United States)

    ... Submit What's this? Submit Button Key Facts About Tularemia Recommend on Facebook Tweet Share Compartir This fact ... and Prevention (CDC) Tularemia Web site . What is Tularemia? Tularemia is a potentially serious illness that occurs ...

  13. Key technologies book

    International Nuclear Information System (INIS)

    1997-01-01

    In this book can be found all the useful information on the French industry key technologies of the years 2000-2005. 136 technologies at the junction of the science advances and of the markets expectations are divided into 9 sectors. Among them, only 4 are interesting here: the environment, the transports, the materials and the energy. In 1995, the secretary's office of State for industry has published a first synthesis book on these key technologies. This 1997 new key technologies book extends and completes the initial study. For each key technology, an encyclopedic sheet is given. Each sheet combines thus some exact and practical information on: advance state of the technology, market characteristics, development forecasts, occupation and involved sectors, technology acquisition cost, research programs but also contacts of the main concerned efficiency poles. (O.M.)

  14. The Key Lake project

    International Nuclear Information System (INIS)

    Glattes, G.

    1985-01-01

    Aspects of project financing for the share of the Canadian subsidiary of Uranerzbergbau-GmbH, Bonn, in the uranium mining and milling facility at Key Lake, Saskatchewan, by a Canadian bank syndicate. (orig.) [de

  15. Revealing Rembrandt

    Directory of Open Access Journals (Sweden)

    Andrew J Parker

    2014-04-01

    Full Text Available The power and significance of artwork in shaping human cognition is self-evident. The starting point for our empirical investigations is the view that the task of neuroscience is to integrate itself with other forms of knowledge, rather than to seek to supplant them. In our recent work, we examined a particular aspect of the appreciation of artwork using present-day functional magnetic resonance imaging (fMRI. Our results emphasised the continuity between viewing artwork and other human cognitive activities. We also showed that appreciation of a particular aspect of artwork, namely authenticity, depends upon the co-ordinated activity between the brain regions involved in multiple decision making and those responsible for processing visual information. The findings about brain function probably have no specific consequences for understanding how people respond to the art of Rembrandt in comparison with their response to other artworks. However, the use of images of Rembrandt’s portraits, his most intimate and personal works, clearly had a significant impact upon our viewers, even though they have been spatially confined to the interior of an MRI scanner at the time of viewing. Neuroscientific studies of humans viewing artwork have the capacity to reveal the diversity of human cognitive responses that may be induced by external advice or context as people view artwork in a variety of frameworks and settings.

  16. Comparison is key.

    Science.gov (United States)

    Stone, Mark H; Stenner, A Jackson

    2014-01-01

    Several concepts from Georg Rasch's last papers are discussed. The key one is comparison because Rasch considered the method of comparison fundamental to science. From the role of comparison stems scientific inference made operational by a properly developed frame of reference producing specific objectivity. The exact specifications Rasch outlined for making comparisons are explicated from quotes, and the role of causality derived from making comparisons is also examined. Understanding causality has implications for what can and cannot be produced via Rasch measurement. His simple examples were instructive, but the implications are far reaching upon first establishing the key role of comparison.

  17. Key World Energy Statistics

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2010-07-01

    The IEA produced its first handy, pocket-sized summary of key energy data in 1997. This new edition responds to the enormously positive reaction to the book since then. Key World Energy Statistics produced by the IEA contains timely, clearly-presented data on supply, transformation and consumption of all major energy sources. The interested businessman, journalist or student will have at his or her fingertips the annual Canadian production of coal, the electricity consumption in Thailand, the price of diesel oil in Spain and thousands of other useful energy facts. It exists in different formats to suit our readers' requirements.

  18. Keyed shear joints

    DEFF Research Database (Denmark)

    Hansen, Klaus

    This report gives a summary of the present information on the behaviour of vertical keyed shear joints in large panel structures. An attemp is made to outline the implications which this information might have on the analysis and design of a complete wall. The publications also gives a short...

  19. Cryptographic Key Management System

    Energy Technology Data Exchange (ETDEWEB)

    No, author

    2014-02-21

    This report summarizes the outcome of U.S. Department of Energy (DOE) contract DE-OE0000543, requesting the design of a Cryptographic Key Management System (CKMS) for the secure management of cryptographic keys for the energy sector infrastructure. Prime contractor Sypris Electronics, in collaboration with Oak Ridge National Laboratories (ORNL), Electric Power Research Institute (EPRI), Valicore Technologies, and Purdue University's Center for Education and Research in Information Assurance and Security (CERIAS) and Smart Meter Integration Laboratory (SMIL), has designed, developed and evaluated the CKMS solution. We provide an overview of the project in Section 3, review the core contributions of all contractors in Section 4, and discuss bene ts to the DOE in Section 5. In Section 6 we describe the technical construction of the CKMS solution, and review its key contributions in Section 6.9. Section 7 describes the evaluation and demonstration of the CKMS solution in different environments. We summarize the key project objectives in Section 8, list publications resulting from the project in Section 9, and conclude with a discussion on commercialization in Section 10 and future work in Section 11.

  20. Turn key contracts

    International Nuclear Information System (INIS)

    Feretic, D.

    1975-01-01

    The aim of this summary is to point out some specific areas which have to be covered in a turn-key contract and which are of primarily interest to the buyer of a nuclear plant. It will be assumed that the buyer is utility company in a developing country and a plant supplier a company in an industrial country. (orig./FW) [de

  1. Key numbers: Energy

    International Nuclear Information System (INIS)

    1994-01-01

    The key numbers of energy give statistical data related to production, consumption, and to foreign trade of each energy in the World and in France. A chapter is dedicated to environment and brings quantitative elements on pollutant emissions connected to energy uses

  2. Key performance indicators

    NARCIS (Netherlands)

    Zwetsloot, G.I.J.M.

    2014-01-01

    This paper addresses how organisations can use OSH performance indicators. This is an important way to mainstream OSH into business management. Key performance indicators (KPIs) should provide objective data on the OSH situation. It is often said that ‘what gets measured gets managed’. Without

  3. Locks and Keys Service

    CERN Multimedia

    Claude Ducastel

    The GS-LS-SEM section is pleased to inform you that as from Monday 30 November 2009, the opening hours of the Locks and Keys service will be the following: 08h30 - 12h30 / 13h30 - 16:30, Mondays to Fridays. GS-SEM-LS 73333

  4. Ancel Keys: a tribute

    Directory of Open Access Journals (Sweden)

    VanItallie Theodore B

    2005-02-01

    Full Text Available Abstract Ancel Keys, Ph.D., who died in November, 2004, at the age of 100, was among the first scientists to recognize that human atherosclerosis is not an inevitable consequence of aging, and that a high-fat diet can be a major risk factor for coronary heart disease. During World War II, he and a group of talented co-workers at the University of Minnesota conducted a large-scale study of experimentally-induced human starvation. The data generated by this study – which was immediately recognized to be a classic – continue to be of inestimable value to nutrition scientists. In his later years, Keys spent more time at his home in Naples, Italy, where he had the opportunity to continue his personal study of the beneficial effects on health and longevity of a Mediterranean diet.

  5. Physician Appraisals: Key Challenges

    Directory of Open Access Journals (Sweden)

    Klich Jacek

    2017-06-01

    Full Text Available The main purpose of the article is to identify key criteria being used for physician appraisals and to find how communication skills of physicians are valued in those appraisals. ScienceDirect and EBSCOhost databases were used for this search. The results show that a physician appraisal is underestimated both theoretically and empirically. The particular gap exists with respect to the communication skills of physicians, which are rarely present in medical training syllabi and physician assessments. The article contributes to the theoretical discourse on physician appraisals and points out at the inconsistency between the high status of physicians as a key hospital resource on the one hand and, on the other hand, at inadequate and poorly researched assessment of their performance with a special emphasis on communication skills. The article may inspire health managers to develop and implement up-to-date assessment forms for physicians and good managerial practices in this respect in hospitals and other health care units.

  6. NAGRADATA. Code key. Geology

    International Nuclear Information System (INIS)

    Mueller, W.H.; Schneider, B.; Staeuble, J.

    1984-01-01

    This reference manual provides users of the NAGRADATA system with comprehensive keys to the coding/decoding of geological and technical information to be stored in or retreaved from the databank. Emphasis has been placed on input data coding. When data is retreaved the translation into plain language of stored coded information is done automatically by computer. Three keys each, list the complete set of currently defined codes for the NAGRADATA system, namely codes with appropriate definitions, arranged: 1. according to subject matter (thematically) 2. the codes listed alphabetically and 3. the definitions listed alphabetically. Additional explanation is provided for the proper application of the codes and the logic behind the creation of new codes to be used within the NAGRADATA system. NAGRADATA makes use of codes instead of plain language for data storage; this offers the following advantages: speed of data processing, mainly data retrieval, economies of storage memory requirements, the standardisation of terminology. The nature of this thesaurian type 'key to codes' makes it impossible to either establish a final form or to cover the entire spectrum of requirements. Therefore, this first issue of codes to NAGRADATA must be considered to represent the current state of progress of a living system and future editions will be issued in a loose leave ringbook system which can be updated by an organised (updating) service. (author)

  7. Manet key management via Mobile Ficlke Key protocol (MFK ...

    African Journals Online (AJOL)

    Manet key management via Mobile Ficlke Key protocol (MFK) ... Journal of Fundamental and Applied Sciences. Journal Home · ABOUT THIS JOURNAL ... No Abstract. Keywords: MANET; key management scheme; simulation environment ...

  8. Comparative Genomics of Methanopyrus sp. SNP6 and KOL6 Revealing Genomic Regions of Plasticity Implicated in Extremely Thermophilic Profiles

    Directory of Open Access Journals (Sweden)

    Zhiliang Yu

    2017-07-01

    Full Text Available Methanopyrus spp. are usually isolated from harsh niches, such as high osmotic pressure and extreme temperature. However, the molecular mechanisms for their environmental adaption are poorly understood. Archaeal species is commonly considered as primitive organism. The evolutional placement of archaea is a fundamental and intriguing scientific question. We sequenced the genomes of Methanopyrus strains SNP6 and KOL6 isolated from the Atlantic and Iceland, respectively. Comparative genomic analysis revealed genetic diversity and instability implicated in niche adaption, including a number of transporter- and integrase/transposase-related genes. Pan-genome analysis also defined the gene pool of Methanopyrus spp., in addition of ~120-Kb genomic region of plasticity impacting cognate genomic architecture. We believe that Methanopyrus genomics could facilitate efficient investigation/recognition of archaeal phylogenetic diverse patterns, as well as improve understanding of biological roles and significance of these versatile microbes.

  9. Key characteristics of different management styles

    OpenAIRE

    AGADZHANYAN A.S.

    2015-01-01

    The article reveals main management styles practiсed by managers all over the world. The author considers key characteristics of management styles, conditions of their using. The paper analyzes cultural differences in management styles in the West and in the East.

  10. Key aspects congenital infection

    Directory of Open Access Journals (Sweden)

    Yu. V. Lobzin

    2014-01-01

    Full Text Available The key questions to solve the problem of congenital infection in the Russian Federation are: using in national practice over world accepted terminology adapted to the recommendations of the World Health Organization; representation of the modern concepts of an infectious process in the classification of congenital infections; scientific development and introducing in clinical practice the «standard case definitions», applied to different congenital infections; optimization of protocols and clinical guidelines for diagnosis, treatment and prevention of congenital infections; improvement a knowledge in the infectious disease for all  pecialists involved in the risk assessment of congenital infections, manage pregnancy and children. Based on our experience and analysis of publications, the authors suggest possible solutions.

  11. Key figures. Year 2006

    International Nuclear Information System (INIS)

    2006-01-01

    This document summarizes in a series of tables the key data of the petroleum industry and of the other energies for the year 2006. Data of the two previous years are given for comparison: 1 - petroleum, France: exploration, reserves, production, transports (tankers, pipelines, crude and refined products), storage capacities, status of resources and uses, foreign trade (imports, prices, exports), refining (capacities, facilities), evolution of supplies, automotive fuels consumption; 2 - energies, France: production, consumption and trade data for coal, natural gas, electricity; total production and consumption of primary energy; consumption per sector of use; 3 - petroleum, world: crude production and reserves per geographical area, OPEC production, imports/exports and refining/consumption per geographical area, international quotation for crudes and refined products; 4 - energies, world: reserves, production and consumption data for coal, natural gas and electricity; uranium production and resources; total primary energy production and consumption per energy source and geographical area. (J.S.)

  12. Key figures. Year 2005

    International Nuclear Information System (INIS)

    2005-01-01

    This document summarizes in a series of tables the key data of the petroleum industry and of the other energies for the year 2005. Data of the two previous years are given for comparison: 1 - petroleum, France: exploration, reserves, production, transports (tankers, pipelines, crude and refined products), storage capacities, status of resources and uses, foreign trade (imports, prices, exports), refining (capacities, facilities), evolution of supplies, automotive fuels consumption; 2 - energies, France: production, consumption and trade data for coal, natural gas, electricity; total production and consumption of primary energy; consumption per sector of use; 3 - petroleum, world: crude production and reserves per geographical area, OPEC production, imports/exports and refining/consumption per geographical area, international quotation for crudes and refined products; 4 - energies, world: reserves, production and consumption data for coal, natural gas and electricity; uranium production and resources; total primary energy production and consumption per energy source and geographical area. (J.S.)

  13. Smooth Phase Interpolated Keying

    Science.gov (United States)

    Borah, Deva K.

    2007-01-01

    Smooth phase interpolated keying (SPIK) is an improved method of computing smooth phase-modulation waveforms for radio communication systems that convey digital information. SPIK is applicable to a variety of phase-shift-keying (PSK) modulation schemes, including quaternary PSK (QPSK), octonary PSK (8PSK), and 16PSK. In comparison with a related prior method, SPIK offers advantages of better performance and less complexity of implementation. In a PSK scheme, the underlying information waveform that one seeks to convey consists of discrete rectangular steps, but the spectral width of such a waveform is excessive for practical radio communication. Therefore, the problem is to smooth the step phase waveform in such a manner as to maintain power and bandwidth efficiency without incurring an unacceptably large error rate and without introducing undesired variations in the amplitude of the affected radio signal. Although the ideal constellation of PSK phasor points does not cause amplitude variations, filtering of the modulation waveform (in which, typically, a rectangular pulse is converted to a square-root raised cosine pulse) causes amplitude fluctuations. If a power-efficient nonlinear amplifier is used in the radio communication system, the fluctuating-amplitude signal can undergo significant spectral regrowth, thus compromising the bandwidth efficiency of the system. In the related prior method, one seeks to solve the problem in a procedure that comprises two major steps: phase-value generation and phase interpolation. SPIK follows the two-step approach of the related prior method, but the details of the steps are different. In the phase-value-generation step, the phase values of symbols in the PSK constellation are determined by a phase function that is said to be maximally smooth and that is chosen to minimize the spectral spread of the modulated signal. In this step, the constellation is divided into two groups by assigning, to information symbols, phase values

  14. The key found

    Directory of Open Access Journals (Sweden)

    Agata Stankowka

    2010-01-01

    Full Text Available Poetycka antropologia Julii Hartwig [Julia Hartwig’s poetic anthropology] written by Marcin Terlecki is a book that fills the yawning gap in our literary understanding of the twentieth century Polish poetry and constitutes the first attempt at a comprehensive and detailed presentation of the lyrical works by J. Hartwig. The modern collection in which the work appears allow M. Terlecki to reveal the poetess’ fundamental insights dominating and underlying her world outlook and epistemological views. This, in turn, puts him in a position to give an explanation to the logic embedded in the evolution under scrutiny. M. Terlecki convincingly supports his own argument concerning J. Hartwig’s poetic reception of the world proving the thesis that its fundamentals are deeply rooted in the anthropological perspective. Terlecki differentiates the latter into three basic categories. First, there is “strangeness/alienation”, which results in the need for self-definition (determination of one’s nature and basic qualities. Then, “identity”, whose reflection turns out to be not only what is different in its external shape, but also what is different inside — within the plane of one’s own culture, biography and personality. And, finally, “empathy”, born out of questions on a feasibility of contact with what is different, alien and absent. The three categories, connected by the logic of anthropological vision, are presented as basic and fundamental for the subsequent stages in Hartwig’s poetical output. At the same time, they reveal themselves as axes of anthropological reading material provided by the author — for the discussed book is the author’s own research project on “poetic anthropology”.

  15. Key to good fit: body measurement problems specific to key ...

    African Journals Online (AJOL)

    Key to good fit: body measurement problems specific to key dimensions. ... to explore and describe the problems that the South African Clothing Industry currently ... A postal survey was conducted among South African apparel and footwear ...

  16. Flow hydrodynamics near inlet key of Piano Key Weir (PKW)

    Indian Academy of Sciences (India)

    Department of Water Resources Development and Management, Indian Institute ... on the hydrodynamic performance near inlet key of Piano Key Weir (PKW). ... nature of flows is clearly understood with the help of advanced instrumentation.

  17. Autoshaping of key pecking in pigeons with negative reinforcement1

    Science.gov (United States)

    Rachlin, Howard

    1969-01-01

    Pigeons exposed to gradually increasing intensities of pulsing electric shock pecked a key and thereby reduced the intensity of shock to zero for 2 min. Acquisition of key pecking was brought about through an autoshaping process in which periodic brief keylight presentations immediately preceded automatic reduction of the shock. On the occasions of such automatic reduction of shock preceding the first measured key peck, little or no orientation to the key was observed. Observations of pigeons with autoshaping of positive reinforcement also revealed little evidence of orientation toward the key. ImagesFig. 3.Fig. 4. PMID:16811371

  18. Autoshaping of key pecking in pigeons with negative reinforcement.

    Science.gov (United States)

    Rachlin, H

    1969-07-01

    Pigeons exposed to gradually increasing intensities of pulsing electric shock pecked a key and thereby reduced the intensity of shock to zero for 2 min. Acquisition of key pecking was brought about through an autoshaping process in which periodic brief keylight presentations immediately preceded automatic reduction of the shock. On the occasions of such automatic reduction of shock preceding the first measured key peck, little or no orientation to the key was observed. Observations of pigeons with autoshaping of positive reinforcement also revealed little evidence of orientation toward the key.

  19. 1,4-Bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene, a small molecule, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular Lens epithelium-derived growth factor.

    Science.gov (United States)

    Gu, Wan-gang; Ip, Denis Tsz-Ming; Liu, Si-jie; Chan, Joseph H; Wang, Yan; Zhang, Xuan; Zheng, Yong-tang; Wan, David Chi-Cheong

    2014-04-25

    Translocation of viral integrase (IN) into the nucleus is a critical precondition of integration during the life cycle of HIV, a causative agent of Acquired Immunodeficiency Syndromes (AIDS). As the first discovered cellular factor to interact with IN, Lens epithelium-derived growth factor (LEDGF/p75) plays an important role in the process of integration. Disruption of the LEDGF/p75-IN interaction has provided a great interest for anti-HIV agent discovery. In this work, we reported that one small molecular compound, 1,4-bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene(Compound 15), potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution at 1 μM. The putative binding mode of Compound 15 was constructed by a molecular docking simulation to provide structural insights into the ligand-binding mechanism. Compound 15 suppressed viral replication by measuring p24 antigen production in HIV-1IIIB acute infected C8166 cells with EC50 value of 11.19 μM. Compound 15 might supply useful structural information for further anti-HIV agent discovery. Copyright © 2014. Published by Elsevier Ireland Ltd.

  20. Experimental single-strain mobilomics reveals events that shape pathogen emergence.

    Science.gov (United States)

    Schoeniger, Joseph S; Hudson, Corey M; Bent, Zachary W; Sinha, Anupama; Williams, Kelly P

    2016-08-19

    Virulence genes on mobile DNAs such as genomic islands (GIs) and plasmids promote bacterial pathogen emergence. Excision is an early step in GI mobilization, producing a circular GI and a deletion site in the chromosome; circular forms are also known for some bacterial insertion sequences (ISs). The recombinant sequence at the junctions of such circles and deletions can be detected sensitively in high-throughput sequencing data, using new computational methods that enable empirical discovery of mobile DNAs. For the rich mobilome of a hospital Klebsiella pneumoniae strain, circularization junctions (CJs) were detected for six GIs and seven IS types. Our methods revealed differential biology of multiple mobile DNAs, imprecision of integrases and transposases, and differential activity among identical IS copies for IS26, ISKpn18 and ISKpn21 Using the resistance of circular dsDNA molecules to exonuclease, internally calibrated with the native plasmids, showed that not all molecules bearing GI CJs were circular. Transpositions were also detected, revealing replicon preference (ISKpn18 prefers a conjugative IncA/C2 plasmid), local action (IS26), regional preferences, selection (against capsule synthesis) and IS polarity inversion. Efficient discovery and global characterization of numerous mobile elements per experiment improves accounting for the new gene combinations that arise in emerging pathogens. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  1. Identifying tier one key suppliers.

    Science.gov (United States)

    Wicks, Steve

    2013-01-01

    In today's global marketplace, businesses are becoming increasingly reliant on suppliers for the provision of key processes, activities, products and services in support of their strategic business goals. The result is that now, more than ever, the failure of a key supplier has potential to damage reputation, productivity, compliance and financial performance seriously. Yet despite this, there is no recognised standard or guidance for identifying a tier one key supplier base and, up to now, there has been little or no research on how to do so effectively. This paper outlines the key findings of a BCI-sponsored research project to investigate good practice in identifying tier one key suppliers, and suggests a scalable framework process model and risk matrix tool to help businesses effectively identify their tier one key supplier base.

  2. Security for Key Management Interfaces

    OpenAIRE

    Kremer , Steve; Steel , Graham; Warinschi , Bogdan

    2011-01-01

    International audience; We propose a much-needed formal definition of security for cryptographic key management APIs. The advantages of our definition are that it is general, intuitive, and applicable to security proofs in both symbolic and computational models of cryptography. Our definition relies on an idealized API which allows only the most essential functions for generating, exporting and importing keys, and takes into account dynamic corruption of keys. Based on this we can define the ...

  3. Model plant Key Measurement Points

    International Nuclear Information System (INIS)

    Schneider, R.A.

    1984-01-01

    For IAEA safeguards a Key Measurement Point is defined as the location where nuclear material appears in such a form that it may be measured to determine material flow or inventory. This presentation describes in an introductory manner the key measurement points and associated measurements for the model plant used in this training course

  4. Breaking chaotic shift key communication via adaptive key identification

    International Nuclear Information System (INIS)

    Ren Haipeng; Han Chongzhao; Liu Ding

    2008-01-01

    This paper proposes an adaptive parameter identification method for breaking chaotic shift key communication from the transmitted signal in public channel. The sensitive dependence property of chaos on parameter mismatch is used for chaos adaptive synchronization and parameter identification. An index function about the synchronization error is defined and conjugate gradient method is used to minimize the index function and to search the transmitter's parameter (key). By using proposed method, secure key is recovered from transmitted signal generated by low dimensional chaos and hyper chaos switching communication. Multi-parameters can also be identified from the transmitted signal with noise

  5. A Distributed Shared Key Generation Procedure Using Fractional Keys

    National Research Council Canada - National Science Library

    Poovendran, Radha; Corson, M. S; Baras, J. S

    1998-01-01

    We present a new class of distributed key generation and recovery algorithms suitable for group communication systems where the group membership is either static or slowly time-varying, and must be tightly controlled...

  6. Key parameters controlling radiology departments

    International Nuclear Information System (INIS)

    Busch, Hans-Peter

    2011-01-01

    For radiology departments and outstanding practises control and optimization of processes demand an efficient management based on key data. Systems of key data deliver indicators for control of medical quality, service quality and economics. For practices effectiveness (productivity), for hospitals effectiveness and efficiency are in the focus of economical optimization strategies. Task of daily key data is continuous monitoring of activities and workflow, task of weekly/monthly key data is control of data quality, process quality and achievement of objectives, task of yearly key data is determination of long term strategies (marketing) and comparison with competitors (benchmarking). Key parameters have to be defined clearly and have to be available directly. For generation, evaluation and control of key parameters suitable forms of organization and processes are necessary. Strategies for the future will be directed more to the total processes of treatment. To think in total processes and to steer and optimize with suitable parameters is the challenge for participants in the healthcare market of the future. (orig.)

  7. 5-Hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as novel dual inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H and integrase.

    Science.gov (United States)

    Sun, Lin; Gao, Ping; Dong, Guanyu; Zhang, Xujie; Cheng, Xiqiang; Ding, Xiao; Wang, Xueshun; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Menéndez-Arias, Luis; Zhan, Peng; Liu, Xinyong

    2018-06-18

    We reported herein the design, synthesis and biological evaluation of a series of 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as HIV-1 reverse transcriptase (RT) ribonuclease H (RNase H) inhibitors using a privileged structure-guided scaffold refining strategy. In view of the similarities between the pharmacophore model of RNase H and integrase (IN) inhibitors as well as their catalytic sites, we also performed IN inhibition assays. Notably, the majority of these derivatives inhibited RNase H and IN at micromolar concentrations. Among them, compound 7a exhibited similar inhibitory activity against RNase H and IN (IC 50 RNase H  = 1.77 μM, IC 50 IN  = 1.18 μM, ratio = 1.50). To the best of our knowledge, this is the first reported dual HIV-1 RNase H-IN inhibitor based on a 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one structure. Molecular modeling has been used to predict the binding mode of 7a in complex with the catalytic cores of HIV-1 RNase H and IN. Taken together these results strongly support the feasibility of developing HIV-1 dual inhibitors from analog-based optimization of divalent metal ion chelators. Recently, the identification of dual inhibitors proved to be a highly effective strategy for novel antivirals discovery. Therefore, these compounds appear to be useful leads that can be further modified to develop more valuable anti-HIV-1 molecules with suitable drug profiles. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  8. Structure-based virtual screening toward the discovery of novel inhibitors for impeding the protein-protein interaction between HIV-1 integrase and human lens epithelium-derived growth factor (LEDGF/p75).

    Science.gov (United States)

    Panwar, Umesh; Singh, Sanjeev Kumar

    2017-10-23

    HIV-1 integrase is a unique promising component of the viral replication cycle, catalyzing the integration of reverse transcribed viral cDNA into the host cell genome. Generally, IN activity requires both viral as well as a cellular co-factor in the processing replication cycle. Among them, the human lens epithelium-derived growth factor (LEDGF/p75) represented as promising cellular co-factor which supports the viral replication by tethering IN to the chromatin. Due to its major importance in the early steps of HIV replication, the interaction between IN and LEDGF/p75 has become a pleasing target for anti-HIV drug discovery. The present study involves the finding of novel inhibitor based on the information of dimeric CCD of IN in complex with known inhibitor, which were carried out by applying a structure-based virtual screening concept with molecular docking. Additionally, Free binding energy, ADME properties, PAINS analysis, Density Functional Theory, and Enrichment Calculations were performed on selected compounds for getting a best lead molecule. On the basis of these analyses, the current study proposes top 3 compounds: Enamine-Z742267384, Maybridge-HTS02400, and Specs-AE-848/37125099 with acceptable pharmacological properties and enhanced binding affinity to inhibit the interaction between IN and LEDGF/p75. Furthermore, Simulation studies were carried out on these molecules to expose their dynamics behavior and stability. We expect that the findings obtained here could be future therapeutic agents and may provide an outline for the experimental studies to stimulate the innovative strategy for research community.

  9. Key economic sectors and services

    NARCIS (Netherlands)

    Arent, Douglas J.; Tol, Richard S.J.; Faust, Eberhard; Hella, Joseph P.; Kumar, Surender; Strzepek, Kenneth M.; Tóth, Ferenc L.; Yan, Denghua; Abdulla, Amjad; Kheshgi, Haroon; Xu, He; Ngeh, Julius

    2015-01-01

    Introduction and Context This chapter discusses the implications of climate change on key economic sectors and services, for example, economic activity. Other chapters discuss impacts from a physical, chemical, biological, or social perspective. Economic impacts cannot be isolated; therefore, there

  10. Algorithms for Lightweight Key Exchange.

    Science.gov (United States)

    Alvarez, Rafael; Caballero-Gil, Cándido; Santonja, Juan; Zamora, Antonio

    2017-06-27

    Public-key cryptography is too slow for general purpose encryption, with most applications limiting its use as much as possible. Some secure protocols, especially those that enable forward secrecy, make a much heavier use of public-key cryptography, increasing the demand for lightweight cryptosystems that can be implemented in low powered or mobile devices. This performance requirements are even more significant in critical infrastructure and emergency scenarios where peer-to-peer networks are deployed for increased availability and resiliency. We benchmark several public-key key-exchange algorithms, determining those that are better for the requirements of critical infrastructure and emergency applications and propose a security framework based on these algorithms and study its application to decentralized node or sensor networks.

  11. Key Injury and Violence Data

    Science.gov (United States)

    ... Traumatic Brain Injury Violence Prevention Key Injury and Violence Data Recommend on Facebook Tweet Share Compartir Injuries ... of death among persons 1-44. Injury- and violence-related deaths are only part of the problem ...

  12. Secret key rates in quantum key distribution using Renyi entropies

    Energy Technology Data Exchange (ETDEWEB)

    Abruzzo, Silvestre; Kampermann, Hermann; Mertz, Markus; Bratzik, Sylvia; Bruss, Dagmar [Institut fuer Theoretische Physik III, Heinrich-Heine-Universitaet Duesseldorf (Germany)

    2010-07-01

    The secret key rate r of a quantum key distribution protocol depends on the involved number of signals and the accepted ''failure probability''. We reconsider a method to calculate r focusing on the analysis of the privacy amplification given by R. Renner and R. Koenig (2005). This approach involves an optimization problem with an objective function depending on the Renyi entropy of the density operator describing the classical outcomes and the eavesdropper system. This problem is analyzed for a generic class of QKD protocols and the current research status is presented.

  13. Three state quantum key distribution for small keys

    International Nuclear Information System (INIS)

    Batuwantudawe, J.; Boileau, J.-C.

