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Sample records for synthetic lethality analysis

  1. Development of Synthetic Lethality Anticancer Therapeutics

    PubMed Central

    2015-01-01

    The concept of synthetic lethality (the creation of a lethal phenotype from the combined effects of mutations in two or more genes) has recently been exploited in various efforts to develop new genotype-selective anticancer therapeutics. These efforts include screening for novel anticancer agents, identifying novel therapeutic targets, characterizing mechanisms of resistance to targeted therapy, and improving efficacies through the rational design of combination therapy. This review discusses recent developments in synthetic lethality anticancer therapeutics, including poly ADP-ribose polymerase inhibitors for BRCA1- and BRCA2-mutant cancers, checkpoint inhibitors for p53 mutant cancers, and small molecule agents targeting RAS gene mutant cancers. Because cancers are caused by mutations in multiple genes and abnormalities in multiple signaling pathways, synthetic lethality for a specific tumor suppressor gene or oncogene is likely cell context-dependent. Delineation of the mechanisms underlying synthetic lethality and identification of treatment response biomarkers will be critical for the success of synthetic lethality anticancer therapy. PMID:24893124

  2. The population genetics of synthetic lethals.

    PubMed

    Phillips, P C; Johnson, N A

    1998-09-01

    Synthetic lethals are variants at different loci that have little or no effect on viability singly but cause lethality in combination. The importance of synthetic lethals and, more generally, of synthetic deleterious loci (SDL) has been controversial. Here, we derive the expected frequencies for SDL under a mutation-selection balance for the complete haploid model and selected cases of the diploid model. We have also obtained simple approximations that demonstrate good fit to exact solutions based on numerical iterations. In the haploid case, equilibrium frequencies of carrier haplotypes (individuals with only a single mutation) are comparable to analogous single-locus results, after allowing for the effects of linkage. Frequencies in the diploid case, however, are much higher and more comparable to the square root of the single-locus results. In particular, when selection operates only on the double-mutant homozygote and linkage is not too tight, the expected frequency of the carriers is approximately the quartic root of the ratio between the mutation rate and the selection coefficient of the synthetics. For a reasonably wide set of models, the frequencies of carriers can be on the order of a few percent. The equilibrium frequencies of these deleterious alleles can be relatively high because, with SDL, both dominance and epistasis act to shield carriers from exposure to selection. We also discuss the possible role of SDL in maintaining genetic variation and in hybrid breakdown. PMID:9725860

  3. Synthetic lethal approaches to breast cancer therapy.

    PubMed

    Rehman, Farah L; Lord, Christopher J; Ashworth, Alan

    2010-12-01

    The promise of personalized therapy for breast cancer is that therapeutic efficacy will be increased while toxic effects are reduced to a minimum. To achieve this goal, there is now an emphasis on the design of therapies that are based not only on the clinical manifestations of the disease, but also on the underlying molecular and cellular biology of cancer. However, identifying targets for personalized therapies in breast cancer is challenging. Here, we describe how biological concepts such as synthetic lethality and oncogene addiction can be used to identify new therapeutic targets and approaches. We discuss the current clinical developments in implementing synthetic lethality therapies, and highlight new ways in which this approach could be used to target specific subsets of breast cancer. PMID:20956981

  4. Synthetic lethal approaches for assessing combinatorial efficacy of chemotherapeutic drugs.

    PubMed

    Jackson, Rebecca A; Chen, Ee Sin

    2016-06-01

    The recent advances in pharmacogenomics have made personalized medicine no longer a pipedream but a precise and powerful way to tailor individualized cancer treatment strategies. Cancer is a devastating disease, and contemporary chemotherapeutic strategies now integrate several agents in the treatment of some types of cancer, with the intent to block more than one target simultaneously. This constitutes the premise of synthetic lethality, an attractive therapeutic strategy already demonstrating clinical success in patients with breast and ovarian cancers. Synthetic lethal combinations offer the potential to also target the hitherto "undruggable" mutations that have challenged the cancer field for decades. However, synthetic lethality in clinical cancer therapy is very much still in its infancy, and selecting the most appropriate combinations-or synthetic lethal pairs-is not always an intuitive process. Here, we review some of the recent progress in identifying synthetic lethal combinations and their potential for therapy and highlight some of the tools through which synthetic lethal pairs are identified. PMID:26803999