    2005-01-01

    Full text: Quantum key distribution (QKD) protocols allow two parties, Alice and Bob, to establish secure keys. The most well-known protocol is BB84, using four distinct states. Recently, Phoenix et al. proposed a three state protocol. We explain the protocol and discuss its security proof. The three state protocol also has an interesting structure that allows for errors estimation from the inconclusive results (i.e.. where Alice and Bob choose different bases). This eliminates the need for sampling, potentially useful when qubits are limited. We discuss the effectiveness of this approach compared to BB84 for the case where a good error estimate is required. (author)

  14. Decoy State Quantum Key Distribution

    Science.gov (United States)

    Lo, Hoi-Kwong

    2005-10-01

    Quantum key distribution (QKD) allows two parties to communicate in absolute security based on the fundamental laws of physics. Up till now, it is widely believed that unconditionally secure QKD based on standard Bennett-Brassard (BB84) protocol is limited in both key generation rate and distance because of imperfect devices. Here, we solve these two problems directly by presenting new protocols that are feasible with only current technology. Surprisingly, our new protocols can make fiber-based QKD unconditionally secure at distances over 100km (for some experiments, such as GYS) and increase the key generation rate from O(η2) in prior art to O(η) where η is the overall transmittance. Our method is to develop the decoy state idea (first proposed by W.-Y. Hwang in "Quantum Key Distribution with High Loss: Toward Global Secure Communication", Phys. Rev. Lett. 91, 057901 (2003)) and consider simple extensions of the BB84 protocol. This part of work is published in "Decoy State Quantum Key Distribution", . We present a general theory of the decoy state protocol and propose a decoy method based on only one signal state and two decoy states. We perform optimization on the choice of intensities of the signal state and the two decoy states. Our result shows that a decoy state protocol with only two types of decoy states--a vacuum and a weak decoy state--asymptotically approaches the theoretical limit of the most general type of decoy state protocols (with an infinite number of decoy states). We also present a one-decoy-state protocol as a special case of Vacuum+Weak decoy method. Moreover, we provide estimations on the effects of statistical fluctuations and suggest that, even for long distance (larger than 100km) QKD, our two-decoy-state protocol can be implemented with only a few hours of experimental data. In conclusion, decoy state quantum key distribution is highly practical. This part of work is published in "Practical Decoy State for Quantum Key Distribution

  15. KeyPathwayMinerWeb

    DEFF Research Database (Denmark)

    List, Markus; Alcaraz, Nicolas; Dissing-Hansen, Martin

    2016-01-01

    , for instance), KeyPathwayMiner extracts connected sub-networks containing a high number of active or differentially regulated genes (proteins, metabolites) in the molecular profiles. The web interface at (http://keypathwayminer.compbio.sdu.dk) implements all core functionalities of the KeyPathwayMiner tool set......We present KeyPathwayMinerWeb, the first online platform for de novo pathway enrichment analysis directly in the browser. Given a biological interaction network (e.g. protein-protein interactions) and a series of molecular profiles derived from one or multiple OMICS studies (gene expression...... such as data integration, input of background knowledge, batch runs for parameter optimization and visualization of extracted pathways. In addition to an intuitive web interface, we also implemented a RESTful API that now enables other online developers to integrate network enrichment as a web service...

  16. Key Lake spill. Final report

    International Nuclear Information System (INIS)

    1984-03-01

    On January 5, 1984 contaminated water overflowed a storage reservoir at the Key Lake uranium mill onto the ice on a neighboring lake, into a muskeg area and onto a road. Outflow continued for two days, partially undercutting a retaining dyke. This report concludes the spill was the result of poor operation by the Key Lake Mining Corp.. The environmental impact will be minimal after cleanup. Improvements can be made in the regulatory process, and it is necessary to prepare for possible future mishaps

  17. Key World Energy Statistics 2013

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2013-08-01

    The IEA produced its first handy, pocket-sized summary of key energy data in 1997 and every year since then it has been more and more successful. Key World Energy Statistics contains timely, clearly-presented data on supply, transformation and consumption of all major energy sources. The interested businessman, journalist or student will have at his or her fingertips the annual Canadian production of coal, the electricity consumption in Thailand, the price of diesel oil in Spain and thousands of other useful energy facts.

  18. Key China Energy Statistics 2012

    Energy Technology Data Exchange (ETDEWEB)

    Levine, Mark [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Fridley, David [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Lu, Hongyou [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Fino-Chen, Cecilia [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2012-05-01

    The China Energy Group at Lawrence Berkeley National Laboratory (LBNL) was established in 1988. Over the years the Group has gained recognition as an authoritative source of China energy statistics through the publication of its China Energy Databook (CED). The Group has published seven editions to date of the CED (http://china.lbl.gov/research/chinaenergy-databook). This handbook summarizes key statistics from the CED and is expressly modeled on the International Energy Agency’s “Key World Energy Statistics” series of publications. The handbook contains timely, clearly-presented data on the supply, transformation, and consumption of all major energy sources.

  19. Key China Energy Statistics 2011

    Energy Technology Data Exchange (ETDEWEB)

    Levine, Mark [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Fridley, David [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Lu, Hongyou [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Fino-Chen, Cecilia [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2012-01-15

    The China Energy Group at Lawrence Berkeley National Laboratory (LBNL) was established in 1988. Over the years the Group has gained recognition as an authoritative source of China energy statistics through the publication of its China Energy Databook (CED). In 2008 the Group published the Seventh Edition of the CED (http://china.lbl.gov/research/chinaenergy-databook). This handbook summarizes key statistics from the CED and is expressly modeled on the International Energy Agency’s “Key World Energy Statistics” series of publications. The handbook contains timely, clearly-presented data on the supply, transformation, and consumption of all major energy sources.

  20. Grouted Connections with Shear Keys

    DEFF Research Database (Denmark)

    Pedersen, Ronnie; Jørgensen, M. B.; Damkilde, Lars

    2012-01-01

    This paper presents a finite element model in the software package ABAQUS in which a reliable analysis of grouted pile-to-sleeve connections with shear keys is the particular purpose. The model is calibrated to experimental results and a consistent set of input parameters is estimated so that dif...... that different structural problems can be reproduced successfully....

  1. Key to marine arthropod larvae

    Directory of Open Access Journals (Sweden)

    John A. Fornshell

    2012-03-01

    Full Text Available The scope of this key is restricted to the larvae of marine arthropods. The key is based solely on their morphology, patterns of body segmentation, numbers of appendages, and mode of locomotion. An effort has been made to treat all traditionally named larval forms, both planktonic and benthic. It is intended that this key be useful for a researcher working with archived museum specimens and therefore, does not include habitat information as a identifying trait, even though this information is usually available in the archived records. Within the phylum Arthropoda there are two sub-phyla and eleven classes having larval stages in the marineenvironment. Where feasible the original names of the various larval types have been used. Because this nomenclature is less commonly used today compared to the past, the more recent taxonomic affinities are included in parentheses after the original larval name. The key includes the following thirty-four larvae: Branchhiopoda nauplii; Cephalocarida nauplii; Mystacocarida nauplii; trilobite larva; protonymphon; hexapod larvae; Remipedia nauplii; nauplius - Y larvae; Cirripedia nauplii; Ascothoracida nauplii; Ostracoda nauplii; Euphausiacea nauplii; Penaeidea nauplii; Cyclopoida nauplii; Calanoida nauplii; Harpacticoida nauplii;Polyarthra nauplii; cypris larva; eryonecius larva; cypris-Y larva; elapthocaris larvae; mysis larvae; lucifer zoea; acetes zoea; acanthosoma larva; phyllosoma; antizoea larva; anomuran zoea; brachyuran zoea; calyptopis larvae; furcilia larva; crytopia larva; puerulus larva; alima larva.

  2. Symmetric Key Authentication Services Revisited

    NARCIS (Netherlands)

    Crispo, B.; Popescu, B.C.; Tanenbaum, A.S.

    2004-01-01

    Most of the symmetric key authentication schemes deployed today are based on principles introduced by Needham and Schroeder [15] more than twenty years ago. However, since then, the computing environment has evolved from a LAN-based client-server world to include new paradigms, including wide area

  3. Key World Energy Statistics 2012

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2012-07-01

    Key World Energy Statistics contains timely, clearly-presented data on supply, transformation and consumption of all major energy sources. The interested businessman, journalist or student will have at his or her fingertips the annual Canadian production of coal, the electricity consumption in Thailand, the price of diesel oil in Spain and thousands of other useful energy facts.

  4. [Key informers. When and How?].

    Science.gov (United States)

    Martín González, R

    2009-03-01

    When information obtained through duly designed and developed studies is not available, the solution to certain problems that affect the population or that respond to certain questions may be approached by using the information and experience provided by the so-called key informer. The key informer is defined as a person who is in contact with the community or with the problem to be studied, who is considered to have good knowledge of the situation and therefore who is considered an expert. The search for consensus is the basis to obtain information through the key informers. The techniques used have different characteristics based on whether the experts chosen meet together or not, whether they are guided or not, whether they interact with each other or not. These techniques include the survey, the Delphi technique, the nominal group technique, brainwriting, brainstorming, the Phillips 66 technique, the 6-3-5 technique, the community forum and the community impressions technique. Information provided by key informers through the search for consensus is relevant when this is not available or cannot be obtained by other methods. It has permitted the analysis of the existing neurological care model, elaboration of recommendations on visit times for the out-patient neurological care, and the elaboration of guidelines and recommendations for the management of prevalent neurological problems.

  5. The Key to School Security.

    Science.gov (United States)

    Hotle, Dan

    1993-01-01

    In addition to legislative accessibility requirements, other security issues facing school administrators who select a security system include the following: access control; user friendliness; durability or serviceability; life safety precautions; possibility of vandalism, theft, and tampering; and key control. Offers steps to take in considering…

  6. Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein-ligand binding challenge.

    Science.gov (United States)

    Perryman, Alexander L; Santiago, Daniel N; Forli, Stefano; Martins, Diogo Santos; Olson, Arthur J

    2014-04-01

    To rigorously assess the tools and protocols that can be used to understand and predict macromolecular recognition, and to gain more structural insight into three newly discovered allosteric binding sites on a critical drug target involved in the treatment of HIV infections, the Olson and Levy labs collaborated on the SAMPL4 challenge. This computational blind challenge involved predicting protein-ligand binding against the three allosteric sites of HIV integrase (IN), a viral enzyme for which two drugs (that target the active site) have been approved by the FDA. Positive control cross-docking experiments were utilized to select 13 receptor models out of an initial ensemble of 41 different crystal structures of HIV IN. These 13 models of the targets were selected using our new "Rank Difference Ratio" metric. The first stage of SAMPL4 involved using virtual screens to identify 62 active, allosteric IN inhibitors out of a set of 321 compounds. The second stage involved predicting the binding site(s) and crystallographic binding mode(s) for 57 of these inhibitors. Our team submitted four entries for the first stage that utilized: (1) AutoDock Vina (AD Vina) plus visual inspection; (2) a new common pharmacophore engine; (3) BEDAM replica exchange free energy simulations, and a Consensus approach that combined the predictions of all three strategies. Even with the SAMPL4's very challenging compound library that displayed a significantly lower amount of structural diversity than most libraries that are conventionally employed in prospective virtual screens, these approaches produced hit rates of 24, 25, 34, and 27 %, respectively, on a set with 19 % declared binders. Our only entry for the second stage challenge was based on the results of AD Vina plus visual inspection, and it ranked third place overall according to several different metrics provided by the SAMPL4 organizers. The successful results displayed by these approaches highlight the utility of the computational

  7. Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein-ligand binding challenge

    Science.gov (United States)

    Perryman, Alexander L.; Santiago, Daniel N.; Forli, Stefano; Santos-Martins, Diogo; Olson, Arthur J.

    2014-04-01

    To rigorously assess the tools and protocols that can be used to understand and predict macromolecular recognition, and to gain more structural insight into three newly discovered allosteric binding sites on a critical drug target involved in the treatment of HIV infections, the Olson and Levy labs collaborated on the SAMPL4 challenge. This computational blind challenge involved predicting protein-ligand binding against the three allosteric sites of HIV integrase (IN), a viral enzyme for which two drugs (that target the active site) have been approved by the FDA. Positive control cross-docking experiments were utilized to select 13 receptor models out of an initial ensemble of 41 different crystal structures of HIV IN. These 13 models of the targets were selected using our new "Rank Difference Ratio" metric. The first stage of SAMPL4 involved using virtual screens to identify 62 active, allosteric IN inhibitors out of a set of 321 compounds. The second stage involved predicting the binding site(s) and crystallographic binding mode(s) for 57 of these inhibitors. Our team submitted four entries for the first stage that utilized: (1) AutoDock Vina (AD Vina) plus visual inspection; (2) a new common pharmacophore engine; (3) BEDAM replica exchange free energy simulations, and a Consensus approach that combined the predictions of all three strategies. Even with the SAMPL4's very challenging compound library that displayed a significantly lower amount of structural diversity than most libraries that are conventionally employed in prospective virtual screens, these approaches produced hit rates of 24, 25, 34, and 27 %, respectively, on a set with 19 % declared binders. Our only entry for the second stage challenge was based on the results of AD Vina plus visual inspection, and it ranked third place overall according to several different metrics provided by the SAMPL4 organizers. The successful results displayed by these approaches highlight the utility of the computational

  8. Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial.

    Directory of Open Access Journals (Sweden)

    Sergio Serrano-Villar

    2016-01-01

    Full Text Available Whether initiation of antiretroviral therapy (ART regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6, lipoteichoic acid (LTA, soluble CD14 (sCD14 and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively, with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease

  9. Key drivers of airline loyalty.

    Science.gov (United States)

    Dolnicar, Sara; Grabler, Klaus; Grün, Bettina; Kulnig, Anna

    2011-10-01

    This study investigates drivers of airline loyalty. It contributes to the body of knowledge in the area by investigating loyalty for a number of a priori market segments identified by airline management and by using a method which accounts for the multi-step nature of the airline choice process. The study is based on responses from 687 passengers. Results indicate that, at aggregate level, frequent flyer membership, price, the status of being a national carrier and the reputation of the airline as perceived by friends are the variables which best discriminate between travellers loyal to the airline and those who are not. Differences in drivers of airline loyalty for a number of segments were identified. For example, loyalty programs play a key role for business travellers whereas airline loyalty of leisure travellers is difficult to trace back to single factors. For none of the calculated models satisfaction emerged as a key driver of airline loyalty.

  10. Key papers in prostate cancer.

    Science.gov (United States)

    Rodney, Simon; Shah, Taimur Tariq; Patel, Hitendra R H; Arya, Manit

    2014-11-01

    Prostate cancer is the most common cancer and second leading cause of death in men. The evidence base for the diagnosis and treatment of prostate cancer is continually changing. We aim to review and discuss past and contemporary papers on these topics to provoke debate and highlight key dilemmas faced by the urological community. We review key papers on prostate-specific antigen screening, radical prostatectomy versus surveillance strategies, targeted therapies, timing of radiotherapy and alternative anti-androgen therapeutics. Previously, the majority of patients, irrespective of risk, underwent radical open surgical procedures associated with considerable morbidity and mortality. Evidence is emerging that not all prostate cancers are alike and that low-grade disease can be safely managed by surveillance strategies and localized treatment to the prostate. The question remains as to how to accurately stage the disease and ultimately choose which treatment pathway to follow.

  11. Key Topics in Sports Medicine

    OpenAIRE

    2006-01-01

    Key Topics in Sports Medicine is a single quick reference source for sports and exercise medicine. It presents the essential information from across relevant topic areas, and includes both the core and emerging issues in this rapidly developing field. It covers: 1) Sports injuries, rehabilitation and injury prevention, 2) Exercise physiology, fitness testing and training, 3) Drugs in sport, 4) Exercise and health promotion, 5) Sport and exercise for special and clinical populations, 6) The ps...

  12. Key issues for passive safety

    International Nuclear Information System (INIS)

    Hayns, M.R.

    1996-01-01

    The paper represents a summary of the introductory presentation made at this Advisory Group Meeting on the Technical Feasibility and Reliability of Passive Safety Systems. It was intended as an overview of our views on what are the key issues and what are the technical problems which might dominate any future developments of passive safety systems. It is, therefore, not a ''review paper'' as such and only record the highlights. (author)

  13. Human Resources Key Performance Indicators

    Directory of Open Access Journals (Sweden)

    Gabčanová Iveta

    2012-03-01

    Full Text Available The article brings out a proposed strategy map and respective key performance indicators (KPIs in human resources (HR. The article provides an overview of how HR activities are supported in order to reach the partial goals of HR as defined in the strategic map. Overall the aim of the paper is to show the possibilities of using the modern Balanced Scorecard method in human capital.

  14. Key issues for passive safety

    Energy Technology Data Exchange (ETDEWEB)

    Hayns, M R [AEA Technology, Harwell, Didcot (United Kingdom). European Institutions; Hicken, E F [Forschungszentrum Juelich GmbH (Germany)

    1996-12-01

    The paper represents a summary of the introductory presentation made at this Advisory Group Meeting on the Technical Feasibility and Reliability of Passive Safety Systems. It was intended as an overview of our views on what are the key issues and what are the technical problems which might dominate any future developments of passive safety systems. It is, therefore, not a ``review paper`` as such and only record the highlights. (author).

  15. Low carbon development. Key issues

    Energy Technology Data Exchange (ETDEWEB)

    Urban, Frauke; Nordensvaard, Johan (eds.)

    2013-03-07

    This comprehensive textbook addresses the interface between international development and climate change in a carbon constrained world. It discusses the key conceptual, empirical and policy-related issues of low carbon development and takes an international and interdisciplinary approach to the subject by drawing on insights from across the natural sciences and social sciences whilst embedding the discussion in a global context. The first part explores the concept of low carbon development and explains the need for low carbon development in a carbon constrained world. The book then discusses the key issues of socio-economic, political and technological nature for low carbon development, exploring topics such as the political economy, social justice, financing and carbon markets, and technologies and innovation for low carbon development. This is followed by key issues for low carbon development in policy and practice, which is presented based on cross-cutting issues such as low carbon energy, forestry, agriculture and transportation. Afterwards, practical case studies are discussed from low carbon development in low income countries in Africa, middle income countries in Asia and Latin America and high income countries in Europe and North America.

  16. Detector decoy quantum key distribution

    International Nuclear Information System (INIS)

    Moroder, Tobias; Luetkenhaus, Norbert; Curty, Marcos

    2009-01-01

    Photon number resolving detectors can enhance the performance of many practical quantum cryptographic setups. In this paper, we employ a simple method to estimate the statistics provided by such a photon number resolving detector using only a threshold detector together with a variable attenuator. This idea is similar in spirit to that of the decoy state technique, and is especially suited to those scenarios where only a few parameters of the photon number statistics of the incoming signals have to be estimated. As an illustration of the potential applicability of the method in quantum communication protocols, we use it to prove security of an entanglement-based quantum key distribution scheme with an untrusted source without the need for a squash model and by solely using this extra idea. In this sense, this detector decoy method can be seen as a different conceptual approach to adapt a single-photon security proof to its physical, full optical implementation. We show that in this scenario, the legitimate users can now even discard the double click events from the raw key data without compromising the security of the scheme, and we present simulations on the performance of the BB84 and the 6-state quantum key distribution protocols.

  17. Key Concepts in Microbial Oceanography

    Science.gov (United States)

    Bruno, B. C.; Achilles, K.; Walker, G.; Weersing, K.; Team, A

    2008-12-01

    The Center for Microbial Oceanography: Research and Education (C-MORE) is a multi-institution Science and Technology Center, established by the National Science Foundation in 2006. C-MORE's research mission is to facilitate a more comprehensive understanding of the diverse assemblages of microorganisms in the sea, ranging from the genetic basis of marine microbial biogeochemistry including the metabolic regulation and environmental controls of gene expression, to the processes that underpin the fluxes of carbon, related bioelements, and energy in the marine environment. The C-MORE education and outreach program is focused on increasing scientific literacy in microbial oceanography among students, educators, and the general public. A first step toward this goal is defining the key concepts that constitute microbial oceanography. After lengthy discussions with scientists and educators, both within and outside C-MORE, we have arrived at six key concepts: 1) Marine microbes are very small and have been around for a long time; 2) Life on Earth could not exist without microbes; 3) Most marine microbes are beneficial; 4) Microbes are everywhere: they are extremely abundant and diverse; 5) Microbes significantly impact our global climate; and 6) There are new discoveries every day in the field of microbial oceanography. A C-MORE-produced brochure on these six key concepts will be distributed at the meeting. Advanced copies may be requested by email or downloaded from the C-MORE web site(http://cmore.soest.hawaii.edu/downloads/MO_key_concepts_hi-res.pdf). This brochure also includes information on career pathways in microbial oceanography, with the aim of broadening participation in the field. C-MORE is eager to work in partnership to incorporate these key concepts into other science literacy publications, particularly those involving ocean and climate literacy. We thank the following contributors and reviewers: P Chisholm, A Dolberry, and A Thompson (MIT); N Lawrence

  18. A Recommended Set of Key Arctic Indicators

    Science.gov (United States)

    Stanitski, D.; Druckenmiller, M.; Fetterer, F. M.; Gerst, M.; Intrieri, J. M.; Kenney, M. A.; Meier, W.; Overland, J. E.; Stroeve, J.; Trainor, S.

    2017-12-01

    The Arctic is an interconnected and environmentally sensitive system of ice, ocean, land, atmosphere, ecosystems, and people. From local to pan-Arctic scales, the area has already undergone major changes in physical and societal systems and will continue at a pace that is greater than twice the global average. Key Arctic indicators can quantify these changes. Indicators serve as the bridge between complex information and policy makers, stakeholders, and the general public, revealing trends and information people need to make important socioeconomic decisions. This presentation evaluates and compiles more than 70 physical, biological, societal and economic indicators into an approachable summary that defines the changing Arctic. We divided indicators into "existing," "in development," "possible," and "aspirational". In preparing a paper on Arctic Indicators for a special issue of the journal Climatic Change, our group established a set of selection criteria to identify indicators to specifically guide decision-makers in their responses to climate change. A goal of the analysis is to select a manageable composite list of recommended indicators based on sustained, reliable data sources with known user communities. The selected list is also based on the development of a conceptual model that identifies components and processes critical to our understanding of the Arctic region. This list of key indicators is designed to inform the plans and priorities of multiple groups such as the U.S. Global Change Research Program (USGCRP), Interagency Arctic Research Policy Committee (IARPC), and the Arctic Council.

  19. Key attributes of expert NRL referees.

    Science.gov (United States)

    Morris, Gavin; O'Connor, Donna

    2017-05-01

    Experiential knowledge of elite National Rugby League (NRL) referees was investigated to determine the key attributes contributing to expert officiating performance. Fourteen current first-grade NRL referees were asked to identify the key attributes they believed contributed to their expert refereeing performance. The modified Delphi method involved a 3-round process of an initial semi-structured interview followed by 2 questionnaires to reach consensus of opinion. The data revealed 25 attributes that were rated as most important that underpin expert NRL refereeing performance. Results illustrate the significance of the cognitive category, with the top 6 ranked attributes all cognitive skills. Of these, the referees ranked decision-making accuracy as the most important attribute, followed by reading the game, communication, game understanding, game management and knowledge of the rules. Player rapport, positioning and teamwork were the top ranked game skill attributes underpinning performance excellence. Expert referees also highlighted a number of psychological attributes (e.g., concentration, composure and mental toughness) that were significant to performance. There were only 2 physiological attributes (fitness, aerobic endurance) that were identified as significant to elite officiating performance. In summary, expert consensus was attained which successfully provided a hierarchy of the most significant attributes of expert NRL refereeing performance.

  20. Fibre Optic Communication Key Devices

    CERN Document Server

    Grote, Norbert

    2012-01-01

    The book gives an in-depth description of the key devices of current and next generation fibre optic communication networks. In particular, the book covers devices such as semiconductor lasers, optical amplifiers, modulators, wavelength filters, and detectors but the relevant properties of optical fibres as well. The presentations include the physical principles underlying the various devices, the technologies used for the realization of the different devices, typical performance characteristics and limitations, and development trends towards more advanced components are also illustrated. Thus the scope of the book spans relevant principles, state-of-the-art implementations, the status of current research and expected future components.

  1. Symmetric autocompensating quantum key distribution

    Science.gov (United States)

    Walton, Zachary D.; Sergienko, Alexander V.; Levitin, Lev B.; Saleh, Bahaa E. A.; Teich, Malvin C.

    2004-08-01

    We present quantum key distribution schemes which are autocompensating (require no alignment) and symmetric (Alice and Bob receive photons from a central source) for both polarization and time-bin qubits. The primary benefit of the symmetric configuration is that both Alice and Bob may have passive setups (neither Alice nor Bob is required to make active changes for each run of the protocol). We show that both the polarization and the time-bin schemes may be implemented with existing technology. The new schemes are related to previously described schemes by the concept of advanced waves.

  2. Key energy technologies for Europe

    DEFF Research Database (Denmark)

    Jørgensen, B.H.

    2005-01-01

    This report on key energy technologies is part of the work undertaken by the High-Level Expert Group to prepare a report on emerging science and technology trends and the implications for EU and Member State research policies. Senior Scientist BirteHolst Jørgensen, Risø National Laboratory...... contributed by Scientific Officer Edgar Thielmann, DG TREN, Head of Department Hans Larsen, RisøNational Laboratory, Senior Asset Manager Aksel Hauge Pedersen, DONG VE, Consultant Timon Wehnert, IZT-Berlin, and Senior Scientist Martine Uyterlinde, ECN...

  3. Key concepts in social pedagogy

    DEFF Research Database (Denmark)

    Harbo, Lotte Junker

    2011-01-01

    and activities around key social pedagogical concepts, such as the Common Third, the 3 P’s, the Zone of Proximal Development and the Learning Zone model. In the article we explore how a joint activity, for example playing soccer, can be seen as a pedagogical activity and with what intentions it is undertaken......“Now I can actually play soccer with the young people without fearing that my colleagues think I am escaping the paper work.” These were the words from a participant in a social pedagogy training course in England a few years ago. This understanding emerged through in-depth discussions...

  4. Public/private key certification authority and key distribution. Draft

    Energy Technology Data Exchange (ETDEWEB)

    Long, J.P.; Christensen, M.J.; Sturtevant, A.P.; Johnston, W.E.

    1995-09-25

    Traditional encryption, which protects messages from prying eyes, has been used for many decades. The present concepts of encryption are built from that heritage. Utilization of modern software-based encryption techniques implies much more than simply converting files to an unreadable form. Ubiquitous use of computers and advances in encryption technology coupled with the use of wide-area networking completely changed the reasons for utilizing encryption technology. The technology demands a new and extensive infrastructure to support these functions. Full understanding of these functions, their utility and value, and the need for an infrastructure, takes extensive exposure to the new paradigm. This paper addresses issues surrounding the establishment and operation of a key management system (i.e., certification authority) that is essential to the successful implementation and wide-spread use of encryption.

  5. Public-Key Encryption with Non-interactive Opening

    DEFF Research Database (Denmark)

    Damgård, Ivan Bjerre; Hofheinz, Dennis; Kiltz, Eike

    2008-01-01

    We formally define the primitive of public-key encryption with non-interactive opening (PKENO), where the receiver of a ciphertext C can, convincingly and without interaction, reveal what the result was of decrypting C, without compromising the scheme’s security. This has numerous applications...

  6. Three key affordances for serendipity

    DEFF Research Database (Denmark)

    Björneborn, Lennart

    2017-01-01

    Purpose Serendipity is an interesting phenomenon to study in information science as it plays a fundamental – but perhaps underestimated – role in how we discover, explore, and learn in all fields of life. The purpose of this paper is to operationalize the concept of serendipity by providing termi...... terminological “building blocks” for understanding connections between environmental and personal factors in serendipitous encounters. Understanding these connections is essential when designing affordances in physical and digital environments that can facilitate serendipity. Design....../methodology/approach In this paper, serendipity is defined as what happens when we, in unplanned ways, encounter resources (information, things, people, etc.) that we find interesting. In the outlined framework, serendipity is understood as an affordance, i.e., a usage potential when environmental and personal factors correspond...... the three key affordances and three key personal serendipity factors: curiosity, mobility, and sensitivity. Ten sub-affordances for serendipity and ten coupled personal sub-factors are also briefly outlined. Related research is compared with and mapped into the framework aiming at a theoretical validation...

  7. Key energy technologies for Europe

    International Nuclear Information System (INIS)

    Holst Joergensen, Birte

    2005-09-01

    The report is part of the work undertaken by the High-Level Expert Group to prepare a report on emerging science and technology trends and the implications for EU and Member State research policies. The outline of the report is: 1) In the introductory section, energy technologies are defined and for analytical reasons further narrowed down; 2) The description of the socio-economic challenges facing Europe in the energy field is based on the analysis made by the International Energy Agency going back to 1970 and with forecasts to 2030. Both the world situation and the European situation are described. This section also contains an overview of the main EU policy responses to energy. Both EU energy R and D as well as Member State energy R and D resources are described in view of international efforts; 3) The description of the science and technology base is made for selected energy technologies, including energy efficiency, biomass, hydrogen, and fuel cells, photovoltaics, clean fossil fuel technologies and CO 2 capture and storage, nuclear fission and fusion. When possible, a SWOT is made for each technology and finally summarised; 4) The forward look highlights some of the key problems and uncertainties related to the future energy situation. Examples of recent energy foresights are given, including national energy foresights in Sweden and the UK as well as links to a number of regional and national foresights and roadmaps; 5) Appendix 1 contains a short description of key international organisations dealing with energy technologies and energy research. (ln)

  8. Information Systems Management: an Australian view of the key issues

    Directory of Open Access Journals (Sweden)

    Graham Pervan

    1994-05-01

    Full Text Available Studies investigating the key issues in IS management serve to better understand the concerns of IS managers and help to guide IS researchers in choosing IS management problems worthy of investigation. This paper presents results from a study of the key issues facing the IS managers of Australia's largest 300 organisations which is part of a three-yearly longitudinal study. In order to gain consensus on the relative importance of the key issues, a three-round Delphi method was applied. The results reveal that IS strategic planning continues to be the paramount issue in our industry, as are many issues associated with IS strategic planning, including responsiveness of the IT infrastructure, effective use of the data resource, IS for competitive advantage, and a comprehensive information architecture. A greater emphasis on quality is also revealed in highly rated issues such as effective use of the data resource, data integrity and quality assurance, and the quality of software development

  9. Key to Language Learning Success

    Directory of Open Access Journals (Sweden)

    Oktavian Mantiri

    2015-01-01

    Full Text Available This paper looks at the important elements of language learning and teaching i.e. the role of teachers as well as the attitude and motivation of learners. Teachers undoubtedly play crucial roles in students’ language learning outcome which could ignite or diminish students’ motivation. Positive attitudes and motivation – instrumental or integrative and intrinsic or extrinsic – are key to successful learning. Therefore it is paramount for language teachers as well as learners to know these roles and nurture the best possible ways where language teaching and learning will thrive. This paper also suggested that both stake-holders should be open to holistic approach of language learning and that other factors such as the environment could play an important part in language teaching and learning success.

  10. Cogeneration: Key feasibility analysis parameters

    International Nuclear Information System (INIS)

    Coslovi, S.; Zulian, A.

    1992-01-01

    This paper first reviews the essential requirements, in terms of scope, objectives and methods, of technical/economic feasibility analyses applied to cogeneration systems proposed for industrial plants in Italy. Attention is given to the influence on overall feasibility of the following factors: electric power and fuel costs, equipment coefficients of performance, operating schedules, maintenance costs, Italian Government taxes and financial and legal incentives. Through an examination of several feasibility studies that were done on cogeneration proposals relative to different industrial sectors, a sensitivity analysis is performed on the effects of varying the weights of different cost benefit analysis parameters. With the use of statistical analyses, standard deviations are then determined for key analysis parameters, and guidelines are suggested for analysis simplifications

  11. Fibre optic communication key devices

    CERN Document Server

    Grote, Norbert

    2017-01-01

    The book gives an in-depth description of key devices of current and next generation fibre optic communication networks. Devices treated include semiconductor lasers, optical amplifiers, modulators, wavelength filters and other passives, detectors, all-optical switches, but relevant properties of optical fibres and network aspects are included as well. The presentations include the physical principles underlying the various devices, technologies used for their realization, typical performance characteristics and limitations, but development trends towards more advanced components are also illustrated. This new edition of a successful book was expanded and updated extensively. The new edition covers among others lasers for optical communication, optical switches, hybrid integration, monolithic integration and silicon photonics. The main focus is on Indium phosphide-based structures but silicon photonics is included as well. The book covers relevant principles, state-of-the-art implementations, status of curren...

  12. Key energy technologies for Europe

    Energy Technology Data Exchange (ETDEWEB)

    Holst Joergensen, Birte

    2005-09-01

    The report is part of the work undertaken by the High-Level Expert Group to prepare a report on emerging science and technology trends and the implications for EU and Member State research policies. The outline of the report is: 1) In the introductory section, energy technologies are defined and for analytical reasons further narrowed down; 2) The description of the socio-economic challenges facing Europe in the energy field is based on the analysis made by the International Energy Agency going back to 1970 and with forecasts to 2030. Both the world situation and the European situation are described. This section also contains an overview of the main EU policy responses to energy. Both EU energy R and D as well as Member State energy R and D resources are described in view of international efforts; 3) The description of the science and technology base is made for selected energy technologies, including energy efficiency, biomass, hydrogen, and fuel cells, photovoltaics, clean fossil fuel technologies and CO{sub 2} capture and storage, nuclear fission and fusion. When possible, a SWOT is made for each technology and finally summarised; 4) The forward look highlights some of the key problems and uncertainties related to the future energy situation. Examples of recent energy foresights are given, including national energy foresights in Sweden and the UK as well as links to a number of regional and national foresights and roadmaps; 5) Appendix 1 contains a short description of key international organisations dealing with energy technologies and energy research. (ln)

  13. Noninvasive imaging technologies reveal edema toxin as a key virulence factor in anthrax.

    Science.gov (United States)

    Dumetz, Fabien; Jouvion, Grégory; Khun, Huot; Glomski, Ian Justin; Corre, Jean-Philippe; Rougeaux, Clémence; Tang, Wei-Jen; Mock, Michèle; Huerre, Michel; Goossens, Pierre Louis

    2011-06-01

    Powerful noninvasive imaging technologies enable real-time tracking of pathogen-host interactions in vivo, giving access to previously elusive events. We visualized the interactions between wild-type Bacillus anthracis and its host during a spore infection through bioluminescence imaging coupled with histology. We show that edema toxin plays a central role in virulence in guinea pigs and during inhalational infection in mice. Edema toxin (ET), but not lethal toxin (LT), markedly modified the patterns of bacterial dissemination leading, to apparent direct dissemination to the spleen and provoking apoptosis of lymphoid cells. Each toxin alone provoked particular histological lesions in the spleen. When ET and LT are produced together during infection, a specific temporal pattern of lesion developed, with early lesions typical of LT, followed at a later stage by lesions typical of ET. Our study provides new insights into the complex spatial and temporal effects of B. anthracis toxins in the infected host, suggesting a greater role than previously suspected for ET in anthrax and suggesting that therapeutic targeting of ET contributes to protection. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  14. Dynamic Metabolic Footprinting Reveals the Key Components of Metabolic Network in Yeast Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Chumnanpuen, Pramote; Hansen, Michael Adsetts Edberg; Smedsgaard, Jørn

    2014-01-01

    relies on analysis at a single time point. Using direct infusion-mass spectrometry (DI-MS), we could observe the dynamic metabolic footprinting in yeast S. cerevisiae BY4709 (wild type) cultured on 3 different C-sources (glucose, glycerol, and ethanol) and sampled along 10 time points with 5 biological...... replicates. In order to analyze the dynamic mass spectrometry data, we developed the novel analysis methods that allow us to perform correlation analysis to identify metabolites that significantly correlate over time during growth on the different carbon sources. Both positive and negative electrospray...... reconstructed an interaction map that provides information of how different metabolic pathways have correlated patterns during growth on the different carbon sources....

  15. Biofuels: Network Analysis of the Literature Reveals Key Environmental and Economic Unknowns

    Science.gov (United States)

    2012-01-01

    Despite rapid growth in biofuel production worldwide, it is uncertain whether decision-makers possess sufficient information to fully evaluate the impacts of the industry and avoid unintended consequences. Doing so requires rigorous peer-reviewed data and analyses across the entire range of direct and indirect effects. To assess the coverage of scientific research, we analyzed over 1600 peer-reviewed articles published between 2000 and 2009 that addressed 23 biofuels-related topics within four thematic areas: environment and human well-being, economics, technology, and geography. Greenhouse gases, fuel production, and feedstock production were well-represented in the literature, while trade, biodiversity, and human health were not. Gaps were especially striking across topics in the Southern Hemisphere, where the greatest potential socio-economic benefits, as well as environmental damages, may co-occur. There was strong asymmetry in the connectedness of research topics; greenhouse gases articles were twice as often connected to other topics as biodiversity articles. This could undermine the ability of scientific and economic analyses to adequately evaluate impacts and avoid significant unintended consequences. At the least, our review suggests caution in this developing industry and the need to pursue more interdisciplinary research to assess complex trade-offs and feedbacks inherent to an industry with wide-reaching potential impacts. PMID:22229835

  16. Transcriptome and metabolome of synthetic Solanum autotetraploids reveal key genomic stress events following polyploidization.

    Science.gov (United States)

    Fasano, Carlo; Diretto, Gianfranco; Aversano, Riccardo; D'Agostino, Nunzio; Di Matteo, Antonio; Frusciante, Luigi; Giuliano, Giovanni; Carputo, Domenico

    2016-06-01

    Polyploids are generally classified as autopolyploids, derived from a single species, and allopolyploids, arising from interspecific hybridization. The former represent ideal materials with which to study the consequences of genome doubling and ascertain whether there are molecular and functional rules operating following polyploidization events. To investigate whether the effects of autopolyploidization are common to different species, or if species-specific or stochastic events are prevalent, we performed a comprehensive transcriptomic and metabolomic characterization of diploids and autotetraploids of Solanum commersonii and Solanum bulbocastanum. Autopolyploidization remodelled the transcriptome and the metabolome of both species. In S. commersonii, differentially expressed genes (DEGs) were highly enriched in pericentromeric regions. Most changes were stochastic, suggesting a strong genotypic response. However, a set of robustly regulated transcripts and metabolites was also detected, including purine bases and nucleosides, which are likely to underlie a common response to polyploidization. We hypothesize that autopolyploidization results in nucleotide pool imbalance, which in turn triggers a genomic shock responsible for the stochastic events observed. The more extensive genomic stress and the higher number of stochastic events observed in S. commersonii with respect to S. bulbocastanum could be the result of the higher nucleoside depletion observed in this species. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  17. DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity

    DEFF Research Database (Denmark)

    Gupta, Rajat; Somyajit, Kumar; Narita, Takeo

    2018-01-01

    Repair of damaged DNA is essential for maintaining genome integrity and for preventing genome-instability-associated diseases, such as cancer. By combining proximity labeling with quantitative mass spectrometry, we generated high-resolution interaction neighborhood maps of the endogenously expres...... and the evolution of antibody CSR in higher vertebrates....

  18. The Chlamydomonas genome reveals the evolution of key animal and plant functions

    Czech Academy of Sciences Publication Activity Database

    Merchant, S.S.; Prochnik, S. E.; Bišová, Kateřina

    2007-01-01

    Roč. 318, - (2007), s. 245-251 ISSN 0036-8075 Institutional research plan: CEZ:AV0Z50200510 Keywords : chlamydomonas reinhardtii * alga * eukaryotic cell Subject RIV: EE - Microbiology, Virology Impact factor: 26.372, year: 2007

  19. Multi-Level Integration of Environmentally Perturbed Internal Phenotypes Reveals Key Points of Connectivity between Them

    Directory of Open Access Journals (Sweden)

    Nirupama Benis

    2017-06-01

    Full Text Available The genotype and external phenotype of organisms are linked by so-called internal phenotypes which are influenced by environmental conditions. In this study, we used five existing -omics datasets representing five different layers of internal phenotypes, which were simultaneously measured in dietarily perturbed mice. We performed 10 pair-wise correlation analyses verified with a null model built from randomized data. Subsequently, the inferred networks were merged and literature mined for co-occurrences of identified linked nodes. Densely connected internal phenotypes emerged. Forty-five nodes have links with all other data-types and we denote them “connectivity hubs.” In literature, we found proof of 6% of the 577 connections, suggesting a biological meaning for the observed correlations. The observed connectivities between metabolite and cytokines hubs showed higher numbers of literature hits as compared to the number of literature hits on the connectivities between the microbiota and gene expression internal phenotypes. We conclude that multi-level integrated networks may help to generate hypotheses and to design experiments aiming to further close the gap between genotype and phenotype. We describe and/or hypothesize on the biological relevance of four identified multi-level connectivity hubs.

  20. Genetic Disruption of 2-Arachidonoylglycerol Synthesis Reveals a Key Role for Endocannabinoid Signaling in Anxiety Modulation

    Directory of Open Access Journals (Sweden)

    Brian C. Shonesy

    2014-12-01

    Full Text Available Summary: Endocannabinoid (eCB signaling has been heavily implicated in the modulation of anxiety and depressive behaviors and emotional learning. However, the role of the most-abundant endocannabinoid 2-arachidonoylglycerol (2-AG in the physiological regulation of affective behaviors is not well understood. Here, we show that genetic deletion of the 2-AG synthetic enzyme diacylglycerol lipase α (DAGLα in mice reduces brain, but not circulating, 2-AG levels. DAGLα deletion also results in anxiety-like and sex-specific anhedonic phenotypes associated with impaired activity-dependent eCB retrograde signaling at amygdala glutamatergic synapses. Importantly, acute pharmacological normalization of 2-AG levels reverses both phenotypes of DAGLα-deficient mice. These data suggest 2-AG deficiency could contribute to the pathogenesis of affective disorders and that pharmacological normalization of 2-AG signaling could represent an approach for the treatment of mood and anxiety disorders. : The role of the primary endogenous cannabinoid 2-AG in mood and anxiety regulation is not well understood. Shonesy et al. show that deletion of a primary 2-AG synthetic enzyme, DAGLα, results in anxiety and sex-specific depressive phenotypes, which can be rapidly reversed by pharmacological normalization of endocannabinoid levels.

  1. De novo Assembly of the Camellia nitidissima Transcriptome Reveals Key Genes of Flower Pigment Biosynthesis

    Directory of Open Access Journals (Sweden)

    Xingwen Zhou

    2017-09-01

    Full Text Available The golden camellia, Camellia nitidissima Chi., is a well-known ornamental plant that is known as “the queen of camellias” because of its golden yellow flowers. The principal pigments in the flowers are carotenoids and flavonol glycosides. Understanding the biosynthesis of the golden color and its regulation is important in camellia breeding. To obtain a comprehensive understanding of flower development in C. nitidissima, a number of cDNA libraries were independently constructed during flower development. Using the Illumina Hiseq2500 platform, approximately 71.8 million raw reads (about 10.8 gigabase pairs were obtained and assembled into 583,194 transcripts and 466, 594 unigenes. A differentially expressed genes (DEGs and co-expression network was constructed to identify unigenes correlated with flower color. The analysis of DEGs and co-expressed network involved in the carotenoid pathway indicated that the biosynthesis of carotenoids is regulated mainly at the transcript level and that phytoene synthase (PSY, β -carotene 3-hydroxylase (CrtZ, and capsanthin synthase (CCS1 exert synergistic effects in carotenoid biosynthesis. The analysis of DEGs and co-expressed network involved in the flavonoid pathway indicated that chalcone synthase (CHS, naringenin 3-dioxygenase (F3H, leucoanthocyanidin dioxygenase(ANS, and flavonol synthase (FLS play critical roles in regulating the formation of flavonols and anthocyanidin. Based on the gene expression analysis of the carotenoid and flavonoid pathways, and determinations of the pigments, we speculate that the high expression of PSY and CrtZ ensures the production of adequate levels of carotenoids, while the expression of CHS, FLS ensures the production of flavonols. The golden yellow color is then the result of the accumulation of carotenoids and flavonol glucosides in the petals. This study of the mechanism of color formation in golden camellia points the way to breeding strategies that exploit gene technology approaches to increase the content of carotenoids and flavonol glucosides and to decrease anthocyanidin synthesis.

  2. Genomic analysis reveals key aspects of prokaryotic symbiosis in the phototrophic consortium "Chlorochromatium aggregatum"

    DEFF Research Database (Denmark)

    Liu, Zhenfeng; Müller, Johannes; Li, Tao

    2013-01-01

    'Chlorochromatium aggregatum' is a phototrophic consortium, a symbiosis that may represent the highest degree of mutual interdependence between two unrelated bacteria not associated with a eukaryotic host. 'Chlorochromatium aggregatum' is a motile, barrel-shaped aggregate formed from a single cell...

  3. Expression pattern of glycoside hydrolase genes in Lutzomyia longipalpis reveals key enzymes involved in larval digestion

    Directory of Open Access Journals (Sweden)

    Caroline da Silva Moraes

    2014-08-01

    Full Text Available The sand fly Lutzomyia longipalpis is the most important vector of American Visceral Leishmaniasis. Adults are phytophagous (males and females or blood feeders (females only, and larvae feed on solid detritus. Digestion in sand fly larvae has scarcely been studied, but some glycosidase activities putatively involved in microorganism digestion were already described. Nevertheless, the molecular nature of these enzymes, as the corresponding genes and transcripts, were not explored yet. Catabolism of microbial carbohydrates in insects generally involves β-1,3-glucanases, chitinases and digestive lysozymes. In this work, the transcripts of digestive β-1,3-glucanase and chitinases were identified in the L. longipalpis larvae throughout analysis of sequences and expression patterns of glycoside hydrolases families 16, 18 and 22. The activity of one i-type lysozyme was also registered. Interestingly, this lysozyme seems to play a role in immunity, rather than digestion. This is the first attempt to identify the molecular nature of sand fly larval digestive enzymes.

  4. Expression pattern of glycoside hydrolase genes in Lutzomyia longipalpis reveals key enzymes involved in larval digestion

    Science.gov (United States)

    Moraes, Caroline da Silva; Diaz-Albiter, Hector M.; Faria, Maiara do Valle; Sant'Anna, Maurício R. V.; Dillon, Rod J.; Genta, Fernando A.

    2014-01-01

    The sand fly Lutzomyia longipalpis is the most important vector of American Visceral Leishmaniasis. Adults are phytophagous (males and females) or blood feeders (females only), and larvae feed on solid detritus. Digestion in sand fly larvae has scarcely been studied, but some glycosidase activities putatively involved in microorganism digestion were already described. Nevertheless, the molecular nature of these enzymes, as the corresponding genes and transcripts, were not explored yet. Catabolism of microbial carbohydrates in insects generally involves β-1,3-glucanases, chitinases, and digestive lysozymes. In this work, the transcripts of digestive β-1,3-glucanase and chitinases were identified in the L. longipalpis larvae throughout analysis of sequences and expression patterns of glycoside hydrolases families 16, 18, and 22. The activity of one i-type lysozyme was also registered. Interestingly, this lysozyme seems to play a role in immunity, rather than digestion. This is the first attempt to identify the molecular nature of sand fly larval digestive enzymes. PMID:25140153

  5. Surface N-glycoproteome patterns reveal key proteins of neuronal differentiation

    Czech Academy of Sciences Publication Activity Database

    Tylečková, Jiřina; Valeková, Ivona; Žižková, Martina; Rákocyová, Michaela; Maršala, S.; Maršala, M.; Gadher, S. J.; Kovářová, Hana

    2016-01-01

    Roč. 132, č. 1 (2016), s. 13-20 ISSN 1874-3919 R&D Projects: GA MŠk ED2.1.00/03.0124; GA TA ČR(CZ) TA01011466 Institutional support: RVO:67985904 Keywords : cell adhesion proteins * cell surface capture * neuronal differentiation Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.914, year: 2016

  6. The University of Canberra quantum key distribution testbed

    International Nuclear Information System (INIS)

    Ganeshkumar, G.; Edwards, P.J.; Cheung, W.N.; Barbopoulos, L.O.; Pham, H.; Hazel, J.C.

    1999-01-01

    Full text: We describe the design, operation and preliminary results obtained from a quantum key distribution (QKD) testbed constructed at the University of Canberra. Quantum cryptographic systems use shared secret keys exchanged in the form of sequences of polarisation coded or phase encoded single photons transmitted over an optical communications channel. Secrecy of this quantum key rests upon fundamental laws of quantum physics: measurements of linear or circular photon polarisation states introduce noise into the conjugate variable and so reveal eavesdropping. In its initial realisation reported here, pulsed light from a 650nm laser diode is attenuated by a factor of 10 6 , plane-polarised and then transmitted through a birefringent liquid crystal modulator (LCM) to a polarisation sensitive single photon receiver. This transmitted key sequence consists of a 1 kHz train of weak coherent 100ns wide light pulses, polarisation coded according to the BB84 protocol. Each pulse is randomly assigned one of four polarisation states (two orthogonal linear and two orthogonal circular) by computer PCA operated by the sender ('Alice'). This quaternary polarisation shift keyed photon stream is detected by the receiver ('Bob') whose computer (PCB) randomly chooses either a linear or a circular polarisation basis. Computer PCB is also used for final key selection, authentication, privacy amplification and eavesdropping. We briefly discuss the realisation of a mesoscopic single photon QKD source and the use of the testbed to simulate a global quantum key distribution system using earth satellites. Copyright (1999) Australian Optical Society

  7. 25 CFR 502.14 - Key employee.

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 2 2010-04-01 2010-04-01 false Key employee. 502.14 Section 502.14 Indians NATIONAL....14 Key employee. Key employee means: (a) A person who performs one or more of the following functions... gaming operation. (d) Any other person designated by the tribe as a key employee. [57 FR 12392, Apr. 9...

  8. VICKEY: Mining Conditional Keys on Knowledge Bases

    DEFF Research Database (Denmark)

    Symeonidou, Danai; Prado, Luis Antonio Galarraga Del; Pernelle, Nathalie

    2017-01-01

    A conditional key is a key constraint that is valid in only a part of the data. In this paper, we show how such keys can be mined automatically on large knowledge bases (KBs). For this, we combine techniques from key mining with techniques from rule mining. We show that our method can scale to KBs...

  9. On the Security of a Simple Three-Party Key Exchange Protocol without Server’s Public Keys

    Directory of Open Access Journals (Sweden)

    Junghyun Nam

    2014-01-01

    Full Text Available Authenticated key exchange protocols are of fundamental importance in securing communications and are now extensively deployed for use in various real-world network applications. In this work, we reveal major previously unpublished security vulnerabilities in the password-based authenticated three-party key exchange protocol according to Lee and Hwang (2010: (1 the Lee-Hwang protocol is susceptible to a man-in-the-middle attack and thus fails to achieve implicit key authentication; (2 the protocol cannot protect clients’ passwords against an offline dictionary attack; and (3 the indistinguishability-based security of the protocol can be easily broken even in the presence of a passive adversary. We also propose an improved password-based authenticated three-party key exchange protocol that addresses the security vulnerabilities identified in the Lee-Hwang protocol.

  10. Quantum key distribution and cryptography

    International Nuclear Information System (INIS)

    Alleaume, R.

    2005-01-01

    Full text: Originally proposed by classical cryptographers, the ideas behind Quantum Key Distribution (QKD) have attracted considerable interest among the quantum optics community, which has significantly helped bring these ideas to reality. Experimental realizations have quickly evolved from early lab demonstrations to QKD systems that are now deployed in real conditions and targeting commercial applications. Although QKD can be theoretically proven to rely on 'unconditional security proofs' and should thus be able to provide security levels unachievable through computationally-based cryptographic techniques, the debate on the cryptographic applications of QKD remains somehow controversial. It seems that a consensus on that matter cannot be reached without a careful analysis of assumptions and definitions related to security models used in classical or in quantum cryptography. In this talk, we will try to present a comprehensive synthesis on this topic. We have initiated this work as a contribution to the European IP SECOQC project, confronting views and knowledge among experimental and theoretical quantum physicists, as well as classical cryptographers. (author)

  11. Simple Web-based interactive key development software (WEBiKEY) and an example key for Kuruna (Poaceae: Bambusoideae).

    Science.gov (United States)

    Attigala, Lakshmi; De Silva, Nuwan I; Clark, Lynn G

    2016-04-01

    Programs that are user-friendly and freely available for developing Web-based interactive keys are scarce and most of the well-structured applications are relatively expensive. WEBiKEY was developed to enable researchers to easily develop their own Web-based interactive keys with fewer resources. A Web-based multiaccess identification tool (WEBiKEY) was developed that uses freely available Microsoft ASP.NET technologies and an SQL Server database for Windows-based hosting environments. WEBiKEY was tested for its usability with a sample data set, the temperate woody bamboo genus Kuruna (Poaceae). WEBiKEY is freely available to the public and can be used to develop Web-based interactive keys for any group of species. The interactive key we developed for Kuruna using WEBiKEY enables users to visually inspect characteristics of Kuruna and identify an unknown specimen as one of seven possible species in the genus.

  12. KEY TOPICS IN SPORTS MEDICINE

    Directory of Open Access Journals (Sweden)

    Amir Ali Narvani

    2006-12-01

    Full Text Available Key Topics in Sports Medicine is a single quick reference source for sports and exercise medicine. It presents the essential information from across relevant topic areas, and includes both the core and emerging issues in this rapidly developing field. It covers: 1 Sports injuries, rehabilitation and injury prevention, 2 Exercise physiology, fitness testing and training, 3 Drugs in sport, 4 Exercise and health promotion, 5 Sport and exercise for special and clinical populations, 6 The psychology of performance and injury. PURPOSE The Key Topics format provides extensive, concise information in an accessible, easy-to-follow manner. AUDIENCE The book is targeted the students and specialists in sports medicine and rehabilitation, athletic training, physiotherapy and orthopaedic surgery. The editors are authorities in their respective fields and this handbook depends on their extensive experience and knowledge accumulated over the years. FEATURES The book contains the information for clinical guidance, rapid access to concise details and facts. It is composed of 99 topics which present the information in an order that is considered logical and progressive as in most texts. Chapter headings are: 1. Functional Anatomy, 2. Training Principles / Development of Strength and Power, 3. Biomechanical Principles, 4. Biomechanical Analysis, 5. Physiology of Training, 6. Monitoring of Training Progress, 7. Nutrition, 8. Hot and Cold Climates, 9. Altitude, 10. Sport and Travelling, 11. Principles of Sport Injury Diagnosis, 12. Principles of Sport and Soft Tissue Management, 13. Principles of Physical Therapy and Rehabilitation, 14. Principles of Sport Injury Prevention, 15. Sports Psychology, 16. Team Sports, 17. Psychological Aspects of Injury in Sport, 18. Injury Repair Process, 19. Basic Biomechanics of Tissue Injury, 20. Plain Film Radiography in Sport, 21. Nuclear Medicine, 22. Diagnostic Ultrasound, 23. MRI Scan, 24. Other Imaging, 5. Head Injury, 26. Eye

  13. Introduction strategies raise key questions.

    Science.gov (United States)

    Finger, W R; Keller, S

    1995-09-01

    Key issues that must be considered before a new contraceptive is introduced center on the need for a trained provider to begin or terminate the method, its side effects, duration of use, method's ability to meet users' needs and preferences, and extra training or staff requirements. Logistics and economic issues to consider are identifying a dependable way of effectively supplying commodities, planning extra services needed for the method, and cost of providing the method. Each contraceptive method presents a different side effect pattern and burdens the service delivery setting differently. The strategy developed to introduce or expand the 3-month injectable Depo-Provera (DMPA) can be used for any method. It includes a needs assessment and addresses regulatory issues, service delivery policies and procedures, information and training, evaluation, and other concerns. Viet Nam's needs assessment showed that Norplant should not be introduced until the service delivery system becomes stronger. Any needs assessment for expansion of contraceptive services should cover sexually transmitted disease/HIV issues. A World Health Organization strategy helps officials identify the best method mix for local situations. Introductory strategies must aim to improve the quality of family planning programs and expand choices. Many begin by examining existing data and conducting interviews with policymakers, users, providers, and women's health advocates. Introductory programs for Norplant focus on provider training, adequate counseling and informed consent for users, and ready access to removal. They need a well-prepared service delivery infrastructure. The first phase of the DMPA introductory strategy for the Philippines comprised a social marketing campaign and DMPA introduction at public clinics in 10 pilot areas with strong service delivery. Successful AIDS prevention programs show that people tend to use barrier methods when they are available. USAID is currently studying

  14. Key issues in transplant tourism.

    Science.gov (United States)

    Akoh, Jacob A

    2012-02-24

    Access to organ transplantation depends on national circumstances, and is partly determined by the cost of health care, availability of transplant services, the level of technical capacity and the availability of organs. Commercial transplantation is estimated to account for 5%-10% (3500-7000) of kidney transplants performed annually throughout the world. This review is to determine the state and outcome of renal transplantation associated with transplant tourism (TT) and the key challenges with such transplantation. The stakeholders of commercial transplantation include: patients on the waiting lists in developed countries or not on any list in developing countries; dialysis funding bodies; middlemen, hosting transplant centres; organ-exporting countries; and organ vendors. TT and commercial kidney transplants are associated with a high incidence of surgical complications, acute rejection and invasive infection which cause major morbidity and mortality. There are ethical and medical concerns regarding the management of recipients of organs from vendors. The growing demand for transplantation, the perceived failure of altruistic donation in providing enough organs has led to calls for a legalised market in organ procurement or regulated trial in incentives for donation. Developing transplant services worldwide has many benefits - improving results of transplantation as they would be performed legally, increasing the donor pool and making TT unnecessary. Meanwhile there is a need to re-examine intrinsic attitudes to TT bearing in mind the cultural and economic realities of globalisation. Perhaps the World Health Organization in conjunction with The Transplantation Society would set up a working party of stakeholders to study this matter in greater detail and make recommendations.

  15. Comparative Genomic Analysis of Clinical and Environmental Vibrio Vulnificus Isolates Revealed Biotype 3 Evolutionary Relationships

    Directory of Open Access Journals (Sweden)

    Yael eKotton

    2015-01-01

    Full Text Available In 1996 a common-source outbreak of severe soft tissue and bloodstream infections erupted among Israeli fish farmers and fish consumers due to changes in fish marketing policies. The causative pathogen was a new strain of Vibrio vulnificus, named biotype 3, which displayed a unique biochemical and genotypic profile. Initial observations suggested that the pathogen erupted as a result of genetic recombination between two distinct populations. We applied a whole genome shotgun sequencing approach using several V. vulnificus strains from Israel in order to study the pan genome of V. vulnificus and determine the phylogenetic relationship of biotype 3 with existing populations. The core genome of V. vulnificus based on 16 draft and complete genomes consisted of 3068 genes, representing between 59% and 78% of the whole genome of 16 strains. The accessory genome varied in size from 781 kbp to 2044 kbp. Phylogenetic analysis based on whole, core, and accessory genomes displayed similar clustering patterns with two main clusters, clinical (C and environmental (E, all biotype 3 strains formed a distinct group within the E cluster. Annotation of accessory genomic regions found in biotype 3 strains and absent from the core genome yielded 1732 genes, of which the vast majority encoded hypothetical proteins, phage-related proteins, and mobile element proteins. A total of 1916 proteins (including 713 hypothetical proteins were present in all human pathogenic strains (both biotype 3 and non-biotype 3 and absent from the environmental strains. Clustering analysis of the non-hypothetical proteins revealed 148 protein clusters shared by all human pathogenic strains; these included transcriptional regulators, arylsulfatases, methyl-accepting chemotaxis proteins, acetyltransferases, GGDEF family proteins, transposases, type IV secretory system (T4SS proteins, and integrases. Our study showed that V. vulnificus biotype 3 evolved from environmental populations and

  16. Key Distribution and Changing Key Cryptosystem Based on Phase Retrieval Algorithm and RSA Public-Key Algorithm

    Directory of Open Access Journals (Sweden)

    Tieyu Zhao

    2015-01-01

    Full Text Available The optical image encryption has attracted more and more researchers’ attention, and the various encryption schemes have been proposed. In existing optical cryptosystem, the phase functions or images are usually used as the encryption keys, and it is difficult that the traditional public-key algorithm (such as RSA, ECC, etc. is used to complete large numerical key transfer. In this paper, we propose a key distribution scheme based on the phase retrieval algorithm and the RSA public-key algorithm, which solves the problem for the key distribution in optical image encryption system. Furthermore, we also propose a novel image encryption system based on the key distribution principle. In the system, the different keys can be used in every encryption process, which greatly improves the security of the system.