  5. Approaches to identifying synthetic lethal interactions in cancer.

    PubMed

    Thompson, Jordan M; Nguyen, Quy H; Singh, Manpreet; Razorenova, Olga V

    2015-06-01

    Targeting synthetic lethal interactions is a promising new therapeutic approach to exploit specific changes that occur within cancer cells. Multiple approaches to investigate these interactions have been developed and successfully implemented, including chemical, siRNA, shRNA, and CRISPR library screens. Genome-wide computational approaches, such as DAISY, also have been successful in predicting synthetic lethal interactions from both cancer cell lines and patient samples. Each approach has its advantages and disadvantages that need to be considered depending on the cancer type and its molecular alterations. This review discusses these approaches and examines case studies that highlight their use. PMID:26029013

  6. Approaches to Identifying Synthetic Lethal Interactions in Cancer

    PubMed Central

    Thompson, Jordan M.; Nguyen, Quy H.; Singh, Manpreet; Razorenova, Olga V.

    2015-01-01

    Targeting synthetic lethal interactions is a promising new therapeutic approach to exploit specific changes that occur within cancer cells. Multiple approaches to investigate these interactions have been developed and successfully implemented, including chemical, siRNA, shRNA, and CRISPR library screens. Genome-wide computational approaches, such as DAISY, also have been successful in predicting synthetic lethal interactions from both cancer cell lines and patient samples. Each approach has its advantages and disadvantages that need to be considered depending on the cancer type and its molecular alterations. This review discusses these approaches and examines case studies that highlight their use. PMID:26029013

  7. Moving ahead on harnessing synthetic lethality to fight cancer

    PubMed Central

    Jerby-Arnon, Livnat; Ruppin, Eytan

    2015-01-01

    We have recently developed a data-mining pipeline that comprehensively identifies cancer unique susceptibilities, following the concept of Synthetic Lethality (SL). The approach enables, for the first time, to identify and harness genome-scale SL-networks to accurately predict gene essentiality, drug response, and clinical prognosis in cancer. PMID:27308440

  8. Annotating novel genes by integrating synthetic lethals and genomic information

    PubMed Central

    Schöner, Daniel; Kalisch, Markus; Leisner, Christian; Meier, Lukas; Sohrmann, Marc; Faty, Mahamadou; Barral, Yves; Peter, Matthias; Gruissem, Wilhelm; Bühlmann, Peter

    2008-01-01

    Background Large scale screening for synthetic lethality serves as a common tool in yeast genetics to systematically search for genes that play a role in specific biological processes. Often the amounts of data resulting from a single large scale screen far exceed the capacities of experimental characterization of every identified target. Thus, there is need for computational tools that select promising candidate genes in order to reduce the number of follow-up experiments to a manageable size. Results We analyze synthetic lethality data for arp1 and jnm1, two spindle migration genes, in order to identify novel members in this process. To this end, we use an unsupervised statistical method that integrates additional information from biological data sources, such as gene expression, phenotypic profiling, RNA degradation and sequence similarity. Different from existing methods that require large amounts of synthetic lethal data, our method merely relies on synthetic lethality information from two single screens. Using a Multivariate Gaussian Mixture Model, we determine the best subset of features that assign the target genes to two groups. The approach identifies a small group of genes as candidates involved in spindle migration. Experimental testing confirms the majority of our candidates and we present she1 (YBL031W) as a novel gene involved in spindle migration. We applied the statistical methodology also to TOR2 signaling as another example. Conclusion We demonstrate the general use of Multivariate Gaussian Mixture Modeling for selecting candidate genes for experimental characterization from synthetic lethality data sets. For the given example, integration of different data sources contributes to the identification of genetic interaction partners of arp1 and jnm1 that play a role in the same biological process. PMID:18194531