  17. Revealing the programming process

    DEFF Research Database (Denmark)

    Bennedsen, Jens; Caspersen, Michael Edelgaard

    2005-01-01

    One of the most important goals of an introductory programming course is that the students learn a systematic approach to the development of computer programs. Revealing the programming process is an important part of this; however, textbooks do not address the issue -- probably because...... the textbook medium is static and therefore ill-suited to expose the process of programming. We have found that process recordings in the form of captured narrated programming sessions are a simple, cheap, and efficient way of providing the revelation.We identify seven different elements of the programming...

  18. TypeScript revealed

    CERN Document Server

    Maharry, Dan

    2013-01-01

    TypeScript Revealed is a quick 100-page guide to Anders Hejlsberg's new take on JavaScript. With this brief, fast-paced introduction to TypeScript, .NET, Web and Windows 8 application developers who are already familiar with JavaScript will easily get up to speed with TypeScript and decide whether or not to start incorporating it into their own development. TypeScript is 'JavaScript for Application-scale development'; a superset of JavaScript that brings to it an additional object-oriented-like syntax familiar to .NET programmers that compiles down into simple, clean JavaScript that any browse

  19. Quantum key distribution network for multiple applications

    Science.gov (United States)

    Tajima, A.; Kondoh, T.; Ochi, T.; Fujiwara, M.; Yoshino, K.; Iizuka, H.; Sakamoto, T.; Tomita, A.; Shimamura, E.; Asami, S.; Sasaki, M.

    2017-09-01

    The fundamental architecture and functions of secure key management in a quantum key distribution (QKD) network with enhanced universal interfaces for smooth key sharing between arbitrary two nodes and enabling multiple secure communication applications are proposed. The proposed architecture consists of three layers: a quantum layer, key management layer and key supply layer. We explain the functions of each layer, the key formats in each layer and the key lifecycle for enabling a practical QKD network. A quantum key distribution-advanced encryption standard (QKD-AES) hybrid system and an encrypted smartphone system were developed as secure communication applications on our QKD network. The validity and usefulness of these systems were demonstrated on the Tokyo QKD Network testbed.

  20. Electronic Nicotine Delivery Systems Key Facts Infographic

    Data.gov (United States)

    U.S. Department of Health & Human Services — Explore the Electronic Nicotine Delivery Systems Key Facts Infographic which outlines key facts related to electronic nicotine delivery systems (ENDS), including...

  1. Quantum key distribution via quantum encryption

    CERN Document Server

    Yong Sheng Zhang; Guang Can Guo

    2001-01-01

    A quantum key distribution protocol based on quantum encryption is presented in this Brief Report. In this protocol, the previously shared Einstein-Podolsky-Rosen pairs act as the quantum key to encode and decode the classical cryptography key. The quantum key is reusable and the eavesdropper cannot elicit any information from the particle Alice sends to Bob. The concept of quantum encryption is also discussed. (21 refs).

  2. SUPPLY CHAIN MANAGEMENT – KEY FACTORS

    OpenAIRE

    Magdalena Daniela DINU

    2014-01-01

    This paper exposes Supply Chain Management by its key factors. Briefly, where the Supply Chain Management is treated as strategic part of a company then maintaining both control and influence throughout the entire supply chain are key factors and critical to success. On the other hand, finding the right partner to manage the non-strategic Supply Chains would be another key factor too. To define the most important key factors within Supply Chain Management means a deeply understanding of bot...

  3. Chemistry of plutonium revealed

    International Nuclear Information System (INIS)

    Connick, R.E.

    1992-01-01

    In 1941 one goal of the Manhattan Project was to unravel the chemistry of the synthetic element plutonium as rapidly as possible. In this paper the work carried out at Berkeley from the spring of 1942 to the summer of 1945 is described briefly. The aqueous chemistry of plutonium is quite remarkable. Important insights were obtained from tracer experiments, but the full complexity was not revealed until macroscopic amounts (milligrams) became available. Because processes for separation from fission products were based on aqueous solutions, such solution chemistry was emphasized, particularly precipitation and oxidation-reduction behavior. The latter turned out to be unusually intricate when it was discovered that two more oxidation states existed in aqueous solution than had previously been suspected. Further, an equilibrium was rapidly established among the four aqueous oxidation states, while at the same time any three were not in equilibrium. These and other observations made while doing a crash study of a previously unknown element are reported

  4. Android Emotions Revealed

    DEFF Research Database (Denmark)

    Vlachos, Evgenios; Schärfe, Henrik

    2012-01-01

    This work presents a method for designing facial interfaces for sociable android robots with respect to the fundamental rules of human affect expression. Extending the work of Paul Ekman towards a robotic direction, we follow the judgment-based approach for evaluating facial expressions to test...... findings are based on the results derived from a number of judgments, and suggest that before programming the facial expressions of a Geminoid, the Original should pass through the proposed procedure. According to our recommendations, the facial expressions of an android should be tested by judges, even...... in which case an android robot like the Geminoid|DK –a duplicate of an Original person- reveals emotions convincingly; when following an empirical perspective, or when following a theoretical one. The methodology includes the processes of acquiring the empirical data, and gathering feedback on them. Our...

  5. Improved Anonymity for Key-trees

    NARCIS (Netherlands)

    Veugen, P.J.M.; Beye, M.

    2013-01-01

    Randomized hash-lock protocols for Radio Frequency IDentification (RFID) tags offer forward untraceability, but incur heavy search on the server. Key trees have been proposed as a way to reduce search times, but because partial keys in such trees are shared, key compromise affects several tags.

  6. Harry Potter and the Dichotomous Key

    Science.gov (United States)

    Crowther, David T.

    2003-01-01

    In this lesson, students use Bertie Bott's Every Flavor Beans--a "wild" candy written about in the Harry Potter books and now available in stores--to learn about classification and dichotomous keys. In these activities, students sort jelly beans according to a key and then construct a key for a "new" flavor of beans. Students then build on their…

  7. Quantum key distribution with an entangled light emitting diode

    Energy Technology Data Exchange (ETDEWEB)

    Dzurnak, B.; Stevenson, R. M.; Nilsson, J.; Dynes, J. F.; Yuan, Z. L.; Skiba-Szymanska, J.; Shields, A. J. [Toshiba Research Europe Limited, 208 Science Park, Milton Road, Cambridge CB4 0GZ (United Kingdom); Farrer, I.; Ritchie, D. A. [Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE (United Kingdom)

    2015-12-28

    Measurements performed on entangled photon pairs shared between two parties can allow unique quantum cryptographic keys to be formed, creating secure links between users. An advantage of using such entangled photon links is that they can be adapted to propagate entanglement to end users of quantum networks with only untrusted nodes. However, demonstrations of quantum key distribution with entangled photons have so far relied on sources optically excited with lasers. Here, we realize a quantum cryptography system based on an electrically driven entangled-light-emitting diode. Measurement bases are passively chosen and we show formation of an error-free quantum key. Our measurements also simultaneously reveal Bell's parameter for the detected light, which exceeds the threshold for quantum entanglement.

  8. Keys to the success of the CB Conquero

    Directory of Open Access Journals (Sweden)

    C. Fernández-Espínola

    2016-12-01

    Full Text Available When a team gets sport successes to level profesional, generates the topics that will be investigated such as the key factors of the succes. The main aim of this study is to analyze the influencie of different factors like the sports context, the social context and training aspects in the success of the Club Baloncesto Conquero through direct perception of thirteen informants associated with the team and the basketball in Huelva. An interview was carried out, related with those factors and the keys to success. The results revealed that workforce planning along the great work of coaching staff, medical staff and physical trainer have been key to the team gets sport successes.

  9. [Key morphofunctional transformations in the evolution of chiropterans (Bats, Chiroptera)].

    Science.gov (United States)

    Kovaleva, I M

    2014-01-01

    Study on the morphology and morphogenesis of wing membranes in Bats has revealed some peculiarities in their structure and development. Understanding the embryogenesis of these animals, as well as attraction of data obtained on their molecular genetics and paleontology, allows one to single out some factors that could have initiated evolutionary modifications in development programs. A scenario of the key morphofunctional transformations in the forelimbs during the evolution of chiropterans is given.

  10. VICKEY: Mining Conditional Keys on Knowledge Bases

    OpenAIRE

    Symeonidou , Danai; Galárraga , Luis; Pernelle , Nathalie; Saïs , Fatiha; Suchanek , Fabian

    2017-01-01

    International audience; A conditional key is a key constraint that is valid in only a part of the data. In this paper, we show how such keys can be mined automatically on large knowledge bases (KBs). For this, we combine techniques from key mining with techniques from rule mining. We show that our method can scale to KBs of millions of facts. We also show that the conditional keys we mine can improve the quality of entity linking by up to 47 percentage points.

  11. The Qualitative Study of Key Performance Indicator on PT. Jiwasraya Manado

    OpenAIRE

    Rangian, Geby Melisa; Tumewu, Ferdinand

    2014-01-01

    Key Performance Indicator (KPI) is one of the most common tools used by the employees of companies to help manage more effectively and guide their progress. To perceive how far the achievement and the performance of the company, PT. Jiwasraya Manado use the Key Performance Indicator (KPI) to reveal the performance of the company. The objective of this study is to analyze the importance from the implementation of the key performance indicator for the insurance employee. There are several facts...

  12. Secret-key expansion from covert communication

    Science.gov (United States)

    Arrazola, Juan Miguel; Amiri, Ryan

    2018-02-01

    Covert communication allows the transmission of messages in such a way that it is not possible for adversaries to detect that the communication is occurring. This provides protection in situations where knowledge that two parties are talking to each other may be incriminating to them. In this work, we study how covert communication can be used for a different purpose: secret key expansion. First, we show that any message transmitted in a secure covert protocol is also secret and therefore unknown to an adversary. We then propose a covert communication protocol where the amount of key consumed in the protocol is smaller than the transmitted key, thus leading to secure secret key expansion. We derive precise conditions for secret key expansion to occur, showing that it is possible when there are sufficiently low levels of noise for a given security level. We conclude by examining how secret key expansion from covert communication can be performed in a computational security model.

  13. Establishing Key Performance Indicators : Case company X

    OpenAIRE

    Singh, Jatinder

    2015-01-01

    The key performance indicators serve as the navigational tools for a business organization to monitor its performance. They enable the management team to take real time decisions to keep organization’s resources aligned to its business strategy to accomplish its strategic objec-tives. This research was conducted to analyse the process of establishing successful key per-formance indicators for a business organization. The research was conducted to recommend key performance indicators developme...

  14. Competency Assessment Using Key Performance Indicators

    OpenAIRE

    Elena Alexandra Toader; Laura Brad

    2015-01-01

    The paper proposes a method for computing the scores of the key performance indicators resulted in the competency assessment process. The key performance indicators are estimated considering four performance levels that an IT professional can obtain at the end of the assessment process. We suggest as the best approach for estimating the performance key indicators an online questionnaire filled by 60 employees that work in IT Romanian companies. The results provide evidence that the difference...

  15. Enciphered Data Steganography Using Secret Key

    Directory of Open Access Journals (Sweden)

    BANGALORE G.Tilak

    2010-10-01

    Full Text Available A new method is proposed to maintain thesecrecy of data by enciphering and embedding using asecret key. There is no restriction on the length of thekey used to encipher and embed the data. Since the keyis not stored for validation, it prevents unauthorizedaccess to the key, even if decoding procedure is known.The correct message can be recovered only with thespecific key used in encipherment and embedding. Thismethod can also be used for multiple levelsteganography.

  16. FPGA BASED HARDWARE KEY FOR TEMPORAL ENCRYPTION

    Directory of Open Access Journals (Sweden)

    B. Lakshmi

    2010-09-01

    Full Text Available In this paper, a novel encryption scheme with time based key technique on an FPGA is presented. Time based key technique ensures right key to be entered at right time and hence, vulnerability of encryption through brute force attack is eliminated. Presently available encryption systems, suffer from Brute force attack and in such a case, the time taken for breaking a code depends on the system used for cryptanalysis. The proposed scheme provides an effective method in which the time is taken as the second dimension of the key so that the same system can defend against brute force attack more vigorously. In the proposed scheme, the key is rotated continuously and four bits are drawn from the key with their concatenated value representing the delay the system has to wait. This forms the time based key concept. Also the key based function selection from a pool of functions enhances the confusion and diffusion to defend against linear and differential attacks while the time factor inclusion makes the brute force attack nearly impossible. In the proposed scheme, the key scheduler is implemented on FPGA that generates the right key at right time intervals which is then connected to a NIOS – II processor (a virtual microcontroller which is brought out from Altera FPGA that communicates with the keys to the personal computer through JTAG (Joint Test Action Group communication and the computer is used to perform encryption (or decryption. In this case the FPGA serves as hardware key (dongle for data encryption (or decryption.

  17. Finite key analysis in quantum cryptography

    International Nuclear Information System (INIS)

    Meyer, T.

    2007-01-01

    In view of experimental realization of quantum key distribution schemes, the study of their efficiency becomes as important as the proof of their security. The latter is the subject of most of the theoretical work about quantum key distribution, and many important results such as the proof of unconditional security have been obtained. The efficiency and also the robustness of quantum key distribution protocols against noise can be measured by figures of merit such as the secret key rate (the fraction of input signals that make it into the key) and the threshold quantum bit error rate (the maximal error rate such that one can still create a secret key). It is important to determine these quantities because they tell us whether a certain quantum key distribution scheme can be used at all in a given situation and if so, how many secret key bits it can generate in a given time. However, these figures of merit are usually derived under the ''infinite key limit'' assumption, that is, one assumes that an infinite number of quantum states are send and that all sub-protocols of the scheme (in particular privacy amplification) are carried out on these infinitely large blocks. Such an assumption usually eases the analysis, but also leads to (potentially) too optimistic values for the quantities in question. In this thesis, we are explicitly avoiding the infinite key limit for the analysis of the privacy amplification step, which plays the most important role in a quantum key distribution scheme. We still assume that an optimal error correction code is applied and we do not take into account any statistical errors that might occur in the parameter estimation step. Renner and coworkers derived an explicit formula for the obtainable key rate in terms of Renyi entropies of the quantum states describing Alice's, Bob's, and Eve's systems. This results serves as a starting point for our analysis, and we derive an algorithm that efficiently computes the obtainable key rate for any

  18. EPA Monthly Key Performance Indicator Dashboards 2017

    Science.gov (United States)

    Each month, the Web Analytics Program posts updated Key Performance Indicator (KPI) dashboards that correspond to three Web performance goals: content consumption, content discovery, and audience engagement.

  19. Nickel exposure from keys: a Brazilian issue.

    Science.gov (United States)

    Suzuki, Nathalie Mie; Duarte, Ida Alzira Gomes; Hafner, Mariana de Figueiredo Silva; Lazzarini, Rosana

    2017-01-01

    Keys are a significant source of exposure to metal allergens and can be a relevant problem for nickel-allergic individuals. This study aimed to perform nickel and cobalt spot testing among the 5 most common Brazilian brands of keys. Among the tested keys, 100% showed positive result to nickel spot test, 83,3% presented strong positive reaction. 50% exhibited cobalt release as well. Nickel release from keys is very common in our country and may cause a negative impact on sensitized individual's quality of life. Study's results highlight the importance of establishing directives to regulate nickel release in Brazil.

  20. 75 FR 17463 - Key West Bank, Key West, Florida; Notice of Appointment of Receiver

    Science.gov (United States)

    2010-04-06

    ... DEPARTMENT OF THE TREASURY Office of Thrift Supervision Key West Bank, Key West, Florida; Notice... section 5(d)(2) of the Home Owners' Loan Act, the Office of Thrift Supervision has duly appointed the Federal Deposit Insurance Corporation as sole Receiver for Key West Bank, Key West, Florida, (OTS No...

  1. Key management of the double random-phase-encoding method using public-key encryption

    Science.gov (United States)

    Saini, Nirmala; Sinha, Aloka

    2010-03-01

    Public-key encryption has been used to encode the key of the encryption process. In the proposed technique, an input image has been encrypted by using the double random-phase-encoding method using extended fractional Fourier transform. The key of the encryption process have been encoded by using the Rivest-Shamir-Adelman (RSA) public-key encryption algorithm. The encoded key has then been transmitted to the receiver side along with the encrypted image. In the decryption process, first the encoded key has been decrypted using the secret key and then the encrypted image has been decrypted by using the retrieved key parameters. The proposed technique has advantage over double random-phase-encoding method because the problem associated with the transmission of the key has been eliminated by using public-key encryption. Computer simulation has been carried out to validate the proposed technique.

  2. Key-value store with internal key-value storage interface

    Science.gov (United States)

    Bent, John M.; Faibish, Sorin; Ting, Dennis P. J.; Tzelnic, Percy; Gupta, Uday; Grider, Gary; Bonnie, David J.

    2018-01-16

    A key-value store is provided having one or more key-value storage interfaces. A key-value store on at least one compute node comprises a memory for storing a plurality of key-value pairs; and an abstract storage interface comprising a software interface module that communicates with at least one persistent storage device providing a key-value interface for persistent storage of one or more of the plurality of key-value pairs, wherein the software interface module provides the one or more key-value pairs to the at least one persistent storage device in a key-value format. The abstract storage interface optionally processes one or more batch operations on the plurality of key-value pairs. A distributed embodiment for a partitioned key-value store is also provided.

  3. Titan Casts Revealing Shadow

    Science.gov (United States)

    2004-05-01

    A rare celestial event was captured by NASA's Chandra X-ray Observatory as Titan -- Saturn's largest moon and the only moon in the Solar System with a thick atmosphere -- crossed in front of the X-ray bright Crab Nebula. The X-ray shadow cast by Titan allowed astronomers to make the first X-ray measurement of the extent of its atmosphere. On January 5, 2003, Titan transited the Crab Nebula, the remnant of a supernova explosion that was observed to occur in the year 1054. Although Saturn and Titan pass within a few degrees of the Crab Nebula every 30 years, they rarely pass directly in front of it. "This may have been the first transit of the Crab Nebula by Titan since the birth of the Crab Nebula," said Koji Mori of Pennsylvania State University in University Park, and lead author on an Astrophysical Journal paper describing these results. "The next similar conjunction will take place in the year 2267, so this was truly a once in a lifetime event." Animation of Titan's Shadow on Crab Nebula Animation of Titan's Shadow on Crab Nebula Chandra's observation revealed that the diameter of the X-ray shadow cast by Titan was larger than the diameter of its solid surface. The difference in diameters gives a measurement of about 550 miles (880 kilometers) for the height of the X-ray absorbing region of Titan's atmosphere. The extent of the upper atmosphere is consistent with, or slightly (10-15%) larger, than that implied by Voyager I observations made at radio, infrared, and ultraviolet wavelengths in 1980. "Saturn was about 5% closer to the Sun in 2003, so increased solar heating of Titan may account for some of this atmospheric expansion," said Hiroshi Tsunemi of Osaka University in Japan, one of the coauthors on the paper. The X-ray brightness and extent of the Crab Nebula made it possible to study the tiny X-ray shadow cast by Titan during its transit. By using Chandra to precisely track Titan's position, astronomers were able to measure a shadow one arcsecond in

  4. Securing information using optically generated biometric keys

    Science.gov (United States)

    Verma, Gaurav; Sinha, Aloka

    2016-11-01

    In this paper, we present a new technique to obtain biometric keys by using the fingerprint of a person for an optical image encryption system. The key generation scheme uses the fingerprint biometric information in terms of the amplitude mask (AM) and the phase mask (PM) of the reconstructed fingerprint image that is implemented using the digital holographic technique. Statistical tests have been conducted to check the randomness of the fingerprint PM key that enables its usage as an image encryption key. To explore the utility of the generated biometric keys, an optical image encryption system has been further demonstrated based on the phase retrieval algorithm and the double random phase encoding scheme in which keys for the encryption are used as the AM and the PM key. The advantage associated with the proposed scheme is that the biometric keys’ retrieval requires the simultaneous presence of the fingerprint hologram and the correct knowledge of the reconstruction parameters at the decryption stage, which not only verifies the authenticity of the person but also protects the valuable fingerprint biometric features of the keys. Numerical results are carried out to prove the feasibility and the effectiveness of the proposed encryption system.

  5. Eight Key Facets of Small Business Management.

    Science.gov (United States)

    Scott, James Calvert

    1980-01-01

    Identifies eight key facets of small business management and suggests activities that may be used to assist in their development. The key facets are (1) product or service, (2) competition, (3) marketing strategies, (4) personnel needs, (5) equipment and facility needs, (6) finances, (7) planning, and (8) entrepreneurship. (JOW)

  6. Quantum key distribution using three basis states

    Indian Academy of Sciences (India)

    Home; Journals; Pramana – Journal of Physics; Volume 54; Issue 5. Quantum key distribution using three ... This note presents a method of public key distribution using quantum communication of photons that simultaneously provides a high probability that the bits have not been tampered. It is a variant of the quantum ...

  7. Optimizing Key Updates in Sensor Networks

    DEFF Research Database (Denmark)

    Yuksel, Ender; Nielson, Hanne Riis; Nielson, Flemming

    2011-01-01

    Sensor networks offer the advantages of simple and low–resource communication. Nevertheless, security is of particular importance in many cases such as when sensitive data is communicated or tamper-resistance is required. Updating the security keys is one of the key points in security, which...

  8. Locks & keys service moves to building 55

    CERN Multimedia

    2012-01-01

    Please note that as of July 12 Locks & keys service will be at building 55 second floor. The opening hours are as follows: 08:30 am to 12:30 pm - 1:30 pm to 5:30 pm. The procedures and rules relating to applications for key and cylinder have not changed. GI-IS Group

  9. Strategy Keys as Tools for Problem Solving

    Science.gov (United States)

    Herold-Blasius, Raja

    2017-01-01

    Problem solving is one of the main competences we seek to teach students at school for use in their future lives. However, when dealing with mathematical problems, teachers encounter a wide variety of difficulties. To foster students' problem-solving skills, the authors developed "strategy keys." Strategy keys can serve as material to…

  10. Secure key distribution by swapping quantum entanglement

    International Nuclear Information System (INIS)

    Song, Daegene

    2004-01-01

    We report two key distribution schemes achieved by swapping quantum entanglement. Using two Bell states, two bits of secret key can be shared between two distant parties that play symmetric and equal roles. We also address eavesdropping attacks against the schemes

  11. A survey on exploring key performance indicators

    Directory of Open Access Journals (Sweden)

    Mohammed Badawy

    2016-12-01

    Full Text Available Key Performance Indicators (KPIs allows gathering knowledge and exploring the best way to achieve organization goals. Many researchers have provided different ideas for determining KPI's either manually, and semi-automatic, or automatic which is applied in different fields. This work concentrates on providing a survey of different approaches for exploring and predicting key performance indicators (KPIs.

  12. The LOFAR Transients Key Science Project

    NARCIS (Netherlands)

    Stappers, B.; Fender, R.; Wijers, R.

    2009-01-01

    The Transients Key Science Project (TKP) is one of six Key Science Projects of the next generation radio telescope LOFAR. Its aim is the study of transient and variable low-frequency radio sources with an extremely broad science case ranging from relativistic jet sources to pulsars, exoplanets,

  13. Optimal grazing management strategies: evaluating key concepts ...

    African Journals Online (AJOL)

    Finally, overstocking will override key management initiatives, such as effective recovery periods, leading to rangeland degradation. Thus, in variable climates, stocking rate should be set conservatively to allow easier adaptation of animal numbers to rainfall variability from year to year. We suggest several key concepts that ...

  14. Multiparty quantum key agreement with single particles

    Science.gov (United States)

    Liu, Bin; Gao, Fei; Huang, Wei; Wen, Qiao-yan

    2013-04-01

    Two conditions must be satisfied in a secure quantum key agreement (QKA) protocol: (1) outside eavesdroppers cannot gain the generated key without introducing any error; (2) the generated key cannot be determined by any non-trivial subset of the participants. That is, a secure QKA protocol can not only prevent the outside attackers from stealing the key, but also resist the attack from inside participants, i.e. some dishonest participants determine the key alone by illegal means. How to resist participant attack is an aporia in the design of QKA protocols, especially the multi-party ones. In this paper we present the first secure multiparty QKA protocol against both outside and participant attacks. Further more, we have proved its security in detail.

  15. SUPPLY CHAIN MANAGEMENT – KEY FACTORS

    Directory of Open Access Journals (Sweden)

    Magdalena Daniela DINU

    2014-06-01

    Full Text Available This paper exposes Supply Chain Management by its key factors. Briefly, where the Supply Chain Management is treated as strategic part of a company then maintaining both control and influence throughout the entire supply chain are key factors and critical to success. On the other hand, finding the right partner to manage the non-strategic Supply Chains would be another key factor too. To define the most important key factors within Supply Chain Management means a deeply understanding of both Supply Chain’ s components, procedures, workflow, processes and the importance of Supply Chain Management into maximizing company's value. SCORE model able to provide solid information about measuring performance and identifying priorities within Supply Chain Management will help us to understand the key factors by analyzing its elements: Plan, Source, Make, Deliver,Return, Enable. These elements covers all the challenging areas from first to third tier of Supply Chain Management.

  16. The ultimate security bounds of quantum key distribution protocols

    International Nuclear Information System (INIS)

    Nikolopoulos, G.M.; Alber, G.

    2005-01-01

    Full text: Quantum key distribution (QKD) protocols exploit quantum correlations in order to establish a secure key between two legitimate users. Recent work on QKD has revealed a remarkable link between quantum and secret correlations. In this talk we report on recent results concerning the ultimate upper security bounds of various QKD schemes (i.e., the maximal disturbance up to which the two legitimate users share quantum correlations) under the assumption of general coherent attacks. In particular, we derive an analytic expression for the ultimate upper security bound of QKD schemes that use two mutually unbiased bases. As long as the two legitimate users focus on the sifted key and treat each pair of data independently during the post processing, our results are valid for arbitrary dimensions of the information carriers. The bound we have derived is well below the predictions of optimal cloning machines. The possibility of extraction of a secret key beyond entanglement distillation is also discussed. In the case of qutrits we argue that any eavesdropping strategy is equivalent to a symmetric one. For higher dimensions, however, such equivalence is generally no longer valid. (author)

  17. New weak keys in simplified IDEA

    Science.gov (United States)

    Hafman, Sari Agustini; Muhafidzah, Arini

    2016-02-01

    Simplified IDEA (S-IDEA) is simplified version of International Data Encryption Algorithm (IDEA) and useful teaching tool to help students to understand IDEA. In 2012, Muryanto and Hafman have found a weak key class in the S-IDEA by used differential characteristics in one-round (0, ν, 0, ν) → (0,0, ν, ν) on the first round to produce input difference (0,0, ν, ν) on the fifth round. Because Muryanto and Hafman only use three differential characteristics in one-round, we conducted a research to find new differential characteristics in one-round and used it to produce new weak key classes of S-IDEA. To find new differential characteristics in one-round of S-IDEA, we applied a multiplication mod 216+1 on input difference and combination of active sub key Z1, Z4, Z5, Z6. New classes of weak keys are obtained by combining all of these characteristics and use them to construct two new differential characteristics in full-round of S-IDEA with or without the 4th round sub key. In this research, we found six new differential characteristics in one round and combined them to construct two new differential characteristics in full-round of S-IDEA. When two new differential characteristics in full-round of S-IDEA are used and the 4th round sub key required, we obtain 2 new classes of weak keys, 213 and 28. When two new differential characteristics in full-round of S-IDEA are used, yet the 4th round sub key is not required, the weak key class of 213 will be 221 and 28 will be 210. Membership test can not be applied to recover the key bits in those weak key classes. The recovery of those unknown key bits can only be done by using brute force attack. The simulation result indicates that the bit of the key can be recovered by the longest computation time of 0,031 ms.

  18. Subcarrier multiplexing optical quantum key distribution

    International Nuclear Information System (INIS)

    Ortigosa-Blanch, A.; Capmany, J.

    2006-01-01

    We present the physical principles of a quantum key distribution system that opens the possibility of parallel quantum key distribution and, therefore, of a substantial improvement in the bit rate of such systems. Quantum mechanics allows for multiple measurements at different frequencies and thus we exploit this concept by extending the concept of frequency coding to the case where more than one radio-frequency subcarrier is used for independently encoding the bits onto an optical carrier. Taking advantage of subcarrier multiplexing techniques we demonstrate that the bit rate can be greatly improved as parallel key distribution is enabled

  19. An Analysis of Key Factors in Developing a Smart City

    Directory of Open Access Journals (Sweden)

    Aidana Šiurytė

    2016-06-01

    Full Text Available The concept Smart City is used widely but it is perceived differently as well. Literature review reveals key elements of the Smart City – Information and Communication Technologies and Smart Citizens. Nevertheless, raising public awareness is not a priority of local municipalities which are trying to develop cities. Focus group discussion aims to analyse citizens’ insights in regards to the Smart City and their contribution to creation of it. Case study of Vilnius examines a position of mu-nicipality in developing city as smart. Study contains suggestions for the improvement of communication in the city. Methods employed: comparative literature analysis, focus group investigation, case study.

  20. Key Facts about Seasonal Flu Vaccine

    Science.gov (United States)

    ... Swine Variant Pandemic Other Key Facts About Seasonal Flu Vaccine Language: English (US) Español Recommend on Facebook ... the flu is to get vaccinated each year. Flu Vaccination Why should people get vaccinated against the ...

  1. China demonstrates intercontinental quantum key distribution

    Science.gov (United States)

    Johnston, Hamish

    2017-11-01

    A quantum cryptography key has been shared between Beijing and Vienna using a satellite - allowing the presidents of the Chinese Academy of Sciences and Austrian Academy of Sciences to communicate via a secure video link.

  2. Key Principles of Superfund Remedy Selection

    Science.gov (United States)

    Guidance on the primary considerations of remedy selection which are universally applicable at Superfund sites. Key guidance here include: Rules of Thumb for Superfund Remedy Selection and Role of the Baseline Risk Assessment.

  3. Key Royale bridge five year evaluation.

    Science.gov (United States)

    2013-06-01

    This report describes the design, construction, instrumentation, and five-year evaluation of the Key Royale Bridge substructure. The primary focus was the evaluation of the implementation of highly reactive supplementary cementitious materials (SCM) ...

  4. Keys to Successful EPIQ Business Demonstrator Implementation

    NARCIS (Netherlands)

    Shoikova, Elena; Denishev, Vladislav

    2009-01-01

    Shoikova, E., & Denishev, V. (2009). Keys to Successful EPIQ Business Demonstrator Implementation. Paper presented at the 'Open workshop of TENCompetence - Rethinking Learning and Employment at a Time of Economic Uncertainty-event'. November, 19, 2009, Manchester, United Kingdom: TENCompetence.

  5. Secure image retrieval with multiple keys

    Science.gov (United States)

    Liang, Haihua; Zhang, Xinpeng; Wei, Qiuhan; Cheng, Hang

    2018-03-01

    This article proposes a secure image retrieval scheme under a multiuser scenario. In this scheme, the owner first encrypts and uploads images and their corresponding features to the cloud; then, the user submits the encrypted feature of the query image to the cloud; next, the cloud compares the encrypted features and returns encrypted images with similar content to the user. To find the nearest neighbor in the encrypted features, an encryption with multiple keys is proposed, in which the query feature of each user is encrypted by his/her own key. To improve the key security and space utilization, global optimization and Gaussian distribution are, respectively, employed to generate multiple keys. The experiments show that the proposed encryption can provide effective and secure image retrieval for each user and ensure confidentiality of the query feature of each user.

  6. Coherent one-way quantum key distribution

    Science.gov (United States)

    Stucki, Damien; Fasel, Sylvain; Gisin, Nicolas; Thoma, Yann; Zbinden, Hugo

    2007-05-01

    Quantum Key Distribution (QKD) consists in the exchange of a secrete key between two distant points [1]. Even if quantum key distribution systems exist and commercial systems are reaching the market [2], there are still improvements to be made: simplify the construction of the system; increase the secret key rate. To this end, we present a new protocol for QKD tailored to work with weak coherent pulses and at high bit rates [3]. The advantages of this system are that the setup is experimentally simple and it is tolerant to reduced interference visibility and to photon number splitting attacks, thus resulting in a high efficiency in terms of distilled secret bits per qubit. After having successfully tested the feasibility of the system [3], we are currently developing a fully integrated and automated prototype within the SECOQC project [4]. We present the latest results using the prototype. We also discuss the issue of the photon detection, which still remains the bottleneck for QKD.

  7. Finite key analysis in quantum cryptography

    Energy Technology Data Exchange (ETDEWEB)

    Meyer, T.

    2007-10-31

    In view of experimental realization of quantum key distribution schemes, the study of their efficiency becomes as important as the proof of their security. The latter is the subject of most of the theoretical work about quantum key distribution, and many important results such as the proof of unconditional security have been obtained. The efficiency and also the robustness of quantum key distribution protocols against noise can be measured by figures of merit such as the secret key rate (the fraction of input signals that make it into the key) and the threshold quantum bit error rate (the maximal error rate such that one can still create a secret key). It is important to determine these quantities because they tell us whether a certain quantum key distribution scheme can be used at all in a given situation and if so, how many secret key bits it can generate in a given time. However, these figures of merit are usually derived under the ''infinite key limit'' assumption, that is, one assumes that an infinite number of quantum states are send and that all sub-protocols of the scheme (in particular privacy amplification) are carried out on these infinitely large blocks. Such an assumption usually eases the analysis, but also leads to (potentially) too optimistic values for the quantities in question. In this thesis, we are explicitly avoiding the infinite key limit for the analysis of the privacy amplification step, which plays the most important role in a quantum key distribution scheme. We still assume that an optimal error correction code is applied and we do not take into account any statistical errors that might occur in the parameter estimation step. Renner and coworkers derived an explicit formula for the obtainable key rate in terms of Renyi entropies of the quantum states describing Alice's, Bob's, and Eve's systems. This results serves as a starting point for our analysis, and we derive an algorithm that efficiently computes

  8. Renyi information gain on quantum key

    International Nuclear Information System (INIS)

    Brandt, Howard E

    2007-01-01

    The concept of maximum Renyi information gain from quantum key is important in eavesdropping and security analyses of quantum key distribution. It is particularly useful in the design optimization of eavesdropping probes. The present work reviews the quantitative measure of Renyi information gain, its optimization, and application to the design of eavesdropping probes in which single-photon probe states become optimally entangled with the signal states on their way between the legitimate transmitter and receiver

  9. Multipartite secret key distillation and bound entanglement

    International Nuclear Information System (INIS)

    Augusiak, Remigiusz; Horodecki, Pawel

    2009-01-01

    Recently it has been shown that quantum cryptography beyond pure entanglement distillation is possible and a paradigm for the associated protocols has been established. Here we systematically generalize the whole paradigm to the multipartite scenario. We provide constructions of new classes of multipartite bound entangled states, i.e., those with underlying twisted Greenberger-Horne-Zeilinger (GHZ) structure and nonzero distillable cryptographic key. We quantitatively estimate the key from below with the help of the privacy squeezing technique.

  10. Mathematical Background of Public Key Cryptography

    DEFF Research Database (Denmark)

    Frey, Gerhard; Lange, Tanja

    2005-01-01

    The two main systems used for public key cryptography are RSA and protocols based on the discrete logarithm problem in some cyclic group. We focus on the latter problem and state cryptographic protocols and mathematical background material.......The two main systems used for public key cryptography are RSA and protocols based on the discrete logarithm problem in some cyclic group. We focus on the latter problem and state cryptographic protocols and mathematical background material....

  11. Soil fauna: key to new carbon models

    OpenAIRE

    Filser, Juliane; Faber, Jack H.; Tiunov, Alexei V.; Brussaard, Lijbert; Frouz, Jan; Deyn, Gerlinde; Uvarov, Alexei V.; Berg, Matty P.; Lavelle, Patrick; Loreau, Michel; Wall, Diana H.; Querner, Pascal; Eijsackers, Herman; Jiménez, Juan José

    2016-01-01

    Soil organic matter (SOM) is key to maintaining soil fertility, mitigating climate change, combatting land degradation, and conserving above- and below-ground biodiversity and associated soil processes and ecosystem services. In order to derive management options for maintaining these essential services provided by soils, policy makers depend on robust, predictive models identifying key drivers of SOM dynamics. Existing SOM models and suggested guidelines for future SOM modelling are defined ...

  12. A Key to the Art of Letters

    DEFF Research Database (Denmark)

    Jensen-Rix, Robert William

    2008-01-01

    The article examines A. Lane's grammar A Key to the Art of Letters and its contexts. Symbolically published at the threshold to the eighteenth century, Lane presents an unusually bold plan to make English a world language. Although Lane's book holds a key position in the development of English...... that Lane is the first to use English as the basis for writing universal grammar, as part of his strategy to promote English as a universal code for learning and science...

  13. Is the Green Key standard the golden key for sustainability measurement in the hospitality sector?

    NARCIS (Netherlands)

    Rietbergen, M.G.; Van Rheede, A.

    2014-01-01

    The Green Key is an eco-rating program that aims at promoting sustainable business practices in the hospitality sector. The Green Key assesses amongst others the sustainable management of energy, water and waste within hotels and other hospitality firms. The Green Key standard awards points if

  14. Fundamental quantitative security in quantum key generation

    International Nuclear Information System (INIS)

    Yuen, Horace P.

    2010-01-01

    We analyze the fundamental security significance of the quantitative criteria on the final generated key K in quantum key generation including the quantum criterion d, the attacker's mutual information on K, and the statistical distance between her distribution on K and the uniform distribution. For operational significance a criterion has to produce a guarantee on the attacker's probability of correctly estimating some portions of K from her measurement, in particular her maximum probability of identifying the whole K. We distinguish between the raw security of K when the attacker just gets at K before it is used in a cryptographic context and its composition security when the attacker may gain further information during its actual use to help get at K. We compare both of these securities of K to those obtainable from conventional key expansion with a symmetric key cipher. It is pointed out that a common belief in the superior security of a quantum generated K is based on an incorrect interpretation of d which cannot be true, and the security significance of d is uncertain. Generally, the quantum key distribution key K has no composition security guarantee and its raw security guarantee from concrete protocols is worse than that of conventional ciphers. Furthermore, for both raw and composition security there is an exponential catch-up problem that would make it difficult to quantitatively improve the security of K in a realistic protocol. Some possible ways to deal with the situation are suggested.

  15. Key handling in wireless sensor networks

    International Nuclear Information System (INIS)

    Li, Y; Newe, T

    2007-01-01

    With the rapid growth of Wireless Sensor Networks (WSNs), many advanced application areas have received significant attention. However, security will be an important factor for their full adoption. Wireless sensor nodes pose unique challenges and as such traditional security protocols, used in traditional networks cannot be applied directly. Some new protocols have been published recently with the goal of providing both privacy of data and authentication of sensor nodes for WSNs. Such protocols can employ private-key and/or public key cryptographic algorithms. Public key algorithms hold the promise of simplifying the network infrastructure required to provide security services such as: privacy, authentication and non-repudiation, while symmetric algorithms require less processing power on the lower power wireless node. In this paper a selection of key establishment/agreement protocols are reviewed and they are broadly divided into two categories: group key agreement protocols and pair-wise key establishment protocols. A summary of the capabilities and security related services provided by each protocol is provided

  16. Key handling in wireless sensor networks

    Energy Technology Data Exchange (ETDEWEB)

    Li, Y; Newe, T [Optical Fibre Sensors Research Centre, Department of Electronic and Computer Engineering, University of Limerick, Limerick (Ireland)

    2007-07-15

    With the rapid growth of Wireless Sensor Networks (WSNs), many advanced application areas have received significant attention. However, security will be an important factor for their full adoption. Wireless sensor nodes pose unique challenges and as such traditional security protocols, used in traditional networks cannot be applied directly. Some new protocols have been published recently with the goal of providing both privacy of data and authentication of sensor nodes for WSNs. Such protocols can employ private-key and/or public key cryptographic algorithms. Public key algorithms hold the promise of simplifying the network infrastructure required to provide security services such as: privacy, authentication and non-repudiation, while symmetric algorithms require less processing power on the lower power wireless node. In this paper a selection of key establishment/agreement protocols are reviewed and they are broadly divided into two categories: group key agreement protocols and pair-wise key establishment protocols. A summary of the capabilities and security related services provided by each protocol is provided.

  17. Key-Phenomenon and Religious Meaning

    Directory of Open Access Journals (Sweden)

    Lomuscio Vincenzo

    2017-09-01

    Full Text Available In this paper I develop a phenomenology of religious experience through the notion of keyphenomenon. My analysis moves from a general phenomenology of situation, in which we have to relate different phenomena according to a sense. What does “according to a sense” mean? My suggestion is that we should look for a relationship among these data when we find a key-phenomenon (among a series of phenomena that would enlighten all the others. This key-phenomenon would show a non-phenomenal meaning which would make all the others understandable. Each other datum, therefore, becomes the witness of invisible meaning through a key-witness. The key-phenomenon we choose determines the role (i.e., the truth of each datum within its situation. This phenomenological relationship belongs to both the sense of day-life situations, and that one of possible religious situations. If the religious interpretation of a situation depends on our choice of key-phenomenon, or key-witness, we have to define what kind of keyphenomenon constitutes a religious intuition.

  18. Key Frame Extraction in the Summary Space.

    Science.gov (United States)

    Li, Xuelong; Zhao, Bin; Lu, Xiaoqiang; Xuelong Li; Bin Zhao; Xiaoqiang Lu; Lu, Xiaoqiang; Li, Xuelong; Zhao, Bin

    2018-06-01

    Key frame extraction is an efficient way to create the video summary which helps users obtain a quick comprehension of the video content. Generally, the key frames should be representative of the video content, meanwhile, diverse to reduce the redundancy. Based on the assumption that the video data are near a subspace of a high-dimensional space, a new approach, named as key frame extraction in the summary space, is proposed for key frame extraction in this paper. The proposed approach aims to find the representative frames of the video and filter out similar frames from the representative frame set. First of all, the video data are mapped to a high-dimensional space, named as summary space. Then, a new representation is learned for each frame by analyzing the intrinsic structure of the summary space. Specifically, the learned representation can reflect the representativeness of the frame, and is utilized to select representative frames. Next, the perceptual hash algorithm is employed to measure the similarity of representative frames. As a result, the key frame set is obtained after filtering out similar frames from the representative frame set. Finally, the video summary is constructed by assigning the key frames in temporal order. Additionally, the ground truth, created by filtering out similar frames from human-created summaries, is utilized to evaluate the quality of the video summary. Compared with several traditional approaches, the experimental results on 80 videos from two datasets indicate the superior performance of our approach.

  19. Image encryption using fingerprint as key based on phase retrieval algorithm and public key cryptography

    Science.gov (United States)

    Zhao, Tieyu; Ran, Qiwen; Yuan, Lin; Chi, Yingying; Ma, Jing

    2015-09-01

    In this paper, a novel image encryption system with fingerprint used as a secret key is proposed based on the phase retrieval algorithm and RSA public key algorithm. In the system, the encryption keys include the fingerprint and the public key of RSA algorithm, while the decryption keys are the fingerprint and the private key of RSA algorithm. If the users share the fingerprint, then the system will meet the basic agreement of asymmetric cryptography. The system is also applicable for the information authentication. The fingerprint as secret key is used in both the encryption and decryption processes so that the receiver can identify the authenticity of the ciphertext by using the fingerprint in decryption process. Finally, the simulation results show the validity of the encryption scheme and the high robustness against attacks based on the phase retrieval technique.

  20. A fast and versatile quantum key distribution system with hardware key distillation and wavelength multiplexing

    International Nuclear Information System (INIS)

    Walenta, N; Gisin, N; Guinnard, O; Houlmann, R; Korzh, B; Lim, C W; Lunghi, T; Portmann, C; Thew, R T; Burg, A; Constantin, J; Caselunghe, D; Kulesza, N; Legré, M; Monat, L; Soucarros, M; Trinkler, P; Junod, P; Trolliet, G; Vannel, F

    2014-01-01

    We present a compactly integrated, 625 MHz clocked coherent one-way quantum key distribution system which continuously distributes secret keys over an optical fibre link. To support high secret key rates, we implemented a fast hardware key distillation engine which allows for key distillation rates up to 4 Mbps in real time. The system employs wavelength multiplexing in order to run over only a single optical fibre. Using fast gated InGaAs single photon detectors, we reliably distribute secret keys with a rate above 21 kbps over 25 km of optical fibre. We optimized the system considering a security analysis that respects finite-key-size effects, authentication costs and system errors for a security parameter of ε QKD  = 4 × 10 −9 . (paper)

  1. Setting objectives for managing Key deer

    Science.gov (United States)

    Diefenbach, Duane R.; Wagner, Tyler; Stauffer, Glenn E.

    2014-01-01

    The U.S. Fish and Wildlife Service (FWS) is responsible for the protection and management of Key deer (Odocoileus virginianus clavium) because the species is listed as Endangered under the Endangered Species Act (ESA). The purpose of the ESA is to protect and recover imperiled species and the ecosystems upon which they depend. There are a host of actions that could possibly be undertaken to recover the Key deer population, but without a clearly defined problem and stated objectives it can be difficult to compare and evaluate alternative actions. In addition, management goals and the acceptability of alternative management actions are inherently linked to stakeholders, who should be engaged throughout the process of developing a decision framework. The purpose of this project was to engage a representative group of stakeholders to develop a problem statement that captured the management problem the FWS must address with Key deer and identify objectives that, if met, would help solve the problem. In addition, the objectives were organized in a hierarchical manner (i.e., an objectives network) to show how they are linked, and measurable attributes were identified for each objective. We organized a group of people who represented stakeholders interested in and potentially affected by the management of Key deer. These stakeholders included individuals who represented local, state, and federal governments, non-governmental organizations, the general public, and local businesses. This stakeholder group met five full days over the course of an eight-week period to identify objectives that would address the following problem:“As recovery and removal from the Endangered Species list is the purpose of the Endangered Species Act, the U.S. Fish and Wildlife Service needs a management approach that will ensure a sustainable, viable, and healthy Key deer population. Urbanization has affected the behavior and population dynamics of the Key deer and the amount and characteristics

  2. Fully device-independent conference key agreement

    Science.gov (United States)

    Ribeiro, Jérémy; Murta, Gláucia; Wehner, Stephanie

    2018-02-01

    We present a security analysis of conference key agreement (CKA) in the most adversarial model of device independence (DI). Our protocol can be implemented by any experimental setup that is capable of performing Bell tests [specifically, the Mermin-Ardehali-Belinskii-Klyshko (MABK) inequality], and security can in principle be obtained for any violation of the MABK inequality that detects genuine multipartite entanglement among the N parties involved in the protocol. As our main tool, we derive a direct physical connection between the N -partite MABK inequality and the Clauser-Horne-Shimony-Holt (CHSH) inequality, showing that certain violations of the MABK inequality correspond to a violation of the CHSH inequality between one of the parties and the other N -1 . We compare the asymptotic key rate for device-independent conference key agreement (DICKA) to the case where the parties use N -1 device-independent quantum key distribution protocols in order to generate a common key. We show that for some regime of noise the DICKA protocol leads to better rates.

  3. Synchronization in Quantum Key Distribution Systems

    Directory of Open Access Journals (Sweden)

    Anton Pljonkin

    2017-10-01

    Full Text Available In the description of quantum key distribution systems, much attention is paid to the operation of quantum cryptography protocols. The main problem is the insufficient study of the synchronization process of quantum key distribution systems. This paper contains a general description of quantum cryptography principles. A two-line fiber-optic quantum key distribution system with phase coding of photon states in transceiver and coding station synchronization mode was examined. A quantum key distribution system was built on the basis of the scheme with automatic compensation of polarization mode distortions. Single-photon avalanche diodes were used as optical radiation detecting devices. It was estimated how the parameters used in quantum key distribution systems of optical detectors affect the detection of the time frame with attenuated optical pulse in synchronization mode with respect to its probabilistic and time-domain characteristics. A design method was given for the process that detects the time frame that includes an optical pulse during synchronization. This paper describes the main quantum communication channel attack methods by removing a portion of optical emission. This paper describes the developed synchronization algorithm that takes into account the time required to restore the photodetector’s operation state after the photon has been registered during synchronization. The computer simulation results of the developed synchronization algorithm were analyzed. The efficiency of the developed algorithm with respect to synchronization process protection from unauthorized gathering of optical emission is demonstrated herein.

  4. Integrated genomics of Mucorales reveals novel therapeutic targets

    Science.gov (United States)

    Mucormycosis is a life-threatening infection caused by Mucorales fungi. We sequenced 30 fungal genomes and performed transcriptomics with three representative Rhizopus and Mucor strains with human airway epithelial cells during fungal invasion to reveal key host and fungal determinants contributing ...

  5. Metropolitan Quantum Key Distribution with Silicon Photonics

    Directory of Open Access Journals (Sweden)

    Darius Bunandar

    2018-04-01

    Full Text Available Photonic integrated circuits provide a compact and stable platform for quantum photonics. Here we demonstrate a silicon photonics quantum key distribution (QKD encoder in the first high-speed polarization-based QKD field tests. The systems reach composable secret key rates of 1.039 Mbps in a local test (on a 103.6-m fiber with a total emulated loss of 9.2 dB and 157 kbps in an intercity metropolitan test (on a 43-km fiber with 16.4 dB loss. Our results represent the highest secret key generation rate for polarization-based QKD experiments at a standard telecom wavelength and demonstrate photonic integrated circuits as a promising, scalable resource for future formation of metropolitan quantum-secure communications networks.

  6. A Novel Method for Generating Encryption Keys

    Directory of Open Access Journals (Sweden)

    Dascalescu Ana Cristina

    2009-12-01

    Full Text Available The development of the informational society, which has led to an impressive growth of the information volume circulating in the computer networks, has accelerated the evolution and especially the use of modern cryptography instruments. Today, the commercial products use standard cryptographic libraries that implement certified and tested cryptographic algorithms. Instead, the fragility ofencryption algorithms is given by compositional operations like key handling or key generation. In this sense, the article proposes an innovative method to generate pseudorandom numbers which can be used for the construction of secure stream encryption keys. The proposed method is based on the mathematical complements based on the algebra of the finite fields and uses a particularized structure of the linear feedback shift registers.

  7. Metropolitan Quantum Key Distribution with Silicon Photonics

    Science.gov (United States)

    Bunandar, Darius; Lentine, Anthony; Lee, Catherine; Cai, Hong; Long, Christopher M.; Boynton, Nicholas; Martinez, Nicholas; DeRose, Christopher; Chen, Changchen; Grein, Matthew; Trotter, Douglas; Starbuck, Andrew; Pomerene, Andrew; Hamilton, Scott; Wong, Franco N. C.; Camacho, Ryan; Davids, Paul; Urayama, Junji; Englund, Dirk

    2018-04-01

    Photonic integrated circuits provide a compact and stable platform for quantum photonics. Here we demonstrate a silicon photonics quantum key distribution (QKD) encoder in the first high-speed polarization-based QKD field tests. The systems reach composable secret key rates of 1.039 Mbps in a local test (on a 103.6-m fiber with a total emulated loss of 9.2 dB) and 157 kbps in an intercity metropolitan test (on a 43-km fiber with 16.4 dB loss). Our results represent the highest secret key generation rate for polarization-based QKD experiments at a standard telecom wavelength and demonstrate photonic integrated circuits as a promising, scalable resource for future formation of metropolitan quantum-secure communications networks.

  8. Public key infrastructure for DOE security research

    Energy Technology Data Exchange (ETDEWEB)

    Aiken, R.; Foster, I.; Johnston, W.E. [and others

    1997-06-01

    This document summarizes the Department of Energy`s Second Joint Energy Research/Defence Programs Security Research Workshop. The workshop, built on the results of the first Joint Workshop which reviewed security requirements represented in a range of mission-critical ER and DP applications, discussed commonalties and differences in ER/DP requirements and approaches, and identified an integrated common set of security research priorities. One significant conclusion of the first workshop was that progress in a broad spectrum of DOE-relevant security problems and applications could best be addressed through public-key cryptography based systems, and therefore depended upon the existence of a robust, broadly deployed public-key infrastructure. Hence, public-key infrastructure ({open_quotes}PKI{close_quotes}) was adopted as a primary focus for the second workshop. The Second Joint Workshop covered a range of DOE security research and deployment efforts, as well as summaries of the state of the art in various areas relating to public-key technologies. Key findings were that a broad range of DOE applications can benefit from security architectures and technologies built on a robust, flexible, widely deployed public-key infrastructure; that there exists a collection of specific requirements for missing or undeveloped PKI functionality, together with a preliminary assessment of how these requirements can be met; that, while commercial developments can be expected to provide many relevant security technologies, there are important capabilities that commercial developments will not address, due to the unique scale, performance, diversity, distributed nature, and sensitivity of DOE applications; that DOE should encourage and support research activities intended to increase understanding of security technology requirements, and to develop critical components not forthcoming from other sources in a timely manner.

  9. KeyPathwayMiner 4.0

    DEFF Research Database (Denmark)

    Alcaraz, Nicolas; Pauling, Josch; Batra, Richa

    2014-01-01

    release of KeyPathwayMiner (version 4.0) that is not limited to analyses of single omics data sets, e.g. gene expression, but is able to directly combine several different omics data types. Version 4.0 can further integrate existing knowledge by adding a search bias towards sub-networks that contain...... (avoid) genes provided in a positive (negative) list. Finally the new release now also provides a set of novel visualization features and has been implemented as an app for the standard bioinformatics network analysis tool: Cytoscape. CONCLUSION: With KeyPathwayMiner 4.0, we publish a Cytoscape app...

  10. Key Recovery Attacks on Recent Authenticated Ciphers

    DEFF Research Database (Denmark)

    Bogdanov, Andrey; Dobraunig, Christoph; Eichlseder, Maria

    2014-01-01

    In this paper, we cryptanalyze three authenticated ciphers: AVALANCHE, Calico, and RBS. While the former two are contestants in the ongoing international CAESAR competition for authenticated encryption schemes, the latter has recently been proposed for lightweight applications such as RFID systems...... and wireless networks. All these schemes use well-established and secure components such as the AES, Grain-like NFSRs, ChaCha and SipHash as their building blocks. However, we discover key recovery attacks for all three designs, featuring square-root complexities. Using a key collision technique, we can...

  11. The emotional importance of key: do Beatles songs written in different keys convey different emotional tones?

    Science.gov (United States)

    Whissel, R; Whissel, C

    2000-12-01

    Lyrics from 155 songs written by the Lennon-McCartney team were scored using the Dictionary of Affect in Language. Resultant scores (pleasantness, activation, and imagery of words) were compared across key signatures using one way analyses of variance. Words from songs written in minor keys were less pleasant and less active than those from songs written in major keys. Words from songs written in the key of F scored extremely low on all three measures. Lyrics from the keys of C, D, and G were relatively active in tone. Results from Dictionary scoring were compared with assignments of character to keys made more than one century ago and with current musicians' opinions.

  12. Designing key-dependent chaotic S-box with larger key space

    International Nuclear Information System (INIS)

    Yin Ruming; Yuan Jian; Wang Jian; Shan Xiuming; Wang Xiqin

    2009-01-01

    The construction of cryptographically strong substitution boxes (S-boxes) is an important concern in designing secure cryptosystems. The key-dependent S-boxes designed using chaotic maps have received increasing attention in recent years. However, the key space of such S-boxes does not seem to be sufficiently large due to the limited parameter range of discretized chaotic maps. In this paper, we propose a new key-dependent S-box based on the iteration of continuous chaotic maps. We explore the continuous-valued state space of chaotic systems, and devise the discrete mapping between the input and the output of the S-box. A key-dependent S-box is constructed with the logistic map in this paper. We show that its key space could be much larger than the current key-dependent chaotic S-boxes.

  13. Quantum key distribution with finite resources: Secret key rates via Renyi entropies

    Energy Technology Data Exchange (ETDEWEB)

    Abruzzo, Silvestre; Kampermann, Hermann; Mertz, Markus; Bruss, Dagmar [Institute for Theoretical Physics III, Heinrich-Heine-universitaet Duesseldorf, D-40225 Duesseldorf (Germany)

    2011-09-15

    A realistic quantum key distribution (QKD) protocol necessarily deals with finite resources, such as the number of signals exchanged by the two parties. We derive a bound on the secret key rate which is expressed as an optimization problem over Renyi entropies. Under the assumption of collective attacks by an eavesdropper, a computable estimate of our bound for the six-state protocol is provided. This bound leads to improved key rates in comparison to previous results.

  14. Quantum key distribution with finite resources: Secret key rates via Renyi entropies

    International Nuclear Information System (INIS)

    Abruzzo, Silvestre; Kampermann, Hermann; Mertz, Markus; Bruss, Dagmar

    2011-01-01

    A realistic quantum key distribution (QKD) protocol necessarily deals with finite resources, such as the number of signals exchanged by the two parties. We derive a bound on the secret key rate which is expressed as an optimization problem over Renyi entropies. Under the assumption of collective attacks by an eavesdropper, a computable estimate of our bound for the six-state protocol is provided. This bound leads to improved key rates in comparison to previous results.

  15. Election 2000: The Keys Point to Gore.

    Science.gov (United States)

    Lichtman, Allan J.

    2000-01-01

    Asserts that Vice President Al Gore will be elected in 2000 based on the performance of the Clinton administration. Utilizes the key to the White House, 13 true-or-false diagnostic questions stated as propositions. If five or less are false then the party in power wins. (CMK)

  16. Radiology Aide. Instructor Key [and] Student Manual.

    Science.gov (United States)

    Hartwein, Jon; Dunham, John

    This manual can be used independently by students in secondary health occupations programs or by persons receiving on-the-job training in a radiology department. The manual includes an instructor's key that provides answers to the activity sheets and unit evaluations. The manual consists of the following five units: (1) orientation to radiology;…

  17. Key Competences in vocational education and training

    DEFF Research Database (Denmark)

    Andersen, Ole Dibbern; Kruse, Katrine

    This article presents and discusses how key competences in the school based learning are embedded in the VET curricula during the last five years. It gives an overview of how their role has developed in light of the comprehensive Danish VET reform agreed in 2014 and implemented since August 2015....

  18. Memory for melody and key in childhood.

    Directory of Open Access Journals (Sweden)

    E Glenn Schellenberg

    Full Text Available After only two exposures to previously unfamiliar melodies, adults remember the tunes for over a week and the key for over a day. Here, we examined the development of long-term memory for melody and key. Listeners in three age groups (7- to 8-year-olds, 9- to 11-year-olds, and adults heard two presentations of each of 12 unfamiliar melodies. After a 10-min delay, they heard the same 12 old melodies intermixed with 12 new melodies. Half of the old melodies were transposed up or down by six semitones from initial exposure. Listeners rated how well they recognized the melodies from the exposure phase. Recognition was better for old than for new melodies, for adults compared to children, and for older compared to younger children. Recognition ratings were also higher for old melodies presented in the same key at test as exposure, and the detrimental effect of the transposition affected all age groups similarly. Although memory for melody improves with age and exposure to music, implicit memory for key appears to be adult-like by 7 years of age.

  19. Secure Hybrid Encryption from Weakened Key Encapsulation

    NARCIS (Netherlands)

    D. Hofheinz (Dennis); E. Kiltz (Eike); A. Menezes

    2007-01-01

    textabstractWe put forward a new paradigm for building hybrid encryption schemes from constrained chosen-ciphertext secure (CCCA) key-encapsulation mechanisms (KEMs) plus authenticated symmetric encryption. Constrained chosen-ciphertext security is a new security notion for KEMs that we propose. It

  20. Public-key encryption with chaos

    Science.gov (United States)

    Kocarev, Ljupco; Sterjev, Marjan; Fekete, Attila; Vattay, Gabor

    2004-12-01

    We propose public-key encryption algorithms based on chaotic maps, which are generalization of well-known and commercially used algorithms: Rivest-Shamir-Adleman (RSA), ElGamal, and Rabin. For the case of generalized RSA algorithm we discuss in detail its software implementation and properties. We show that our algorithm is as secure as RSA algorithm.