  9. Gene essentiality and synthetic lethality in haploid human cells.

    PubMed

    Blomen, Vincent A; Májek, Peter; Jae, Lucas T; Bigenzahn, Johannes W; Nieuwenhuis, Joppe; Staring, Jacqueline; Sacco, Roberto; van Diemen, Ferdy R; Olk, Nadine; Stukalov, Alexey; Marceau, Caleb; Janssen, Hans; Carette, Jan E; Bennett, Keiryn L; Colinge, Jacques; Superti-Furga, Giulio; Brummelkamp, Thijn R

    2015-11-27

    Although the genes essential for life have been identified in less complex model organisms, their elucidation in human cells has been hindered by technical barriers. We used extensive mutagenesis in haploid human cells to identify approximately 2000 genes required for optimal fitness under culture conditions. To study the principles of genetic interactions in human cells, we created a synthetic lethality network focused on the secretory pathway based exclusively on mutations. This revealed a genetic cross-talk governing Golgi homeostasis, an additional subunit of the human oligosaccharyltransferase complex, and a phosphatidylinositol 4-kinase β adaptor hijacked by viruses. The synthetic lethality map parallels observations made in yeast and projects a route forward to reveal genetic networks in diverse aspects of human cell biology. PMID:26472760

  10. Synthetic lethality for linking the mycophenolate mofetil mode of action with molecular disease and drug profiles.

    PubMed

    Söllner, Johannes; Mayer, Paul; Heinzel, Andreas; Fechete, Raul; Siehs, Christian; Oberbauer, Rainer; Mayer, Bernd

    2012-10-30

    Systematic study of the effect of mycophenolate mofetil (MMF) on the molecular level in the context of other drugs and molecular disease profiles became possible due to the availability of large scale molecular profiles on both disease characterization and drug mode of action. Such analysis is of particular value in elucidating alternative drug use for addressing clinically unmet needs, and the concept of synthetic lethality provides an alternative tool for such repositioning strategies. Resting on consolidation of transcriptomics data and literature mining, a MMF molecular footprint became available including a set of 170 genes specifically affected by the drug. Analysis of this profile on a molecular pathway level reveals a set of 14 pathways as affected. Next to assignment of molecular pathways and associated diseases synergistic drug combinations are proposed by utilizing the synthetic lethal interaction network. Of particular interest is the combination of MMF with adenosine deaminase inhibitors, sulfasalazine, and other selected drugs interfering with calcium-based regulatory pathways and metabolism. Indeed analysis of drugs in clinical trials positively identifies combinations with MMF in the context of synthetic lethality and affected pathways, particularly in diseases such as multiple sclerosis, vasculitis, GVHD and lupus nephritis. Importantly, the synthetic lethal interaction of the drug mode of action is an interesting basis for rational repositioning strategies by suggesting combinations which exhibit a synergistic rather than a mere additive effect, as for example is evident for the combination of tacrolimus and MMF. Inherent is also the assessment of possible adverse effects of drug combinations. PMID:23014771

  11. Syn-Lethality: An Integrative Knowledge Base of Synthetic Lethality towards Discovery of Selective Anticancer Therapies

    PubMed Central

    Li, Xue-juan; Mishra, Shital K.; Wu, Min; Zhang, Fan

    2014-01-01

    Synthetic lethality (SL) is a novel strategy for anticancer therapies, whereby mutations of two genes will kill a cell but mutation of a single gene will not. Therefore, a cancer-specific mutation combined with a drug-induced mutation, if they have SL interactions, will selectively kill cancer cells. While numerous SL interactions have been identified in yeast, only a few have been known in human. There is a pressing need to systematically discover and understand SL interactions specific to human cancer. In this paper, we present Syn-Lethality, the first integrative knowledge base of SL that is dedicated to human cancer. It integrates experimentally discovered and verified human SL gene pairs into a network, associated with annotations of gene function, pathway, and molecular mechanisms. It also includes yeast SL genes from high-throughput screenings which are mapped to orthologous human genes. Such an integrative knowledge base, organized as a relational database with user interface for searching and network visualization, will greatly expedite the discovery of novel anticancer drug targets based on synthetic lethality interactions. The database can be downloaded as a stand-alone Java application. PMID:24864230

  12. Synthetic lethality-based targets for discovery of new cancer therapeutics.

    PubMed

    Weidle, Ulrich H; Maisel, Daniela; Eick, Dirk

    2011-01-01

    Synthetic lethality is based on the incompatibility of cell survival with the loss of function of two or more genes, not with loss of function of a single gene. If targets of synthetic lethality are deregulated or mutated in cancer cells, the strategy of synthetic lethality can result in significant increase of therapeutic efficacy and a favourable therapeutic window. In this review, we discuss synthetic lethality based on deficient DNA repair mechanisms, activating mutations of RAS, loss of function mutations of the tumor suppressor genes p53, Rb and von Hippel-Lindau, and disruption of interactive protein kinase networks in the context of development of new anticancer agents. PMID:21737609

  13. Synthetic lethal approaches exploiting DNA damage in aggressive myeloma

    PubMed Central

    Cottini, Francesca; Hideshima, Teru; Suzuki, Rikio; Tai, Yu-Tzu; Bianchini, Giampaolo; Richardson, Paul G.; Anderson, Kenneth C.; Tonon, Giovanni

    2015-01-01

    Ongoing DNA damage is a common feature of epithelial cancers. Here we show that tumor cells derived from multiple myeloma (MM), a disease of clonal plasma cells, demonstrate DNA replicative stress leading to DNA damage. We identified a poor prognosis subset of MM with extensive chromosomal instability and replicative stress which rely on ATR to compensate for DNA replicative stress; conversely, silencing of ATR or treatment with a specific ATR inhibitor triggers MM cell apoptosis. We show that oncogenes such as MYC induce DNA damage in MM cells not only by increased replicative stress, but also via increased oxidative stress, and that ROS-inducer piperlongumine triggers further DNA damage and apoptosis. Importantly, ATR inhibition combined with piperlongumine triggers synergistic MM cytotoxicity. This synthetic lethal approach, enhancing oxidative stress while concomitantly blocking replicative stress response, provides a novel combination targeted therapy to address an unmet medical need in this subset of MM. PMID:26080835

  14. RAS Synthetic Lethal Screens Revisited: Still Seeking the Elusive Prize?

    PubMed Central

    Downward, Julian

    2015-01-01

    The RAS genes are critical oncogenic drivers activated by point mutation in some 20% of human malignancies. However, no pharmacological approaches to targeting RAS proteins directly have yet succeeded, leading to suggestions that these proteins may be “undruggable.” This has led to two alternative indirect approaches to targeting RAS function in cancer. One has been to target RAS signaling pathways downstream at tractable enzymes such as kinases, particularly in combination. The other, which is the focus of this review, has been to seek targets that are essential in cells bearing an activated RAS oncogene, but not those without. This synthetic lethal approach, while rooted in ideas from invertebrate genetics, has been inspired most strongly by the successful use of PARP inhibitors, such as olaparib, in the clinic to treat BRCA defective cancers. Several large-scale screens have been carried out using RNA interference-mediated expression silencing to find genes that are uniquely essential to RAS mutant but not wild type cells. These screens have been notable for the low degree of overlap between their results, with the possible exception of proteasome components, and have yet to lead to successful new clinical approaches to the treatment of RAS mutant cancers. Possible reasons for these disappointing results are discussed here, along with a re-evaluation of the approaches taken. Based on experience to date, RAS synthetic lethality has so far fallen some way short of its original promise and remains unproven as an approach to finding effective new ways of tackling RAS mutant cancers. PMID:25878361

  15. Synthetic lethality in ATM-deficient RAD50-mutant tumors underlie outlier response to cancer therapy

    PubMed Central

    Al-Ahmadie, Hikmat; Iyer, Gopa; Hohl, Marcel; Asthana, Saurabh; Inagaki, Akiko; Schultz, Nikolaus; Hanrahan, Aphrothiti J.; Scott, Sasinya N.; Brannon, A. Rose; McDermott, Gregory C.; Pirun, Mono; Ostrovnaya, Irina; Kim, Philip; Socci, Nicholas D.; Viale, Agnes; Schwartz, Gary K.; Reuter, Victor; Bochner, Bernard H.; Rosenberg, Jonathan E.; Bajorin, Dean F.; Berger, Michael F.; Petrini, John H.J.; Solit, David B.; Taylor, Barry S.