  1. Quantum key distribution on Hannover Campus

    Energy Technology Data Exchange (ETDEWEB)

    Duhme, Joerg; Franz, Torsten; Werner, Reinhard F. [Leibniz Universitaet Hannover, Institut fuer Theoretische Physik, AG Quanteninformation (Germany); Haendchen, Vitus; Eberle, Tobias; Schnabel, Roman [Albert Einstein Institut, Quantum Interferometry (Germany)

    2012-07-01

    We report on the progress of the implementation of an entanglement-based quantum key distribution on Hannover campus using squeezed gaussian states (continuous variables). This poster focuses on the theoretical aspects of the project. Experimental data has been compared with the theoretical simulation of the experimental setup. We especially discuss effects of the homodyne detection and postprocessing in use on the measurement outcome.

  2. Memory for melody and key in childhood.

    Science.gov (United States)

    Schellenberg, E Glenn; Poon, Jaimie; Weiss, Michael W

    2017-01-01

    After only two exposures to previously unfamiliar melodies, adults remember the tunes for over a week and the key for over a day. Here, we examined the development of long-term memory for melody and key. Listeners in three age groups (7- to 8-year-olds, 9- to 11-year-olds, and adults) heard two presentations of each of 12 unfamiliar melodies. After a 10-min delay, they heard the same 12 old melodies intermixed with 12 new melodies. Half of the old melodies were transposed up or down by six semitones from initial exposure. Listeners rated how well they recognized the melodies from the exposure phase. Recognition was better for old than for new melodies, for adults compared to children, and for older compared to younger children. Recognition ratings were also higher for old melodies presented in the same key at test as exposure, and the detrimental effect of the transposition affected all age groups similarly. Although memory for melody improves with age and exposure to music, implicit memory for key appears to be adult-like by 7 years of age.

  3. Quantum cryptography beyond quantum key distribution

    NARCIS (Netherlands)

    Broadbent, A.; Schaffner, C.

    2016-01-01

    Quantum cryptography is the art and science of exploiting quantum mechanical effects in order to perform cryptographic tasks. While the most well-known example of this discipline is quantum key distribution (QKD), there exist many other applications such as quantum money, randomness generation,

  4. Five Keys for Teaching Mental Math

    Science.gov (United States)

    Olsen, James R.

    2015-01-01

    After studying the Common Core State Standards for Mathematics (CCSSM) and brain-based learning research, James Olsen believes mental math instruction in secondary school mathematics (grades 7-12) and in teacher education programs needs increased attention. The purpose of this article is to share some keys for teaching mental math. Olsen also…

  5. Number Theory and Public-Key Cryptography.

    Science.gov (United States)

    Lefton, Phyllis

    1991-01-01

    Described are activities in the study of techniques used to conceal the meanings of messages and data. Some background information and two BASIC programs that illustrate the algorithms used in a new cryptographic system called "public-key cryptography" are included. (CW)

  6. Student Engagement: Key to Personalized Learning

    Science.gov (United States)

    Ferlazzo, Larry

    2017-01-01

    Personalized learning has the potential to greatly improve student achievement--but realistic teachers know that any instructional strategy will only be effective if students are willing to do the work. That is why Larry Ferlazzo emphasizes the importance of weaving intrinsic motivation into every personalized learning classroom. Four key elements…

  7. Time to refine key climate policy models

    Science.gov (United States)

    Barron, Alexander R.

    2018-05-01

    Ambition regarding climate change at the national level is critical but is often calibrated with the projected costs — as estimated by a small suite of energy-economic models. Weaknesses in several key areas in these models will continue to distort policy design unless collectively addressed by a diversity of researchers.

  8. The LOFAR Magnetism Key Science Project

    NARCIS (Netherlands)

    Anderson, James; Beck, Rainer; Bell, Michael; de Bruyn, Ger; Chyzy, Krzysztof; Eislöffel, Jochen; Enßlin, Torsten; Fletcher, Andrew; Haverkorn, Marijke; Heald, George; Horneffer, Andreas; Noutsos, Aris; Reich, Wolfgang; Scaife, Anna; the LOFAR collaboration, [No Value

    2012-01-01

    Measuring radio waves at low frequencies offers a new window to study cosmic magnetism, and LOFAR is the ideal radio telescope to open this window widely. The LOFAR Magnetism Key Science Project (MKSP) draws together expertise from multiple fields of magnetism science and intends to use LOFAR to

  9. Memory for melody and key in childhood

    Science.gov (United States)

    Poon, Jaimie; Weiss, Michael W.

    2017-01-01

    After only two exposures to previously unfamiliar melodies, adults remember the tunes for over a week and the key for over a day. Here, we examined the development of long-term memory for melody and key. Listeners in three age groups (7- to 8-year-olds, 9- to 11-year-olds, and adults) heard two presentations of each of 12 unfamiliar melodies. After a 10-min delay, they heard the same 12 old melodies intermixed with 12 new melodies. Half of the old melodies were transposed up or down by six semitones from initial exposure. Listeners rated how well they recognized the melodies from the exposure phase. Recognition was better for old than for new melodies, for adults compared to children, and for older compared to younger children. Recognition ratings were also higher for old melodies presented in the same key at test as exposure, and the detrimental effect of the transposition affected all age groups similarly. Although memory for melody improves with age and exposure to music, implicit memory for key appears to be adult-like by 7 years of age. PMID:29077726

  10. Soil fauna: key to new carbon models

    NARCIS (Netherlands)

    Filser, Juliane; Faber, J.H.; Tiunov, Alexei V.; Brussaard, L.; Frouz, J.; Deyn, de G.B.; Uvarov, Alexei V.; Berg, Matty P.; Lavelle, Patrick; Loreau, M.; Wall, D.H.; Querner, Pascal; Eijsackers, Herman; Jimenez, Juan Jose

    2016-01-01

    Soil organic matter (SOM) is key to maintaining soil fertility, mitigating climate change, combatting land degradation, and conserving above- and below-ground biodiversity and associated soil processes and ecosystem services. In order to derive management options for maintaining these essential

  11. Using USB Keys to Promote Mobile Learning

    Directory of Open Access Journals (Sweden)

    Marilyne Rosselle

    2009-07-01

    Full Text Available M-learning (i.e. mobile learning is a field of e-learning that provides learners learning environments using mobile technology. In this context, learning can take place anywhere and anytime, in open and distance learning. Depending on the type of technology it may be done through software called nomadic (i.e. prepared to mobility. Among these technologies, there are those composed of digital interfaces and with autonomy of treatment: Smartphone, PDA, calculator and even mp3 key. In this article we propose to take into account storage devices as mobile technologies. Our focus was on the USB key. We present a procedure to test whether a learning environment embarked on a USB key can be described as nomadic or not. This procedure has been tested on a sample of three ILE (Interactive Learning Environment. This approach has allowed us to define criteria of nomadism, criteria which were then included in the design of a synchronous Weblog on USB key.

  12. Key Management in Wireless Sensor Networks

    Directory of Open Access Journals (Sweden)

    Ismail Mansour

    2015-09-01

    Full Text Available Wireless sensor networks are a challenging field of research when it comes to security issues. Using low cost sensor nodes with limited resources makes it difficult for cryptographic algorithms to function without impacting energy consumption and latency. In this paper, we focus on key management issues in multi-hop wireless sensor networks. These networks are easy to attack due to the open nature of the wireless medium. Intruders could try to penetrate the network, capture nodes or take control over particular nodes. In this context, it is important to revoke and renew keys that might be learned by malicious nodes. We propose several secure protocols for key revocation and key renewal based on symmetric encryption and elliptic curve cryptography. All protocols are secure, but have different security levels. Each proposed protocol is formally proven and analyzed using Scyther, an automatic verification tool for cryptographic protocols. For efficiency comparison sake, we implemented all protocols on real testbeds using TelosB motes and discussed their performances.

  13. Expectations as a key element in trusting

    DEFF Research Database (Denmark)

    Rasmussen, Mette Apollo; Hansen, Uffe Kjærgaard; Conradsen, Maria Bosse

    Considering the need for a tangible focus for qualitative research on trusting, we propose that expectations to the behavior of others can provide that. By focusing on expectations, researchers can produce narrative descriptions that explains how trusting develops and changes. Then the key theore...

  14. Key Performance Indicators for Primary Schools.

    Science.gov (United States)

    Strand, Steve

    Focusing mostly on their application for primary schools, this document describes the educational key performance indicators (KPI) employed by the Wendsworth, England, Local Educational Authority (LEA). Indicators are divided into 3 areas, educational context, resource development, and outcomes. Contextual indicators include pupil mobility, home…

  15. Social patterns revealed through random matrix theory

    Science.gov (United States)

    Sarkar, Camellia; Jalan, Sarika

    2014-11-01

    Despite the tremendous advancements in the field of network theory, very few studies have taken weights in the interactions into consideration that emerge naturally in all real-world systems. Using random matrix analysis of a weighted social network, we demonstrate the profound impact of weights in interactions on emerging structural properties. The analysis reveals that randomness existing in particular time frame affects the decisions of individuals rendering them more freedom of choice in situations of financial security. While the structural organization of networks remains the same throughout all datasets, random matrix theory provides insight into the interaction pattern of individuals of the society in situations of crisis. It has also been contemplated that individual accountability in terms of weighted interactions remains as a key to success unless segregation of tasks comes into play.

  16. Two-Dimensional Key Table-Based Group Key Distribution in Advanced Metering Infrastructure

    Directory of Open Access Journals (Sweden)

    Woong Go

    2014-01-01

    Full Text Available A smart grid provides two-way communication by using the information and communication technology. In order to establish two-way communication, the advanced metering infrastructure (AMI is used in the smart grid as the core infrastructure. This infrastructure consists of smart meters, data collection units, maintenance data management systems, and so on. However, potential security problems of the AMI increase owing to the application of the public network. This is because the transmitted information is electricity consumption data for charging. Thus, in order to establish a secure connection to transmit electricity consumption data, encryption is necessary, for which key distribution is required. Further, a group key is more efficient than a pairwise key in the hierarchical structure of the AMI. Therefore, we propose a group key distribution scheme using a two-dimensional key table through the analysis result of the sensor network group key distribution scheme. The proposed scheme has three phases: group key predistribution, selection of group key generation element, and generation of group key.

  17. Identification of the Key Fields and Their Key Technical Points of Oncology by Patent Analysis.

    Science.gov (United States)

    Zhang, Ting; Chen, Juan; Jia, Xiaofeng

    2015-01-01

    This paper aims to identify the key fields and their key technical points of oncology by patent analysis. Patents of oncology applied from 2006 to 2012 were searched in the Thomson Innovation database. The key fields and their key technical points were determined by analyzing the Derwent Classification (DC) and the International Patent Classification (IPC), respectively. Patent applications in the top ten DC occupied 80% of all the patent applications of oncology, which were the ten fields of oncology to be analyzed. The number of patent applications in these ten fields of oncology was standardized based on patent applications of oncology from 2006 to 2012. For each field, standardization was conducted separately for each of the seven years (2006-2012) and the mean of the seven standardized values was calculated to reflect the relative amount of patent applications in that field; meanwhile, regression analysis using time (year) and the standardized values of patent applications in seven years (2006-2012) was conducted so as to evaluate the trend of patent applications in each field. Two-dimensional quadrant analysis, together with the professional knowledge of oncology, was taken into consideration in determining the key fields of oncology. The fields located in the quadrant with high relative amount or increasing trend of patent applications are identified as key ones. By using the same method, the key technical points in each key field were identified. Altogether 116,820 patents of oncology applied from 2006 to 2012 were retrieved, and four key fields with twenty-nine key technical points were identified, including "natural products and polymers" with nine key technical points, "fermentation industry" with twelve ones, "electrical medical equipment" with four ones, and "diagnosis, surgery" with four ones. The results of this study could provide guidance on the development direction of oncology, and also help researchers broaden innovative ideas and discover new

  18. Nonmarket economic user values of the Florida Keys/Key West

    Science.gov (United States)

    Vernon R. Leeworthy; J. Michael Bowker

    1997-01-01

    This report provides estimates of the nonmarket economic user values for recreating visitors to the Florida Keys/Key West that participated in natural resource-based activities. Results from estimated travel cost models are presented, including visitor’s responses to prices and estimated per person-trip user values. Annual user values are also calculated and presented...

  19. New hematological key for bovine leukemia virus-infected Japanese Black cattle.

    Science.gov (United States)

    Mekata, Hirohisa; Yamamoto, Mari; Kirino, Yumi; Sekiguchi, Satoshi; Konnai, Satoru; Horii, Yoichiro; Norimine, Junzo

    2018-02-20

    The European Community's (EC) Key, which is also called Bendixen's Key, is a well-established bovine leukemia virus (BLV) diagnostic method that classifies cattle according to the absolute lymphocyte count and age. The EC Key was originally designed for dairy cattle and is not necessarily suitable for Japanese Black (JB) beef cattle. This study revealed the lymphocyte counts in the BLV-free and -infected JB cattle were significantly lower than those in the Holstein cattle. Therefore, applying the EC Key to JB cattle could result in a large number of undetected BLV-infected cattle. Our proposed hematological key, which was designed for JB cattle, improves the detection of BLV-infected cattle by approximately 20%. We believe that this study could help promote BLV control.

  20. Key Exchange Trust Evaluation in Peer-to-Peer Sensor Networks With Unconditionally Secure Key Exchange

    Science.gov (United States)

    Gonzalez, Elias; Kish, Laszlo B.

    2016-03-01

    As the utilization of sensor networks continue to increase, the importance of security becomes more profound. Many industries depend on sensor networks for critical tasks, and a malicious entity can potentially cause catastrophic damage. We propose a new key exchange trust evaluation for peer-to-peer sensor networks, where part of the network has unconditionally secure key exchange. For a given sensor, the higher the portion of channels with unconditionally secure key exchange the higher the trust value. We give a brief introduction to unconditionally secured key exchange concepts and mention current trust measures in sensor networks. We demonstrate the new key exchange trust measure on a hypothetical sensor network using both wired and wireless communication channels.

  1. GLOBAL TRADE. THE KEY TO TRANSATLANTIC COMPETITIVENESS

    Directory of Open Access Journals (Sweden)

    Mădălina Laura CUCIURIANU

    2015-04-01

    Full Text Available Global trade has an important characteristic in terms of open global markets by means of eliminating barriers to trade and investment. The United States and the European Union, two major international actors and competitors in the economic field, have both the opportunity to change the global trade by concluding the negotiations of the Transatlantic Trade and Investment Partnership. For this reason, this paper tries to find the connections between global trade and transatlantic competitiveness in the way that the global trade can be considered a key to transatlantic competitiveness. The United States and the European Union are global actors and competitors in the global economy and the play field is the global trade. In order to be aware of the importance ofglobal trade in the transatlantic competitiveness, this paper includes also an analysis of the concrete actions that both economic powers are taking in key-sectors of the transatlantic economy.

  2. Quantum key distribution without alternative measurements

    CERN Document Server

    Cabello, A

    2000-01-01

    Entanglement swapping between Einstein-Podolsky-Rosen (EPR) pairs can be used to generate the same sequence of random bits in two remote places. A quantum key distribution protocol based on this idea is described. The scheme exhibits the following features. (a) It does not require that Alice and Bob choose between alternative measurements, therefore improving the rate of generated bits by transmitted qubit. (b) It allows Alice and Bob to generate a key of arbitrary length using a single quantum system (three EPR pairs), instead of a long sequence of them. (c) Detecting Eve requires the comparison of fewer bits. (d) Entanglement is an essential ingredient. The scheme assumes reliable measurements of the Bell operator. (20 refs).

  3. Secure quantum key distribution using squeezed states

    International Nuclear Information System (INIS)

    Gottesman, Daniel; Preskill, John

    2001-01-01

    We prove the security of a quantum key distribution scheme based on transmission of squeezed quantum states of a harmonic oscillator. Our proof employs quantum error-correcting codes that encode a finite-dimensional quantum system in the infinite-dimensional Hilbert space of an oscillator, and protect against errors that shift the canonical variables p and q. If the noise in the quantum channel is weak, squeezing signal states by 2.51 dB (a squeeze factor e r =1.34) is sufficient in principle to ensure the security of a protocol that is suitably enhanced by classical error correction and privacy amplification. Secure key distribution can be achieved over distances comparable to the attenuation length of the quantum channel

  4. Anonymity-Preserving Public-Key Encryption

    DEFF Research Database (Denmark)

    Kohlweiss, Markulf; Maurer, Ueli; Onete, Cristina

    2013-01-01

    security properties have been proposed. We investigate constructions as well as limitations for preserving receiver anonymity when using public-key encryption (PKE). We use the constructive cryptography approach by Maurer and Renner and interpret cryptographic schemes as constructions of a certain ideal...... literature (IND-CCA, key-privacy, weak robustness). We also show that a desirable stronger variant, preventing the adversary from selective ”trial-deliveries” of messages, is unfortunately unachievable by any PKE scheme, no matter how strong. The constructive approach makes the guarantees achieved...... by applying a cryptographic scheme explicit in the constructed (ideal) resource; this specifies the exact requirements for the applicability of a cryptographic scheme in a given context. It also allows to decide which of the existing security properties of such a cryptographic scheme are adequate...

  5. Key parameters analysis of hybrid HEMP simulator

    International Nuclear Information System (INIS)

    Mao Congguang; Zhou Hui

    2009-01-01

    According to the new standards on the high-altitude electromagnetic pulse (HEMP) developed by International Electrotechnical Commission (IEC), the target parameter requirements of the key structure of the hybrid HEMP simulator are decomposed. Firstly, the influences of the different excitation sources and biconical structures to the key parameters of the radiated electric field wave shape are investigated and analyzed. Then based on the influence curves the target parameter requirements of the pulse generator are proposed. Finally the appropriate parameters of the biconical structure and the excitation sources are chosen, and the computational result of the electric field in free space is presented. The results are of great value for the design of the hybrid HEMP simulator. (authors)

  6. A ''master key'' to chemical separation processes

    International Nuclear Information System (INIS)

    Madic, Ch.; Hill, C.

    2002-01-01

    One of the keys to sorting nuclear waste is extracting minor actinides - the most troublesome long-lived elements - from the flow of waste by separating them from lanthanides, which have very similar chemical properties to actinides, for possible transmutation into shorter-lived elements. Thanks to a European initiative coordinated by CEA, this key is now available: its name is Sanex. There now remains to develop tough, straightforward industrial processes to integrate it into a new nuclear waste management approach by 2005. Sanex joins the Diamex process, used for the combined separation of lanthanides and minor actinides from fission products. A third process, Sesame, designed to separate americium, completes the list of available separation processes. (authors)

  7. Privacy amplification for quantum key distribution

    International Nuclear Information System (INIS)

    Watanabe, Yodai

    2007-01-01

    This paper examines classical privacy amplification using a universal family of hash functions. In quantum key distribution, the adversary's measurement can wait until the choice of hash functions is announced, and so the adversary's information may depend on the choice. Therefore the existing result on classical privacy amplification, which assumes the independence of the choice from the other random variables, is not applicable to this case. This paper provides a security proof of privacy amplification which is valid even when the adversary's information may depend on the choice of hash functions. The compression rate of the proposed privacy amplification can be taken to be the same as that of the existing one with an exponentially small loss in secrecy of a final key. (fast track communication)

  8. Molecular beam epitaxy applications to key materials

    CERN Document Server

    Farrow, Robin F C

    1995-01-01

    In this volume, the editor and contributors describe the use of molecular beam epitaxy (MBE) for a range of key materials systems that are of interest for both technological and fundamental reasons. Prior books on MBE have provided an introduction to the basic concepts and techniques of MBE and emphasize growth and characterization of GaAs-based structures. The aim in this book is somewhat different; it is to demonstrate the versatility of the technique by showing how it can be utilized to prepare and explore a range of distinct and diverse materials. For each of these materials systems MBE has played a key role both in their development and application to devices.

  9. Short Review on Quantum Key Distribution Protocols.

    Science.gov (United States)

    Giampouris, Dimitris

    2017-01-01

    Cryptographic protocols and mechanisms are widely investigated under the notion of quantum computing. Quantum cryptography offers particular advantages over classical ones, whereas in some cases established protocols have to be revisited in order to maintain their functionality. The purpose of this paper is to provide the basic definitions and review the most important theoretical advancements concerning the BB84 and E91 protocols. It also aims to offer a summary on some key developments on the field of quantum key distribution, closely related with the two aforementioned protocols. The main goal of this study is to provide the necessary background information along with a thorough review on the theoretical aspects of QKD, concentrating on specific protocols. The BB84 and E91 protocols have been chosen because most other protocols are similar to these, a fact that makes them important for the general understanding of how the QKD mechanism functions.

  10. Key Success Factors in Medical Tourism Marketing

    OpenAIRE

    Yung-Sheng Yang

    2013-01-01

    The planners in tourism businesses and medical institutes, the evaluation criteria and dimensions for Medical Tourism Marketing are determined by experts through expert interviews. The weights and correlations among the dimensions and criteria are determined by Analytic Hierarchy Process (AHP) to construct an evaluating indicator model suitable for Medical Tourism Marketing. By organizing the overall weight of the key success factors in Medical Tourism Marketing, the top five indicators conta...

  11. PROVIDING QUALITY – A KEY TO SUCCESS

    OpenAIRE

    Oana Staiculescu; Angel-Cristian Staiculescu

    2012-01-01

    Providing a high quality products and services is a key to business success. That is because high quality promotes customer satisfaction and customer satisfaction has a direct link to business revenue. Clients want quality products and services in order to feel they are getting value for money, especially in these hard economic times. Although it is well known that advertising may win new customers, quality can be the reason to keep them. A good manager is aware that the costs of winning mark...

  12. Cryptographic key generation using handwritten signature

    OpenAIRE

    Freire, Manuel R.; Fiérrez, Julián; Ortega-García, Javier

    2006-01-01

    M. Freire-Santos ; J. Fierrez-Aguilar ; J. Ortega-Garcia; "Cryptographic key generation using handwritten signature", Biometric Technology for Human Identification III, Proc. SPIE 6202 (April 17, 2006); doi:10.1117/12.665875. Copyright 2006 Society of Photo‑Optical Instrumentation Engineers. One print or electronic copy may be made for personal use only. Systematic reproduction and distribution, duplication of any material in this paper for a fee or for commercial purposes, or modification of...

  13. Key factors of teenagers' mobile advertising acceptance

    OpenAIRE

    Martí Parreño, José; Sanz Blas, Silvia; Ruiz Mafé, Carla; Aldás Manzano, Joaquín

    2013-01-01

    Purpose – The purpose of this paper is to analyse key drivers of teenagers’ attitude toward mobile advertising and its effects on teenagers’ mobile advertising acceptance. Design/methodology/approach – A proposed model of affective (irritation and entertainment) and cognitive (perceived usefulness) antecedents of attitude toward mobile advertising and its effects on mobile advertising acceptance is analysed. The sample consisted of 355 Spanish teenagers. The model was tested us...

  14. Key performance indicators for successful simulation projects

    OpenAIRE

    Jahangirian, M; Taylor, SJE; Young, T; Robinson, S

    2016-01-01

    There are many factors that may contribute to the successful delivery of a simulation project. To provide a structured approach to assessing the impact various factors have on project success, we propose a top-down framework whereby 15 Key Performance Indicators (KPI) are developed that represent the level of successfulness of simulation projects from various perspectives. They are linked to a set of Critical Success Factors (CSF) as reported in the simulation literature. A single measure cal...

  15. Some Key Principles for Developing Grammar Skills

    Institute of Scientific and Technical Information of China (English)

    张威

    2008-01-01

    Grammar is sometimes defined aft"the way words are put together to make correct sentences"(Ur,2004,P.75).The aim of teaching grammar is to raise the rates of the correctness of language use and help the students transfer the isolated language points to apply language.In this essay,the author introduces two kinds of Conlnlon methods in English grammar class. And there are some key principles in grammar teaching.

  16. George's secret key to the universe

    CERN Document Server

    Hawking, Lucy; Galfard, Christophe; Parsons, Gary

    2007-01-01

    In their bestselling book for young readers, noted physicist Stephen Hawking and his daughter, Lucy, provide a grand and funny adventure that explains fascinating information about our universe, including Dr. Hawking's latest ideas about black holes. It's the story of George, who's taken through the vastness of space by a scientist, his daughter, and their super-computer named Cosmos. George's Secret Key to the Universe was a New York Times bestseller and a selection of Al's Book Club on the Today show.

  17. Parallel Device-Independent Quantum Key Distribution

    OpenAIRE

    Jain, Rahul; Miller, Carl A.; Shi, Yaoyun

    2017-01-01

    A prominent application of quantum cryptography is the distribution of cryptographic keys with unconditional security. Recently, such security was extended by Vazirani and Vidick (Physical Review Letters, 113, 140501, 2014) to the device-independent (DI) scenario, where the users do not need to trust the integrity of the underlying quantum devices. The protocols analyzed by them and by subsequent authors all require a sequential execution of N multiplayer games, where N is the security parame...

  18. Feasibility of satellite quantum key distribution

    OpenAIRE

    Bonato, Cristian; Tomaello, Andrea; Da Deppo, Vania; Naletto, Giampiero; Villoresi, Paolo

    2009-01-01

    In this paper we present a novel analysis of the feasibility of quantum key distribution between a LEO satellite and a ground station. First of all, we study signal propagation through a turbulent atmosphere for uplinks and downlinks, discussing the contribution of beam spreading and beam wandering. Then we introduce a model for the background noise of the channel during night-time and day-time, calculating the signal-to-noise ratio for different configurations. We also discuss the expected e...

  19. Mars’ First Billion Years: Key Findings, Key Unsolved Paradoxes, and Future Exploration

    Science.gov (United States)

    Ehlmann, Bethany

    2017-10-01

    In the evolution of terrestrial planets, the first billion years are the period most shrouded in mystery: How vigorous is early atmospheric loss? How do planetary climates respond to a brightening sun? When and how are plate tectonic recycling processes initiated? How do voluminous volcanism and heavy impact bombardment influence the composition of the atmosphere? Under what conditions might life arise? Looking outward to terrestrial planets around other stars, the record from Venus, Earth and Mars in this solar system is crucial for developing models of physical can chemical processes. Of these three worlds, Mars provides the longest record of planetary evolution from the first billion years, comprising >50% of exposed geologic units, which are only lightly overprinted by later processes.Orbital observations of the last decade have revealed abundant evidence for surface waters in the form of lakes, valley networks, and evidence of chemically open-system near-surface weathering. Groundwaters at temperatures ranging from just above freezing to hydrothermal have also left a rich record of process in the mineralogical record. A rsuite of environments - similar in diversity to Earth’s - has been discovered on Mars with water pH, temperature, redox, and chemistries varying in space and time.Here, I will focus on the consequences of the aqueous alteration of the Martian crust on the composition of the atmosphere based on recent work studying aspects of the volatile budget (Usui et al., 2015; Edwards & Ehlmann, 2015; Hu et al., 2015; Jakosky et al., 2017, Wordsworth et al., 2017, and Ehlmann, in prep.). The solid crust and mantle of Mars act as volatile reservoirs and volatile sources through volcanism, mineral precipitation, and release of gases. We examine the extent to which the budget is understood or ill-understood for hydrogen and carbon, and associated phases H2O, CO2, and CH4. Additionally, I identify some key stratigraphies where a combination of focused in

  20. Interactive simulations for quantum key distribution

    International Nuclear Information System (INIS)

    Kohnle, Antje; Rizzoli, Aluna

    2017-01-01

    Secure communication protocols are becoming increasingly important, e.g. for internet-based communication. Quantum key distribution (QKD) allows two parties, commonly called Alice and Bob, to generate a secret sequence of 0s and 1s called a key that is only known to themselves. Classically, Alice and Bob could never be certain that their communication was not compromised by a malicious eavesdropper. Quantum mechanics however makes secure communication possible. The fundamental principle of quantum mechanics that taking a measurement perturbs the system (unless the measurement is compatible with the quantum state) also applies to an eavesdropper. Using appropriate protocols to create the key, Alice and Bob can detect the presence of an eavesdropper by errors in their measurements. As part of the QuVis Quantum Mechanics Visualisation Project, we have developed a suite of four interactive simulations that demonstrate the basic principles of three different QKD protocols. The simulations use either polarised photons or spin 1/2 particles as physical realisations. The simulations and accompanying activities are freely available for use online or download, and run on a wide range of devices including tablets and PCs. Evaluation with students over three years was used to refine the simulations and activities. Preliminary studies show that the refined simulations and activities help students learn the basic principles of QKD at both the introductory and advanced undergraduate levels. (paper)

  1. Interactive simulations for quantum key distribution

    Science.gov (United States)

    Kohnle, Antje; Rizzoli, Aluna

    2017-05-01

    Secure communication protocols are becoming increasingly important, e.g. for internet-based communication. Quantum key distribution (QKD) allows two parties, commonly called Alice and Bob, to generate a secret sequence of 0s and 1s called a key that is only known to themselves. Classically, Alice and Bob could never be certain that their communication was not compromised by a malicious eavesdropper. Quantum mechanics however makes secure communication possible. The fundamental principle of quantum mechanics that taking a measurement perturbs the system (unless the measurement is compatible with the quantum state) also applies to an eavesdropper. Using appropriate protocols to create the key, Alice and Bob can detect the presence of an eavesdropper by errors in their measurements. As part of the QuVis Quantum Mechanics Visualisation Project, we have developed a suite of four interactive simulations that demonstrate the basic principles of three different QKD protocols. The simulations use either polarised photons or spin 1/2 particles as physical realisations. The simulations and accompanying activities are freely available for use online or download, and run on a wide range of devices including tablets and PCs. Evaluation with students over three years was used to refine the simulations and activities. Preliminary studies show that the refined simulations and activities help students learn the basic principles of QKD at both the introductory and advanced undergraduate levels.