    2014-01-01

    Metastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small cell cancer to combined checkpoint kinase 1 (Chk1) inhibition and DNA damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of Chk1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan. As Mre11 mutations occur in a diversity of human tumors, the results suggest a tumor-specific combination therapy strategy whereby checkpoint inhibition in combination with DNA damaging chemotherapy is synthetically lethal in tumor but not normal cells with somatic mutations that impair Mre11 complex function. PMID:24934408

  16. Malignancy of Cancers and Synthetic Lethal Interactions Associated With Mutations of Cancer Driver Genes

    PubMed Central

    Wang, Xiaosheng; Zhang, Yue; Han, Ze-Guang; He, Kun-Yan

    2016-01-01

    Abstract The mutation status of cancer driver genes may correlate with different degrees of malignancy of cancers. The doubling time and multidrug resistance are 2 phenotypes that reflect the degree of malignancy of cancer cells. Because most of cancer driver genes are hard to target, identification of their synthetic lethal partners might be a viable approach to treatment of the cancers with the relevant mutations. The genome-wide screening for synthetic lethal partners is costly and labor intensive. Thus, a computational approach facilitating identification of candidate genes for a focus synthetic lethal RNAi screening will accelerate novel anticancer drug discovery. We used several publicly available cancer cell lines and tumor tissue genomic data in this study. We compared the doubling time and multidrug resistance between the NCI-60 cell lines with mutations in some cancer driver genes and those without the mutations. We identified some candidate synthetic lethal genes to the cancer driver genes APC, KRAS, BRAF, PIK3CA, and TP53 by comparison of their gene phenotype values in cancer cell lines with the relevant mutations and wild-type background. Further, we experimentally validated some of the synthetic lethal relationships we predicted. We reported that mutations in some cancer driver genes mutations in some cancer driver genes such as APC, KRAS, or PIK3CA might correlate with cancer proliferation or drug resistance. We identified 40, 21, 5, 43, and 18 potential synthetic lethal genes to APC, KRAS, BRAF, PIK3CA, and TP53, respectively. We found that some of the potential synthetic lethal genes show significantly higher expression in the cancers with mutations of their synthetic lethal partners and the wild-type counterparts. Further, our experiments confirmed several synthetic lethal relationships that are novel findings by our methods. We experimentally validated a part of the synthetic lethal relationships we predicted. We plan to perform further

  17. A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy.

    PubMed

    Srivas, Rohith; Shen, John Paul; Yang, Chih Cheng; Sun, Su Ming; Li, Jianfeng; Gross, Andrew M; Jensen, James; Licon, Katherine; Bojorquez-Gomez, Ana; Klepper, Kristin; Huang, Justin; Pekin, Daniel; Xu, Jia L; Yeerna, Huwate; Sivaganesh, Vignesh; Kollenstart, Leonie; van Attikum, Haico; Aza-Blanc, Pedro; Sobol, Robert W; Ideker, Trey

    2016-08-01

    An emerging therapeutic strategy for cancer is to induce selective lethality in a tumor by exploiting interactions between its driving mutations and specific drug targets. Here we use a multi-species approach to develop a resource of synthetic lethal interactions relevant to cancer therapy. First, we screen in yeast ∼169,000 potential interactions among orthologs of human tumor suppressor genes (TSG) and genes encoding drug targets across multiple genotoxic environments. Guided by the strongest signal, we evaluate thousands of TSG-drug combinations in HeLa cells, resulting in networks of conserved synthetic lethal interactions. Analysis of these networks reveals that interaction stability across environments and shared gene function increase the likelihood of observing an interaction in human cancer cells. Using these rules, we prioritize ∼10(5) human TSG-drug combinations for future follow-up. We validate interactions based on cell and/or patient survival, including topoisomerases with RAD17 and checkpoint kinases with BLM. PMID:27453043