  2. Ancestors protocol for scalable key management

    Directory of Open Access Journals (Sweden)

    Dieter Gollmann

    2010-06-01

    Full Text Available Group key management is an important functional building block for secure multicast architecture. Thereby, it has been extensively studied in the literature. The main proposed protocol is Adaptive Clustering for Scalable Group Key Management (ASGK. According to ASGK protocol, the multicast group is divided into clusters, where each cluster consists of areas of members. Each cluster uses its own Traffic Encryption Key (TEK. These clusters are updated periodically depending on the dynamism of the members during the secure session. The modified protocol has been proposed based on ASGK with some modifications to balance the number of affected members and the encryption/decryption overhead with any number of the areas when a member joins or leaves the group. This modified protocol is called Ancestors protocol. According to Ancestors protocol, every area receives the dynamism of the members from its parents. The main objective of the modified protocol is to reduce the number of affected members during the leaving and joining members, then 1 affects n overhead would be reduced. A comparative study has been done between ASGK protocol and the modified protocol. According to the comparative results, it found that the modified protocol is always outperforming the ASGK protocol.

  3. Triple symmetric key cryptosystem for data security

    Science.gov (United States)

    Fuzail, C. Md; Norman, Jasmine; Mangayarkarasi, R.

    2017-11-01

    As the technology is getting spreads in the macro seconds of speed and in which the trend changing era from human to robotics the security issue is also getting increased. By means of using machine attacks it is very easy to break the cryptosystems in very less amount of time. Cryptosystem is a process which provides the security in all sorts of processes, communications and transactions to be done securely with the help of electronical mechanisms. Data is one such thing with the expanded implication and possible scraps over the collection of data to secure predominance and achievement, Information Security is the process where the information is protected from invalid and unverified accessibilities and data from mishandling. So the idea of Information Security has risen. Symmetric key which is also known as private key.Whereas the private key is mostly used to attain the confidentiality of data. It is a dynamic topic which can be implemented over different applications like android, wireless censor networks, etc. In this paper, a new mathematical manipulation algorithm along with Tea cryptosystem has been implemented and it can be used for the purpose of cryptography. The algorithm which we proposed is straightforward and more powerful and it will authenticate in harder way and also it will be very difficult to break by someone without knowing in depth about its internal mechanisms.

  4. Key Research Issues in Clostridium difficile

    Directory of Open Access Journals (Sweden)

    George Zhanel

    2005-01-01

    Full Text Available Clostridium difficile is an emerging pathogen that causes C difficile-associated diarrhea, an important nosocomial infection. Control of this infection remains a challenge, and much needs to be determined about the antimicrobial resistance of the organism, antibiotic stewardship, contamination of the patient environment, and various host factors that determine susceptibility or resistance to infection. A national symposium focusing on C difficile infections, the Clostridium difficile Symposium on Emerging Issues and Research, was hosted on November 23, 2004, by the Department of Medical Microbiology and Infectious Diseases at the University of Manitoba, Winnipeg, Manitoba, in partnership with the Canadian Institutes of Health Research. This symposium, which aimed to summarize key research issues regarding C difficile infections in Canada, had the following objectives: to provide a forum for learning and discussion about C difficile and its impact on the health of Canadians; to identify the key research issues that should be addressed; and to explore potential research funding opportunities and collaboration. The present report summarizes key research issues identified for C difficile infections in Canada by addressing four major themes: diagnosis and surveillance, infection prevention and control, antibiotic stewardship, and clinical management.

  5. Commitment is the key to these accounts

    International Nuclear Information System (INIS)

    Yborra, S.

    1996-01-01

    Key accounts--A.G.A.'s name for regional and national multi-unit accounts--affect gas load and market share in several ways. Many make their equipment and energy policies and decisions at the corporate or regional level, making gas company sales and marketing efforts to them critical, since multiple installations will likely emanate from a single decision. To survive, chains often mimic each other; a money-saving idea implemented by one chain can lead to others in that market sector copying it. A successful equipment field trial with one of these accounts can lead to others following suit. Chains also can play a critical role in launching a new or emerging technology. It a gas equipment test demonstrate meets the chain's energy goals, it can lead to a significant number of orders, accelerating a product's market penetration, improving manufacturing economies of scale, lowering prices and speeding up delivery times. A.G.A.'s key-accounts program's marketing activities fall into three basic categories: assisting chain clients, either directly or through members; enhancing members' key-account program development through training and networking; and increasing chains' awareness of the benefits of gas energy, equipment and services through national forums such as trade expos, seminars, conferences and press exposure

  6. Benchmarking Organisational Capability using The 20 Keys

    Directory of Open Access Journals (Sweden)

    Dino Petrarolo

    2012-01-01

    Full Text Available Organisations have over the years implemented many improvement initiatives, many of which were applied individually with no real, lasting improvement. Approaches such as quality control, team activities, setup reduction and many more seldom changed the fundamental constitution or capability of an organisation. Leading companies in the world have come to realise that an integrated approach is required which focuses on improving more than one factor at the same time - by recognising the importance of synergy between different improvement efforts and the need for commitment at all levels of the company to achieve total system-wide improvement.

    The 20 Keys approach offers a way to look at the strenqth of organisations and to systemically improve it, one step at a time by focusing on 20 different but interrelated aspects. One feature of the approach is the benchmarking system which forms the main focus of this paper. The benchmarking system is introduced as an important part of the 20 Keys philosophy in measuring organisational strength. Benchmarking results from selected South African companies are provided, as well as one company's results achieved through the adoption of the 20 Keys philosophy.

  7. Destination image and key drivers of perceived destination attractiveness

    Directory of Open Access Journals (Sweden)

    Josip Mikulić

    2008-12-01

    Full Text Available In this exploratory study authors combine several approaches to explore the images of two highly attractive tourist destinations: Hawai’i and Croatia. Two convenience samples were used: the image of Hawai’i was measured among Croatian undergraduate business students, and the image of Croatia was measured among Hawaiian tourism students. Functional and psychological image components were assessed at both a holistic and the attribute level. In addition, an importance-perception analysis was performed to assess the degree to which the destination image at the attribute level coincides with the students’ perception of an optimal destination. Finally, the authors conduct an importance grid analysis to explore the key drivers of the overall perceived destination attractiveness. The results provide a detailed insight into the images of Croatia and Hawaii, and reveal several interesting differences between the two student samples.

  8. Revealed preference with limited consideration

    NARCIS (Netherlands)

    Demuynck, T.; Seel, C.

    2014-01-01

    We derive revealed preference tests for models where individuals use consideration sets to simplify their consumption problem. Our basic test provides necessary and sufficient conditions for consistency of observed choices with the existence of consideration set restrictions. The same conditions can

  9. Decision Making and Revealed Preference

    DEFF Research Database (Denmark)

    de la Rosa, Leonidas Enrique

    If our decision-making processes are to some extent shaped by evolutionary pressures and our environment is different from that to which we adapted, some of our choices will not be in our best interest. But revealed preference is the only tool that we have so far to conduct a normative analysis...

  10. Analysis of the differential-phase-shift-keying protocol in the quantum-key-distribution system

    International Nuclear Information System (INIS)

    Rong-Zhen, Jiao; Chen-Xu, Feng; Hai-Qiang, Ma

    2009-01-01

    The analysis is based on the error rate and the secure communication rate as functions of distance for three quantum-key-distribution (QKD) protocols: the Bennett–Brassard 1984, the Bennett–Brassard–Mermin 1992, and the coherent differential-phase-shift keying (DPSK) protocols. We consider the secure communication rate of the DPSK protocol against an arbitrary individual attack, including the most commonly considered intercept-resend and photon-number splitting attacks, and concluded that the simple and efficient differential-phase-shift-keying protocol allows for more than 200 km of secure communication distance with high communication rates. (general)

  11. Cooperative Secret Sharing Using QR Codes and Symmetric Keys

    Directory of Open Access Journals (Sweden)

    Yang-Wai Chow

    2018-04-01

    Full Text Available Secret sharing is an information security technique where a dealer divides a secret into a collection of shares and distributes these to members of a group. The secret will only be revealed when a predefined number of group members cooperate to recover the secret. The purpose of this study is to investigate a method of distributing shares by embedding them into cover Quick Response (QR codes in a secure manner using cryptographic keys. The advantage of this approach is that the shares can be disseminated over public channels, as anyone who scans the QR codes will only obtain public information. Only authorized individuals who are in possession of the required keys will be able to recover the shares. This also means that when group members cooperate to recover a secret, the group can determine the presence of an illegitimate participant if the person does not produce a valid share. This study proposes a protocol for accomplishing this and discusses the underlying security of the protocol.

  12. Soil fauna: key to new carbon models

    Science.gov (United States)

    Filser, Juliane; Faber, Jack H.; Tiunov, Alexei V.; Brussaard, Lijbert; Frouz, Jan; De Deyn, Gerlinde; Uvarov, Alexei V.; Berg, Matty P.; Lavelle, Patrick; Loreau, Michel; Wall, Diana H.; Querner, Pascal; Eijsackers, Herman; José Jiménez, Juan

    2016-11-01

    Soil organic matter (SOM) is key to maintaining soil fertility, mitigating climate change, combatting land degradation, and conserving above- and below-ground biodiversity and associated soil processes and ecosystem services. In order to derive management options for maintaining these essential services provided by soils, policy makers depend on robust, predictive models identifying key drivers of SOM dynamics. Existing SOM models and suggested guidelines for future SOM modelling are defined mostly in terms of plant residue quality and input and microbial decomposition, overlooking the significant regulation provided by soil fauna. The fauna controls almost any aspect of organic matter turnover, foremost by regulating the activity and functional composition of soil microorganisms and their physical-chemical connectivity with soil organic matter. We demonstrate a very strong impact of soil animals on carbon turnover, increasing or decreasing it by several dozen percent, sometimes even turning C sinks into C sources or vice versa. This is demonstrated not only for earthworms and other larger invertebrates but also for smaller fauna such as Collembola. We suggest that inclusion of soil animal activities (plant residue consumption and bioturbation altering the formation, depth, hydraulic properties and physical heterogeneity of soils) can fundamentally affect the predictive outcome of SOM models. Understanding direct and indirect impacts of soil fauna on nutrient availability, carbon sequestration, greenhouse gas emissions and plant growth is key to the understanding of SOM dynamics in the context of global carbon cycling models. We argue that explicit consideration of soil fauna is essential to make realistic modelling predictions on SOM dynamics and to detect expected non-linear responses of SOM dynamics to global change. We present a decision framework, to be further developed through the activities of KEYSOM, a European COST Action, for when mechanistic SOM models

  13. Quantum key distribution with entangled photon sources

    International Nuclear Information System (INIS)

    Ma Xiongfeng; Fung, Chi-Hang Fred; Lo, H.-K.

    2007-01-01

    A parametric down-conversion (PDC) source can be used as either a triggered single-photon source or an entangled-photon source in quantum key distribution (QKD). The triggering PDC QKD has already been studied in the literature. On the other hand, a model and a post-processing protocol for the entanglement PDC QKD are still missing. We fill in this important gap by proposing such a model and a post-processing protocol for the entanglement PDC QKD. Although the PDC model is proposed to study the entanglement-based QKD, we emphasize that our generic model may also be useful for other non-QKD experiments involving a PDC source. Since an entangled PDC source is a basis-independent source, we apply Koashi and Preskill's security analysis to the entanglement PDC QKD. We also investigate the entanglement PDC QKD with two-way classical communications. We find that the recurrence scheme increases the key rate and the Gottesman-Lo protocol helps tolerate higher channel losses. By simulating a recent 144-km open-air PDC experiment, we compare three implementations: entanglement PDC QKD, triggering PDC QKD, and coherent-state QKD. The simulation result suggests that the entanglement PDC QKD can tolerate higher channel losses than the coherent-state QKD. The coherent-state QKD with decoy states is able to achieve highest key rate in the low- and medium-loss regions. By applying the Gottesman-Lo two-way post-processing protocol, the entanglement PDC QKD can tolerate up to 70 dB combined channel losses (35 dB for each channel) provided that the PDC source is placed in between Alice and Bob. After considering statistical fluctuations, the PDC setup can tolerate up to 53 dB channel losses

  14. Key-data of energy (June 2001)

    International Nuclear Information System (INIS)

    2001-06-01

    The energy actors and the economical context of energy are changing: the world exchanges and the deregulation of markets impose to dispose of reliable and relevant indicators to understand the French energy choices and stakes and to compare them with the European and worldwide data. This 2001 edition of the key energy data of France aims at shading light on the French energy policy which is based on: an imperative of supply security, an abatement of CO 2 emissions and a respect of environment, a growth of the economic competitiveness, a maintenance of the public utility missions, and on employment. Graphs, curves, charts and appendixes illustrate and complete this document. (J.S.)

  15. Data key to quest for quality.

    Science.gov (United States)

    Chang, Florence S; Nielsen, Jon; Macias, Charles

    2013-11-01

    Late-binding data warehousing reduces the time it takes to obtain data needed to make crucial decisions. Late binding refers to when and how tightly data from the source applications are bound to the rules and vocabularies that make it useful. In some cases, data can be seen in real time. In historically paper-driven environments where data-driven decisions may be a new concept, buy-in from clinicians, physicians, and hospital leaders is key to success in using data to improve outcomes.

  16. Stahlschüssel key to steel

    CERN Document Server

    Wegst, W S

    2016-01-01

    The Key to Steel (Stahlschlüssel/Stahlschluessel) cross reference book will help you to decode / decipher steel designations and find equivalent materials worldwide. The 2016 edition includes more than 70,000 standard designations and trade names from approximately 300 steelmakers and suppliers. Presentation is trilingual: English, French, and German. Materials covered include structural steels, tool steels, valve steels, high temperature steels and alloys, stainless and heat-resisting steels, and more. Standards and designations from 25 countries are cross-referenced.

  17. Noiseless Steganography The Key to Covert Communications

    CERN Document Server

    Desoky, Abdelrahman

    2012-01-01

    Among the features that make Noiseless Steganography: The Key to Covert Communications a first of its kind: The first to comprehensively cover Linguistic Steganography The first to comprehensively cover Graph Steganography The first to comprehensively cover Game Steganography Although the goal of steganography is to prevent adversaries from suspecting the existence of covert communications, most books on the subject present outdated steganography approaches that are detectable by human and/or machine examinations. These approaches often fail because they camouflage data as a detectable noise b

  18. Key Developments in Ionic Liquid Crystals

    OpenAIRE

    Fernandez, A.A.; Kouwer, P.H.J.

    2016-01-01

    Ionic liquid crystals are materials that combine the classes of liquid crystals and ionic liquids. The first one is based on the multi-billion-dollar flat panel display industry, whilst the latter quickly developed in the past decades into a family of highly-tunable non-volatile solvents. The combination yields materials with a unique set of properties, but also with many challenges ahead. In this review, we provide an overview of the key concepts in ionic liquid crystals, particularly from a...

  19. NCAP projection displays: key issues for commercialization

    Science.gov (United States)

    Tomita, Akira; Jones, Philip J.

    1992-06-01

    Recently there has been much interest in a new polymer nematic dispersion technology, often called as NCAP, PDLC, PNLC, LCPC, etc., since projection displays using this technology have been shown to produce much brighter display images than projectors using conventional twisted nematic (TN) lightvalves. For commercializing projection displays based on this polymer nematic dispersion technology, the new materials must not only meet various electro- optic requirements, e.g., operational voltage, `off-state'' scattering angle, voltage holding ratio and hysteresis, but must also be stable over the lifetime of the product. This paper reports recent progress in the development of NCAP based projection displays and discusses some of the key commercialization issues.

  20. Public key cryptography from weaker assumptions

    DEFF Research Database (Denmark)

    Zottarel, Angela

    This dissertation is focused on the construction of public key cryptographic primitives and on the relative security analysis in a meaningful theoretic model. This work takes two orthogonal directions. In the first part, we study cryptographic constructions preserving their security properties also...... in the case the adversary is granted access to partial information about the secret state of the primitive. To do so, we work in an extension of the standard black-box model, a new framework where possible leakage from the secret state is taken into account. In particular, we give the first construction...

  1. Ocean energy: key legal issues and challenges

    International Nuclear Information System (INIS)

    Wright, Glen; Rochette, Julien; O'Hagan, Anne Marie; De Groot, Jiska; Leroy, Yannick; Soininen, Niko; Salcido, Rachael; Castelos, Montserrat Abad; Jude, Simon; Kerr, Sandy

    2015-01-01

    Ocean energy is a novel renewable energy resource being developed as part of the push towards a 'Blue Economy'. The literature on ocean energy has focused on technical, environmental, and, increasingly, social and political aspects. Legal and regulatory factors have received less attention, despite their importance in supporting this new technology and ensuring its sustainable development. In this Issue Brief, we set out some key legal challenges for the development of ocean energy technologies, structured around the following core themes of marine governance: (i) international law; (ii) environmental impacts; (iii) rights and ownership; (iv) consenting processes; and (v) management of marine space and resources. (authors)

  2. 5 keys to business analytics program success

    CERN Document Server

    Boyer, John; Green, Brian; Harris, Tracy; Van De Vanter, Kay

    2012-01-01

    With business analytics is becoming increasingly strategic to all types of organizations and with many companies struggling to create a meaningful impact with this emerging technology, this work-based on the combined experience of 10 organizations that display excellence and expertise on the subject-shares the best practices, discusses the management aspects and sociology that drives success, and uncovers the five key aspects behind the success of some of the top business analytics programs in the industry. Readers will learn about numerous topics, including how to create and manage a changing

  3. Local innovation: The key to globalisation

    Directory of Open Access Journals (Sweden)

    Srivardhini K. Jha

    2013-12-01

    Full Text Available The round table discussion draws the panellists to weigh in on how multinational enterprises from developed countries are innovating in and for emerging markets, the challenges faced, and lessons learnt. The key takeaways are that MNEs are increasingly innovating for the Indian market, alongside their contribution to global products. They are doing so by developing close relationships with field facing organisations, co-creating with customers, empowering engineers, and taking a clean slate approach to product development. This approach has given them dividends not only in the local market but also in the global market.

  4. Cryptographic Key Management and Critical Risk Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Abercrombie, Robert K [ORNL

    2014-05-01

    The Department of Energy Office of Electricity Delivery and Energy Reliability (DOE-OE) CyberSecurity for Energy Delivery Systems (CSEDS) industry led program (DE-FOA-0000359) entitled "Innovation for Increasing CyberSecurity for Energy Delivery Systems (12CSEDS)," awarded a contract to Sypris Electronics LLC to develop a Cryptographic Key Management System for the smart grid (Scalable Key Management Solutions for Critical Infrastructure Protection). Oak Ridge National Laboratory (ORNL) and Sypris Electronics, LLC as a result of that award entered into a CRADA (NFE-11-03562) between ORNL and Sypris Electronics, LLC. ORNL provided its Cyber Security Econometrics System (CSES) as a tool to be modified and used as a metric to address risks and vulnerabilities in the management of cryptographic keys within the Advanced Metering Infrastructure (AMI) domain of the electric sector. ORNL concentrated our analysis on the AMI domain of which the National Electric Sector Cyber security Organization Resource (NESCOR) Working Group 1 (WG1) has documented 29 failure scenarios. The computational infrastructure of this metric involves system stakeholders, security requirements, system components and security threats. To compute this metric, we estimated the stakes that each stakeholder associates with each security requirement, as well as stochastic matrices that represent the probability of a threat to cause a component failure and the probability of a component failure to cause a security requirement violation. We applied this model to estimate the security of the AMI, by leveraging the recently established National Institute of Standards and Technology Interagency Report (NISTIR) 7628 guidelines for smart grid security and the International Electrotechnical Commission (IEC) 63351, Part 9 to identify the life cycle for cryptographic key management, resulting in a vector that assigned to each stakeholder an estimate of their average loss in terms of dollars per day of system

  5. Geotechnics - the key to ground water protection

    DEFF Research Database (Denmark)

    Baumann, Jens; Foged, Niels; Jørgensen, Peter

    2000-01-01

    During the past 5 to 10 years research into ground water protection has proved that fractures in clay till may increase the hydraulic conductivity and herby the vulnerability of the ground water considerably. However, research has not identified a non-expensive and efficient method to map...... the fracture conditions of the various clay tills. Tests performed at the Danish Geotechnical Institute with large undisturbed columns of clay till show that there is a relation between the strength of the clay till and the hydraulic conductivity. Geotechnical methods may therefore be the key to determine...

  6. User-Centric Key Entropy: Study of Biometric Key Derivation Subject to Spoofing Attacks

    Directory of Open Access Journals (Sweden)

    Lavinia Mihaela Dinca

    2017-02-01

    Full Text Available Biometric data can be used as input for PKI key pair generation. The concept of not saving the private key is very appealing, but the implementation of such a system shouldn’t be rushed because it might prove less secure then current PKI infrastructure. One biometric characteristic can be easily spoofed, so it was believed that multi-modal biometrics would offer more security, because spoofing two or more biometrics would be very hard. This notion, of increased security of multi-modal biometric systems, was disproved for authentication and matching, studies showing that not only multi-modal biometric systems are not more secure, but they introduce additional vulnerabilities. This paper is a study on the implications of spoofing biometric data for retrieving the derived key. We demonstrate that spoofed biometrics can yield the same key, which in turn will lead an attacker to obtain the private key. A practical implementation is proposed using fingerprint and iris as biometrics and the fuzzy extractor for biometric key extraction. Our experiments show what happens when the biometric data is spoofed for both uni-modal systems and multi-modal. In case of multi-modal system tests were performed when spoofing one biometric or both. We provide detailed analysis of every scenario in regard to successful tests and overall key entropy. Our paper defines a biometric PKI scenario and an in depth security analysis for it. The analysis can be viewed as a blueprint for implementations of future similar systems, because it highlights the main security vulnerabilities for bioPKI. The analysis is not constrained to the biometric part of the system, but covers CA security, sensor security, communication interception, RSA encryption vulnerabilities regarding key entropy, and much more.

  7. Key rate of quantum key distribution with hashed two-way classical communication

    International Nuclear Information System (INIS)

    Watanabe, Shun; Matsumoto, Ryutaroh; Uyematsu, Tomohiko; Kawano, Yasuhito

    2007-01-01

    We propose an information reconciliation protocol that uses two-way classical communication. The key rates of quantum key distribution (QKD) protocols that use our protocol are higher than those using previously known protocols for a wide range of error rates for the Bennett-Brassard 1984 and six-state protocols. We also clarify the relation between the proposed and known QKD protocols, and the relation between the proposed protocol and entanglement distillation protocols

  8. Il governo della performance dei processi di business : dai Key Performance Indicators ai Key Risk Indicators

    OpenAIRE

    Sergio Beretta; Saverio Bozzolan

    2013-01-01

    The recent paper issued by COSO ["Developing Key Risk Indicators to Strengthen Enterprise Risk Management" (Coso, 2010)] is the starting point of this article whose aim is to discuss the relevance of the business process dimension in the design and implementation of Key Risk Indicators. The Authors analyze the reasons of the systematic underestimation of the business process dimension in the COSO papers and debate the implications that the explicit consideration of the business process dimens...

  9. Finite-key analysis for quantum key distribution with weak coherent pulses based on Bernoulli sampling

    Science.gov (United States)

    Kawakami, Shun; Sasaki, Toshihiko; Koashi, Masato

    2017-07-01

    An essential step in quantum key distribution is the estimation of parameters related to the leaked amount of information, which is usually done by sampling of the communication data. When the data size is finite, the final key rate depends on how the estimation process handles statistical fluctuations. Many of the present security analyses are based on the method with simple random sampling, where hypergeometric distribution or its known bounds are used for the estimation. Here we propose a concise method based on Bernoulli sampling, which is related to binomial distribution. Our method is suitable for the Bennett-Brassard 1984 (BB84) protocol with weak coherent pulses [C. H. Bennett and G. Brassard, Proceedings of the IEEE Conference on Computers, Systems and Signal Processing (IEEE, New York, 1984), Vol. 175], reducing the number of estimated parameters to achieve a higher key generation rate compared to the method with simple random sampling. We also apply the method to prove the security of the differential-quadrature-phase-shift (DQPS) protocol in the finite-key regime. The result indicates that the advantage of the DQPS protocol over the phase-encoding BB84 protocol in terms of the key rate, which was previously confirmed in the asymptotic regime, persists in the finite-key regime.

  10. A global analysis of the impacts of urbanization on bird and plant diversity reveals key anthropogenic drivers

    Czech Academy of Sciences Publication Activity Database

    Aronson, M. F. J.; La Sorte, F. A.; Nilon, C. H.; Katti, M.; Goddard, M. A.; Lepczyk, C. A.; Warren, P. S.; Williams, N. S. G.; Cilliers, S.; Clarkson, B.; Dobbs, C.; Dolan, R.; Hedblom, M.; Klotz, S.; Kooijmans, J. L.; Kühn, I.; MacGregor-Fors, I.; McDonell, M.; Mörtberg, U.; Pyšek, Petr; Siebert, S.; Sushinsky, J.; Werner, P.; Winter, M.

    2014-01-01

    Roč. 281, č. 1780 (2014), s. 1-8, no.20133330 ISSN 0962-8452 Institutional support: RVO:67985939 Keywords : urbanization * plant s * birds Subject RIV: EF - Botanics Impact factor: 5.051, year: 2014

  11. A global analysis of the impacts of urbanization on bird and plant diversity reveals key anthropogenic drivers.

    Science.gov (United States)

    Aronson, Myla F J; La Sorte, Frank A; Nilon, Charles H; Katti, Madhusudan; Goddard, Mark A; Lepczyk, Christopher A; Warren, Paige S; Williams, Nicholas S G; Cilliers, Sarel; Clarkson, Bruce; Dobbs, Cynnamon; Dolan, Rebecca; Hedblom, Marcus; Klotz, Stefan; Kooijmans, Jip Louwe; Kühn, Ingolf; Macgregor-Fors, Ian; McDonnell, Mark; Mörtberg, Ulla; Pysek, Petr; Siebert, Stefan; Sushinsky, Jessica; Werner, Peter; Winter, Marten

    2014-04-07

    Urbanization contributes to the loss of the world's biodiversity and the homogenization of its biota. However, comparative studies of urban biodiversity leading to robust generalities of the status and drivers of biodiversity in cities at the global scale are lacking. Here, we compiled the largest global dataset to date of two diverse taxa in cities: birds (54 cities) and plants (110 cities). We found that the majority of urban bird and plant species are native in the world's cities. Few plants and birds are cosmopolitan, the most common being Columba livia and Poa annua. The density of bird and plant species (the number of species per km(2)) has declined substantially: only 8% of native bird and 25% of native plant species are currently present compared with estimates of non-urban density of species. The current density of species in cities and the loss in density of species was best explained by anthropogenic features (landcover, city age) rather than by non-anthropogenic factors (geography, climate, topography). As urbanization continues to expand, efforts directed towards the conservation of intact vegetation within urban landscapes could support higher concentrations of both bird and plant species. Despite declines in the density of species, cities still retain endemic native species, thus providing opportunities for regional and global biodiversity conservation, restoration and education.

  12. A genome-wide RNAi screen reveals MAP kinase phosphatases as key ERK pathway regulators during embryonic stem cell differentiation.

    Directory of Open Access Journals (Sweden)

    Shen-Hsi Yang

    Full Text Available Embryonic stem cells and induced pluripotent stem cells represent potentially important therapeutic agents in regenerative medicine. Complex interlinked transcriptional and signaling networks control the fate of these cells towards maintenance of pluripotency or differentiation. In this study we have focused on how mouse embryonic stem cells begin to differentiate and lose pluripotency and, in particular, the role that the ERK MAP kinase and GSK3 signaling pathways play in this process. Through a genome-wide siRNA screen we have identified more than 400 genes involved in loss of pluripotency and promoting the onset of differentiation. These genes were functionally associated with the ERK and/or GSK3 pathways, providing an important resource for studying the roles of these pathways in controlling escape from the pluripotent ground state. More detailed analysis identified MAP kinase phosphatases as a focal point of regulation and demonstrated an important role for these enzymes in controlling ERK activation kinetics and subsequently determining early embryonic stem cell fate decisions.

  13. A global analysis of the impacts of urbanization on bird and plant diversity reveals key anthropogenic drivers

    Science.gov (United States)

    Aronson, Myla F. J.; La Sorte, Frank A.; Nilon, Charles H.; Katti, Madhusudan; Goddard, Mark A.; Lepczyk, Christopher A.; Warren, Paige S.; Williams, Nicholas S. G.; Cilliers, Sarel; Clarkson, Bruce; Dobbs, Cynnamon; Dolan, Rebecca; Hedblom, Marcus; Klotz, Stefan; Kooijmans, Jip Louwe; Kühn, Ingolf; MacGregor-Fors, Ian; McDonnell, Mark; Mörtberg, Ulla; Pyšek, Petr; Siebert, Stefan; Sushinsky, Jessica; Werner, Peter; Winter, Marten

    2014-01-01

    Urbanization contributes to the loss of the world's biodiversity and the homogenization of its biota. However, comparative studies of urban biodiversity leading to robust generalities of the status and drivers of biodiversity in cities at the global scale are lacking. Here, we compiled the largest global dataset to date of two diverse taxa in cities: birds (54 cities) and plants (110 cities). We found that the majority of urban bird and plant species are native in the world's cities. Few plants and birds are cosmopolitan, the most common being Columba livia and Poa annua. The density of bird and plant species (the number of species per km2) has declined substantially: only 8% of native bird and 25% of native plant species are currently present compared with estimates of non-urban density of species. The current density of species in cities and the loss in density of species was best explained by anthropogenic features (landcover, city age) rather than by non-anthropogenic factors (geography, climate, topography). As urbanization continues to expand, efforts directed towards the conservation of intact vegetation within urban landscapes could support higher concentrations of both bird and plant species. Despite declines in the density of species, cities still retain endemic native species, thus providing opportunities for regional and global biodiversity conservation, restoration and education. PMID:24523278

  14. Gene expression profiles reveal key pathways and genes associated with neuropathic pain in patients with spinal cord injury.

    Science.gov (United States)

    He, Xijing; Fan, Liying; Wu, Zhongheng; He, Jiaxuan; Cheng, Bin

    2017-04-01

    Previous gene expression profiling studies of neuropathic pain (NP) following spinal cord injury (SCI) have predominantly been performed in animal models. The present study aimed to investigate gene alterations in patients with spinal cord injury and to further examine the mechanisms underlying NP following SCI. The GSE69901 gene expression profile was downloaded from the public Gene Expression Omnibus database. Samples of peripheral blood mononuclear cells (PBMCs) derived from 12 patients with intractable NP and 13 control patients without pain were analyzed to identify the differentially expressed genes (DEGs), followed by functional enrichment analysis and protein‑protein interaction (PPI) network construction. In addition, a transcriptional regulation network was constructed and functional gene clustering was performed. A total of 70 upregulated and 61 downregulated DEGs were identified in the PBMC samples from patients with NP. The upregulated and downregulated genes were significantly involved in different Gene Ontology terms and pathways, including focal adhesion, T cell receptor signaling pathway and mitochondrial function. Glycogen synthase kinase 3 β (GSK3B) was identified as a hub protein in the PPI network. In addition, ornithine decarboxylase 1 (ODC1) and ornithine aminotransferase (OAT) were regulated by additional transcription factors in the regulation network. GSK3B, OAT and ODC1 were significantly enriched in two functional gene clusters, the function of mitochondrial membrane and DNA binding. Focal adhesion and the T cell receptor signaling pathway may be significantly linked with NP, and GSK3B, OAT and ODC1 may be potential targets for the treatment of NP.

  15. Comparative proteomics reveals key proteins recruited at the nucleoid of Deinococcus after irradiation-induced DNA damage

    International Nuclear Information System (INIS)

    Bouthier de la Tour, Claire; Passot, Fanny Marie; Toueille, Magali; Servant, Pascale; Sommer, Suzanne; Mirabella, Boris; Blanchard, Laurence; Groot, Arjan de; Guerin, Philippe; Armengaud, Jean

    2013-01-01

    The nucleoids of radiation-resistant Deinococcus species show a high degree of compaction maintained after ionizing irradiation. We identified proteins recruited after irradiation in nucleoids of Deinococcus radiodurans and Deinococcus deserti by means of comparative proteomics. Proteins in nucleoid-enriched fractions from unirradiated and irradiated Deinococcus were identified and semi quantified by shotgun proteomics. The ssDNA-binding protein SSB, DNA gyrase subunits GyrA and GyrB, DNA topoisomerase I, RecA recombinase, UvrA excinuclease, RecQ helicase, DdrA, DdrB, and DdrD proteins were found in significantly higher amounts in irradiated nucleoids of both Deinococcus species. We observed, by immunofluorescence microscopy, the subcellular localization of these proteins in D. radiodurans, showing for the first time the recruitment of the DdrD protein into the D. radiodurans nucleoid. We specifically followed the kinetics of recruitment of RecA, DdrA, and DdrD to the nucleoid after irradiation. Remarkably, RecA proteins formed irregular filament-like structures 1 h after irradiation, before being redistributed throughout the cells by 3 h post-irradiation. Comparable dynamics of DdrD localization were observed, suggesting a possible functional interaction between RecA and DdrD. Several proteins involved in nucleotide synthesis were also seen in higher quantities in the nucleoids of irradiated cells, indicative of the existence of a mechanism for orchestrating the presence of proteins involved in DNA metabolism in nucleoids in response to massive DNA damage. All MS data have been deposited in the ProteomeXchange with identifier PXD00196. (authors)

  16. Transcriptomic analysis reveals metabolic switches and surface remodeling as key processes for stage transition in Trypanosoma cruzi

    Directory of Open Access Journals (Sweden)

    Luisa Berná

    2017-03-01

    Full Text Available American trypanosomiasis is a chronic and endemic disease which affects millions of people. Trypanosoma cruzi, its causative agent, has a life cycle that involves complex morphological and functional transitions, as well as a variety of environmental conditions. This requires a tight regulation of gene expression, which is achieved mainly by post-transcriptional regulation. In this work we conducted an RNAseq analysis of the three major life cycle stages of T. cruzi: amastigotes, epimastigotes and trypomastigotes. This analysis allowed us to delineate specific transcriptomic profiling for each stage, and also to identify those biological processes of major relevance in each state. Stage specific expression profiling evidenced the plasticity of T. cruzi to adapt quickly to different conditions, with particular focus on membrane remodeling and metabolic shifts along the life cycle. Epimastigotes, which replicate in the gut of insect vectors, showed higher expression of genes related to energy metabolism, mainly Krebs cycle, respiratory chain and oxidative phosphorylation related genes, and anabolism related genes associated to nucleotide and steroid biosynthesis; also, a general down-regulation of surface glycoprotein coding genes was seen at this stage. Trypomastigotes, living extracellularly in the bloodstream of mammals, express a plethora of surface proteins and signaling genes involved in invasion and evasion of immune response. Amastigotes mostly express membrane transporters and genes involved in regulation of cell cycle, and also express a specific subset of surface glycoprotein coding genes. In addition, these results allowed us to improve the annotation of the Dm28c genome, identifying new ORFs and set the stage for construction of networks of co-expression, which can give clues about coded proteins of unknown functions.

  17. Careful assessment key in managing prostatitis.

    Science.gov (United States)

    Gujadhur, Rahul; Aning, Jonathan

    2015-04-01

    Prostatitis is a common condition estimated to affect up to 30% of men in their lifetime, it is most prevalent in men aged between 35 and 50. Prostatitis is subclassified into: acute bacterial prostatitis, chronic bacterial prostatitis, chronic pelvic pain and asymptomatic inflammatory prostatitis. Acute bacterial prostatitis presents with acute onset pelvic pain which may or may not be related to voiding, lower urinary tract symptoms, sometimes haematuria or haematospermia and systemic symptoms such as fever and rigors. A documented history of recurrent urinary tract infections is the key feature of chronic bacterial prostatitis. Duration of symptoms > 3 months defines chronicity. The key symptom of chronic pelvic pain syndrome is pain. Patients may describe pain during or after ejaculation as their predominant symptom. Clinical assessment includes a thorough history and examination. A digital rectal examination should be performed after a midstream urine (MSU) sample has been collected for urine dipstick, microscopy and culture. The prostate should be checked for nodules. In acute bacterial prostatitis the MSU is the only laboratory investigation required. Chronic pelvic pain syndrome may be multifactorial and part of a more generalised pain disorder. Pelvic floor muscle abnormalities, altered neuroendocrine pathways, chemically induced inflammation, bacterial infection, autoimmune processes, dysfunctional voiding as well intraprostatic ductal reflux mechanisms have all been identified in men with chronic pelvic pain syndrome.

  18. Fully Device-Independent Quantum Key Distribution

    Science.gov (United States)

    Vazirani, Umesh; Vidick, Thomas

    2014-10-01

    Quantum cryptography promises levels of security that are impossible to replicate in a classical world. Can this security be guaranteed even when the quantum devices on which the protocol relies are untrusted? This central question dates back to the early 1990s when the challenge of achieving device-independent quantum key distribution was first formulated. We answer this challenge by rigorously proving the device-independent security of a slight variant of Ekert's original entanglement-based protocol against the most general (coherent) attacks. The resulting protocol is robust: While assuming only that the devices can be modeled by the laws of quantum mechanics and are spatially isolated from each other and from any adversary's laboratory, it achieves a linear key rate and tolerates a constant noise rate in the devices. In particular, the devices may have quantum memory and share arbitrary quantum correlations with the eavesdropper. The proof of security is based on a new quantitative understanding of the monogamous nature of quantum correlations in the context of a multiparty protocol.

  19. SARS: Key factors in crisis management.

    Science.gov (United States)

    Tseng, Hsin-Chao; Chen, Thai-Form; Chou, Shieu-Ming

    2005-03-01

    This study was conducted at a single hospital selected in Taipei during the SARS (Severe Acute Respiratory Syndrome) outbreak from March to July, 2003 in Taiwan. During this period of time, 104 SARS patients were admitted to the hospital. There were no negative reports related to the selected hospital despite its being located right in the center of an area struck by the epidemic. The purpose of this study was to identify the key factors enabling the hospital to survive SARS unscathed. Data were collected from in-depth interviews with the nursing directors and nursing managers of the SARS units, along with a review of relevant hospital documents. The five key elements identified as survival factors during this SARS crisis are as follows: 1. good control of timing for crisis management, 2. careful decision-making, 3. thorough implementation, 4. effective communication, and 5. trust between management and employees. The results of this study reconfirmed the selected hospital as a model for good crisis management during the SARS epidemic.

  20. KEY FACTORS IN MARKETING FOCUSED SERVICES BUSINESSES

    Directory of Open Access Journals (Sweden)

    Doris Yohanna Martínez Castrillón

    2016-07-01

    Full Text Available This article aims to identify the key success factors in the marketing area and describe them as managerial allies for companies that wish to position themselves in the market under a good sustainable performance , for it has been consulted theoretical references of Marketing as a management partner with collection and integration of data. Methodologically, it is located within the type of descriptive research field, with a design of transactional non-experimental, with an intentional non-probabilistic stratified sample of four reporting units. The findings established fifteen (15 points of influence called "key success factors (FCE in the area of marketing, and managerial allies of service companies in the security, surveillance and protection sector in industrial, commercial and residential sectors. Finally, it is intended that the actions of marketing service companies should focus to the welfare of both the organization, such as users, both in the environment, and economic, social and technological, characterized by ethics, sustainable development and transparency to respond appropriately.

  1. Keys of educational change in Ecuador

    Directory of Open Access Journals (Sweden)

    Agustín De la Herrán Gascón

    2018-01-01

    Full Text Available The article analyzes the educational system in Ecuador. The Ecuadorian education system arouses international interest, especially in Latin America. In this essay we will try to answer these questions: What might be the relevant keys from the public education in Ecuador? Why has it reached its present level of development, particularly in inclusive education? What fundaments and policies are behind the results of the goals from Education for All (EFA 2000-2015 From the Dakar framework for Action? (World Education Forum, 2000. In light of these issues, the goal is to understand key factors and reasons that have contributed to the development of the Ecuadorian public education. In terms of methodology, the approach is qualitative, dialectical, documentary and descriptive (Mc Millan and Schumacher, 2005. The research is proposed as a case study, where the choice of the case is justified by its novelty, its degree of development and its emphasis on inclusion and equity in all educational levels. With this aim, it is made a descriptive analysis of the rules underlying the changes in the educational system in Ecuador in the last three decades and it is carried out, particularly since 2008, following the last Constitution (Constituent Assembly, 2008. Tables as an analytical contribution of the authors are offered. Also data endorsed by authors and agencies of maximum national and international prestige are detailed and they realize the effectiveness of policies and such changes.

  2. Key Questions in Marine Megafauna Movement Ecology

    KAUST Repository

    Hays, Graeme C.; Ferreira, Luciana C.; Sequeira, Ana M.M.; Meekan, Mark G.; Duarte, Carlos M.; Bailey, Helen; Bailleul, Fred; Bowen, W. Don; Caley, M. Julian; Costa, Daniel P.; Eguí luz, Victor M.; Fossette, Sabrina; Friedlaender, Ari S.; Gales, Nick; Gleiss, Adrian C.; Gunn, John; Harcourt, Rob; Hazen, Elliott L.; Heithaus, Michael R.; Heupel, Michelle; Holland, Kim; Horning, Markus; Jonsen, Ian; Kooyman, Gerald L.; Lowe, Christopher G.; Madsen, Peter T.; Marsh, Helene; Phillips, Richard A.; Righton, David; Ropert-Coudert, Yan; Sato, Katsufumi; Shaffer, Scott A.; Simpfendorfer, Colin A.; Sims, David W.; Skomal, Gregory; Takahashi, Akinori; Trathan, Philip N.; Wikelski, Martin; Womble, Jamie N.; Thums, Michele

    2016-01-01

    It is a golden age for animal movement studies and so an opportune time to assess priorities for future work. We assembled 40 experts to identify key questions in this field, focussing on marine megafauna, which include a broad range of birds, mammals, reptiles, and fish. Research on these taxa has both underpinned many of the recent technical developments and led to fundamental discoveries in the field. We show that the questions have broad applicability to other taxa, including terrestrial animals, flying insects, and swimming invertebrates, and, as such, this exercise provides a useful roadmap for targeted deployments and data syntheses that should advance the field of movement ecology. Technical advances make this an exciting time for animal movement studies, with a range of small, reliable data-loggers and transmitters that can record horizontal and vertical movements as well as aspects of physiology and reproductive biology.Forty experts identified key questions in the field of movement ecology.Questions have broad applicability across species, habitats, and spatial scales, and apply to animals in both marine and terrestrial habitats as well as both vertebrates and invertebrates, including birds, mammals, reptiles, fish, insects, and plankton. © 2016 Elsevier Ltd.

  3. Key Questions in Marine Megafauna Movement Ecology

    KAUST Repository

    Hays, Graeme C.

    2016-03-12

    It is a golden age for animal movement studies and so an opportune time to assess priorities for future work. We assembled 40 experts to identify key questions in this field, focussing on marine megafauna, which include a broad range of birds, mammals, reptiles, and fish. Research on these taxa has both underpinned many of the recent technical developments and led to fundamental discoveries in the field. We show that the questions have broad applicability to other taxa, including terrestrial animals, flying insects, and swimming invertebrates, and, as such, this exercise provides a useful roadmap for targeted deployments and data syntheses that should advance the field of movement ecology. Technical advances make this an exciting time for animal movement studies, with a range of small, reliable data-loggers and transmitters that can record horizontal and vertical movements as well as aspects of physiology and reproductive biology.Forty experts identified key questions in the field of movement ecology.Questions have broad applicability across species, habitats, and spatial scales, and apply to animals in both marine and terrestrial habitats as well as both vertebrates and invertebrates, including birds, mammals, reptiles, fish, insects, and plankton. © 2016 Elsevier Ltd.

  4. Key Nuclear Verification Priorities: Safeguards and Beyond

    International Nuclear Information System (INIS)

    Carlson, J.

    2010-01-01

    In addressing nuclear verification priorities, we should look beyond the current safeguards system. Non-proliferation, which the safeguards system underpins, is not an end in itself, but an essential condition for achieving and maintaining nuclear disarmament. Effective safeguards are essential for advancing disarmament, and safeguards issues, approaches and techniques are directly relevant to the development of future verification missions. The extent to which safeguards challenges are successfully addressed - or otherwise - will impact not only on confidence in the safeguards system, but on the effectiveness of, and confidence in, disarmament verification. To identify the key nuclear verification priorities, we need to consider the objectives of verification, and the challenges to achieving these. The strategic objective of IAEA safeguards might be expressed as: To support the global nuclear non-proliferation regime by: - Providing credible assurance that states are honouring their safeguards commitments - thereby removing a potential motivation to proliferate; and - Early detection of misuse of nuclear material and technology - thereby deterring proliferation by the risk of early detection, enabling timely intervention by the international community. Or to summarise - confidence-building, detection capability, and deterrence. These will also be essential objectives for future verification missions. The challenges to achieving these involve a mix of political, technical and institutional dimensions. Confidence is largely a political matter, reflecting the qualitative judgment of governments. Clearly assessments of detection capability and deterrence have a major impact on confidence. Detection capability is largely thought of as 'technical', but also involves issues of legal authority, as well as institutional issues. Deterrence has both political and institutional aspects - including judgments on risk of detection and risk of enforcement action being taken. The

  5. Key Nuclear Verification Priorities - Safeguards and Beyond

    International Nuclear Information System (INIS)

    Carlson, J.

    2010-01-01

    In addressing nuclear verification priorities, we should look beyond the current safeguards system. Non-proliferation, which the safeguards system underpins, is not an end in itself, but an essential condition for achieving and maintaining nuclear disarmament. Effective safeguards are essential for advancing disarmament, and safeguards issues, approaches and techniques are directly relevant to the development of future verification missions. The extent to which safeguards challenges are successfully addressed - or otherwise - will impact not only on confidence in the safeguards system, but on the effectiveness of, and confidence in, disarmament verification. To identify the key nuclear verification priorities, we need to consider the objectives of verification, and the challenges to achieving these. The strategic objective of IAEA safeguards might be expressed as: To support the global nuclear non-proliferation regime by: - Providing credible assurance that states are honouring their safeguards commitments - thereby removing a potential motivation to proliferate; and - Early detection of misuse of nuclear material and technology - thereby deterring proliferation by the risk of early detection, enabling timely intervention by the international community. Or to summarise - confidence-building, detection capability, and deterrence. These will also be essential objectives for future verification missions. The challenges to achieving these involve a mix of political, technical and institutional dimensions. Confidence is largely a political matter, reflecting the qualitative judgment of governments. Clearly assessments of detection capability and deterrence have a major impact on confidence. Detection capability is largely thought of as 'technical', but also involves issues of legal authority, as well as institutional issues. Deterrence has both political and institutional aspects - including judgments on risk of detection and risk of enforcement action being taken. The

  6. Talent Management: Working lines and key processes

    Directory of Open Access Journals (Sweden)

    Alvaro Alonso

    2014-12-01

    Full Text Available Purpose: Talent management represents today a challenge for companies, since the contribution of value comes increasingly from the area of intangible capital. The current paradigm of expanding technology and competitive dynamics, makes talent management that companies realize a critical success factor in today's markets. However, there is no generally accepted theoretical framework and empirical studies sufficient to demonstrate the role of talent management in creating competitive advantage. Therefore, the first objective of this paper is to analyze the evolution of talent management, to understand more deeply their fundamental dimensions: people and key positions in the organization. From these dimensions, as a second objective of the research is proposed to classify and characterize the literature about four alternative ways of study, according to the treatment they receive such dimensions and thus improve understanding of the role of talent management in business strategyDesign/methodology: To develop this paper we have selected the major contributions to the field of talent management, with particular emphasis on certain meta-analysis very quoted by the scientific community (Lewis and Heckman, 2006; Mellahi and Collings, 2009; Tarique and Schuler, 2010. In addition we have select additional papers published in high impact journals seen in ABI/Inform, Science Direct, SCOPUS, and EBSCO (Business Source Complete, through the keywords "Gestion del talento", "Plan de Gestion del Talento" and "Modelo de Gestion de Talento" and its English equivalent "Talent Management ", "Talent Management Plans/Systems" and "Talent Management Framework/Model ".Findings: From this review, we extracted the existence of different ways of understanding and talent management apply in organizations and even different understandings of what is talent itself. For this, we describe the basic dimensions of talent management (people and key positions and four alternative

  7. Key Lake Mining Corporation metallurgical complex

    International Nuclear Information System (INIS)

    Lendrum, F.C.

    1984-02-01

    The Key Lake uranium mine is located in Saskatchewan, 550 km northeast of Saskatoon. It began operations in 1983, and is licensed and regulated by both Saskatchewan government agencies and the Canadian Atomic Energy Control Board. This report examines the metallurgical processes used at the mill and discusses the spills that occurred in the first four months the mine was in operation. It finds that all spills of an acidic nature in the mill were small amounts in the CCD or solution pretreatment sections. Contingency procedures are in place and sumps are capable of handling spills. The only major change in design contemplated will be converting the secondary crushing from the use of an impact crusher to the use of a semi-autogeneous grinding mill. The monitoring program set out by the AECB and Saskatchewan Environment is thorough. It monitors effluents and water pathways, and includes aquatic biota and sediments. Air monitoring is also required by Saskatchewan Environment

  8. Key policy choices in groundwater quality management

    International Nuclear Information System (INIS)

    Batie, S.S.; Diebel, P.L.

    1990-01-01

    The fundamental policy choice of who has the right to do what to whom is a pivotal issue of governance. Over the last few decades, the answer to that question has become more restrictive to those who own and use natural resources as inputs into production processes. Increasingly, the beneficiaries of new policy initiatives are those who desire higher protection of groundwater quality. With respect to groundwater management, policy design increasingly reflects such diverse interests as agriculturists, industrialists, homeowners, local government officials and state officials. Policy design is becoming complex, in part because of this diversity and in part because scientific uncertainty hampers informed policy design. No umbrella federal legislation exists for managing groundwater resources. EPA's role has been mainly an advisory one on groundwater issues. The difficulties and responsibilities of protecting groundwater thus remain with the states. For the near future, it is the states that will address key policy choices with respect to groundwater quality management issues

  9. Key Developments in Ionic Liquid Crystals.

    Science.gov (United States)

    Alvarez Fernandez, Alexandra; Kouwer, Paul H J

    2016-05-16

    Ionic liquid crystals are materials that combine the classes of liquid crystals and ionic liquids. The first one is based on the multi-billion-dollar flat panel display industry, whilst the latter quickly developed in the past decades into a family of highly-tunable non-volatile solvents. The combination yields materials with a unique set of properties, but also with many challenges ahead. In this review, we provide an overview of the key concepts in ionic liquid crystals, particularly from a molecular perspective. What are the important molecular parameters that determine the phase behavior? How should they be introduced into the molecules? Finally, which other tools does one have to realize specific properties in the material?

  10. Key Developments in Ionic Liquid Crystals

    Directory of Open Access Journals (Sweden)

    Alexandra Alvarez Fernandez

    2016-05-01

    Full Text Available Ionic liquid crystals are materials that combine the classes of liquid crystals and ionic liquids. The first one is based on the multi-billion-dollar flat panel display industry, whilst the latter quickly developed in the past decades into a family of highly-tunable non-volatile solvents. The combination yields materials with a unique set of properties, but also with many challenges ahead. In this review, we provide an overview of the key concepts in ionic liquid crystals, particularly from a molecular perspective. What are the important molecular parameters that determine the phase behavior? How should they be introduced into the molecules? Finally, which other tools does one have to realize specific properties in the material?

  11. Secure Key Management in the Cloud

    DEFF Research Database (Denmark)

    Damgård, Ivan Bjerre; Jakobsen, Thomas Pelle; Nielsen, Jesper Buus

    2013-01-01

    information such as cryptographic keys. Applications like this include many cases where secure multiparty computation is outsourced to the cloud, and in particular a number of online auctions and benchmark computations with confidential inputs. We consider fully autonomous servers that switch between online......We consider applications involving a number of servers in the cloud that go through a sequence of online periods where the servers communicate, separated by offline periods where the servers are idle. During the offline periods, we assume that the servers need to securely store sensitive...... and offline periods without communicating with anyone from outside the cloud, and semi-autonomous servers that need a limited kind of assistance from outside the cloud when doing the transition. We study the levels of security one can – and cannot – obtain in this model, propose light-weight protocols...

  12. Climate Watchlist: Key issues for Cancun negotiations

    Energy Technology Data Exchange (ETDEWEB)

    Chandani, Achala; Siegele, Linda

    2010-11-15

    We must mitigate and adapt to climate change. On this, the international community is agreed. But exactly how to do that is still up for debate. There were high hopes that last year's UN climate talks in Copenhagen would deliver a legally binding agreement for action on climate change. But the outcome — the Copenhagen Accord — was instead a political 'statement of intent' that fell significantly short of expectations. Now, after a year of interim meetings and several negotiating texts, parties to the UN Framework Convention on Climate Change (UNFCCC) are gathering in Cancun, Mexico, to try again. Their success will largely depend on settling disputes — particularly between the developed and developing world — about six key issues: shared vision; adaptation; climate finance; technology transfer; reducing emissions from deforestation and degradation; and post-2012 emissions reduction targets.

  13. Accountability in district nursing practice: key concepts.

    Science.gov (United States)

    Griffith, Richard

    2015-03-01

    Public trust and confidence in district nurses is essential to the nurse-patient relationship that underpins effective care and treatment. That trust and confidence has even greater focus for district nurses who care for patients in their own homes. Those patients need to be able to count on the professionalism and probity of their district nurses. The professionalism and probity of district nurses is based on their accountability, which protects the public by imposing standards on district nurses and holds them answerable for their acts and omissions. This is the first of a series of articles on accountability in district nursing practice to mark the introduction of the revised Nursing and Midwifery Code on the 31 March 2015. This month's article considers the key concepts of accountability.

  14. Phosphoinositides: Key modulators of energy metabolism☆

    Science.gov (United States)

    Bridges, Dave; Saltiel, Alan R.

    2014-01-01

    Phosphoinositides are key players in many trafficking and signaling pathways. Recent advances regarding the synthesis, location and functions of these lipids have dramatically improved our understanding of how and when these lipids are generated and what their roles are in animal physiology. In particular, phosphoinositides play a central role in insulin signaling, and manipulation of PtdIns(3,4,5)P3 levels in particular, may be an important potential therapeutic target for the alleviation of insulin resistance associated with obesity and the metabolic syndrome. In this article we review the metabolism, regulation and functional roles of phosphoinositides in insulin signaling and the regulation of energy metabolism. This article is part of a Special Issue entitled Phosphoinositides. PMID:25463477

  15. Key Questions in Marine Megafauna Movement Ecology.

    Science.gov (United States)

    Hays, Graeme C; Ferreira, Luciana C; Sequeira, Ana M M; Meekan, Mark G; Duarte, Carlos M; Bailey, Helen; Bailleul, Fred; Bowen, W Don; Caley, M Julian; Costa, Daniel P; Eguíluz, Victor M; Fossette, Sabrina; Friedlaender, Ari S; Gales, Nick; Gleiss, Adrian C; Gunn, John; Harcourt, Rob; Hazen, Elliott L; Heithaus, Michael R; Heupel, Michelle; Holland, Kim; Horning, Markus; Jonsen, Ian; Kooyman, Gerald L; Lowe, Christopher G; Madsen, Peter T; Marsh, Helene; Phillips, Richard A; Righton, David; Ropert-Coudert, Yan; Sato, Katsufumi; Shaffer, Scott A; Simpfendorfer, Colin A; Sims, David W; Skomal, Gregory; Takahashi, Akinori; Trathan, Philip N; Wikelski, Martin; Womble, Jamie N; Thums, Michele

    2016-06-01

    It is a golden age for animal movement studies and so an opportune time to assess priorities for future work. We assembled 40 experts to identify key questions in this field, focussing on marine megafauna, which include a broad range of birds, mammals, reptiles, and fish. Research on these taxa has both underpinned many of the recent technical developments and led to fundamental discoveries in the field. We show that the questions have broad applicability to other taxa, including terrestrial animals, flying insects, and swimming invertebrates, and, as such, this exercise provides a useful roadmap for targeted deployments and data syntheses that should advance the field of movement ecology. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Teamwork the key to good patient care.

    Science.gov (United States)

    Baillie, Jonathan

    2013-05-01

    In a year when, with the inception of the new Clinical Commissioning Groups, the way that healthcare is procured and delivered will see radical changes, this month's HefmA 2013 National Conference & Exhibition will have as its theme, 'Many Players, One Goal: The Patient'. As HEJ editor, Jonathan Baillie reports, among the wide-ranging estates and facilities topics set for discussion will be 'Getting the patient environment right'; 'Dementia Building for the Future'; 'Waterborne Infections; Lessons Learned'; 'Incorporating lean thinking into design', and the key challenges faced by the estates and facilities sector. The keynote address, touching on a wide range of issues common to all large organisations, will be given by one of the best known 'women in football', and will also reflect particularly on the importance of teamwork.

  17. Security of practical quantum key distribution systems

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Nitin

    2015-02-24

    This thesis deals with practical security aspects of quantum key distribution (QKD) systems. At the heart of the theoretical model of any QKD system lies a quantum-mechanical security proof that guarantees perfect secrecy of messages - based on certain assumptions. However, in practice, deviations between the theoretical model and the physical implementation could be exploited by an attacker to break the security of the system. These deviations may arise from technical limitations and operational imperfections in the physical implementation and/or unrealistic assumptions and insufficient constraints in the theoretical model. In this thesis, we experimentally investigate in depth several such deviations. We demonstrate the resultant vulnerabilities via proof-of-principle attacks on a commercial QKD system from ID Quantique. We also propose countermeasures against the investigated loopholes to secure both existing and future QKD implementations.

  18. BENCHMARKING - PRACTICAL TOOLS IDENTIFY KEY SUCCESS FACTORS

    Directory of Open Access Journals (Sweden)

    Olga Ju. Malinina

    2016-01-01

    Full Text Available The article gives a practical example of the application of benchmarking techniques. The object of study selected fashion store Company «HLB & M Hennes & Mauritz», located in the shopping center «Gallery», Krasnodar. Hennes & Mauritz. The purpose of this article is to identify the best ways to develop a fashionable brand clothing store Hennes & Mauritz on the basis of benchmarking techniques. On the basis of conducted market research is a comparative analysis of the data from different perspectives. The result of the author’s study is a generalization of the ndings, the development of the key success factors that will allow to plan a successful trading activities in the future, based on the best experience of competitors.

  19. Bench press exercise: the key points.

    Science.gov (United States)

    Padulo, J; Laffaye, G; Chaouachi, A; Chamari, K

    2015-06-01

    The bench press exercise (BPE) is receiving increasing interest as a field testing, training/therapeutic modality to improve neuromuscular performance or to increase bone mass density. Several studies have been performed using BPE as a standard for increasing upper-limb strength. For this purpose, the position of the bar, the loads, the sets, the number of repetitions, the recovery time in-between sets, the movement speed, the muscular work and the use of the determination of the one repetition maximum (1-RM) are the classical tools investigated in the literature that have been shown to affect the BPE effect on neuromuscular. The goal of the present short review is to make a picture of the current knowledge on the bench press exercise, which could be very helpful for a better understanding of this standard movement and its effects. Based on the related literature, several recommendations on these key points are presented here.

  20. Low-Power Public Key Cryptography

    Energy Technology Data Exchange (ETDEWEB)

    BEAVER,CHERYL L.; DRAELOS,TIMOTHY J.; HAMILTON,VICTORIA A.; SCHROEPPEL,RICHARD C.; GONZALES,RITA A.; MILLER,RUSSELL D.; THOMAS,EDWARD V.

    2000-11-01

    This report presents research on public key, digital signature algorithms for cryptographic authentication in low-powered, low-computation environments. We assessed algorithms for suitability based on their signature size, and computation and storage requirements. We evaluated a variety of general purpose and special purpose computing platforms to address issues such as memory, voltage requirements, and special functionality for low-powered applications. In addition, we examined custom design platforms. We found that a custom design offers the most flexibility and can be optimized for specific algorithms. Furthermore, the entire platform can exist on a single Application Specific Integrated Circuit (ASIC) or can be integrated with commercially available components to produce the desired computing platform.