  18. A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments

    PubMed Central

    Mohni, Kareem N.; Thompson, Petria S.; Luzwick, Jessica W.; Glick, Gloria G.; Pendleton, Christopher S.; Lehmann, Brian D.; Pietenpol, Jennifer A.; Cortez, David

    2015-01-01

    The DNA damage response kinase ATR may be a useful cancer therapeutic target. ATR inhibition synergizes with loss of ERCC1, ATM, XRCC1 and DNA damaging chemotherapy agents. Clinical trials have begun using ATR inhibitors in combination with cisplatin. Here we report the first synthetic lethality screen with a combination treatment of an ATR inhibitor (ATRi) and cisplatin. Combination treatment with ATRi/cisplatin is synthetically lethal with loss of the TLS polymerase ζ and 53BP1. Other DNA repair pathways including homologous recombination and mismatch repair do not exhibit synthetic lethal interactions with ATRi/cisplatin, even though loss of some of these repair pathways sensitizes cells to cisplatin as a single-agent. We also report that ATRi strongly synergizes with PARP inhibition, even in homologous recombination-proficient backgrounds. Lastly, ATR inhibitors were able to resensitize cisplatin-resistant cell lines to cisplatin. These data provide a comprehensive analysis of DNA repair pathways that exhibit synthetic lethality with ATR inhibitors when combined with cisplatin chemotherapy, and will help guide patient selection strategies as ATR inhibitors progress into the cancer clinic. PMID:25965342

  19. ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency.

    PubMed

    Mohni, Kareem N; Kavanaugh, Gina M; Cortez, David

    2014-05-15

    The DNA damage response kinase ATR and its effector kinase CHEK1 are required for cancer cells to survive oncogene-induced replication stress. ATR inhibitors exhibit synthetic lethal interactions, with deficiencies in the DNA damage response enzymes ATM and XRCC1 and with overexpression of the cell cycle kinase cyclin E. Here, we report a systematic screen to identify synthetic lethal interactions with ATR pathway-targeted drugs, rationalized by their predicted therapeutic utility in the oncology clinic. We found that reduced function in the ATR pathway itself provided the strongest synthetic lethal interaction. In addition, we found that loss of the structure-specific endonuclease ERCC1-XPF (ERCC4) is synthetic lethal with ATR pathway inhibitors. ERCC1-deficient cells exhibited elevated levels of DNA damage, which was increased further by ATR inhibition. When treated with ATR or CHEK1 inhibitors, ERCC1-deficient cells were arrested in S-phase and failed to complete cell-cycle transit even after drug removal. Notably, triple-negative breast cancer cells and non-small cell lung cancer cells depleted of ERCC1 exhibited increased sensitivity to ATR pathway-targeted drugs. Overall, we concluded that ATR pathway-targeted drugs may offer particular utility in cancers with reduced ATR pathway function or reduced levels of ERCC4 activity. PMID:24662920

  20. Synthetic Lethality Reveals Mechanisms of Mycobacterium tuberculosis Resistance to β-Lactams

    PubMed Central

    Lun, Shichun; Miranda, David; Kubler, Andre; Guo, Haidan; Maiga, Mariama C.; Winglee, Kathryn; Pelly, Shaaretha

    2014-01-01

    ABSTRACT Most β-lactam antibiotics are ineffective against Mycobacterium tuberculosis due to the microbe’s innate resistance. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has prompted interest to repurpose this class of drugs. To identify the genetic determinants of innate β-lactam resistance, we carried out a synthetic lethality screen on a transposon mutant library for susceptibility to imipenem, a carbapenem β-lactam antibiotic. Mutations in 74 unique genes demonstrated synthetic lethality. The majority of mutations were in genes associated with cell wall biosynthesis. A second quantitative real-time PCR (qPCR)-based synthetic lethality screen of randomly selected mutants confirmed the role of cell wall biosynthesis in β-lactam resistance. The global transcriptional response of the bacterium to β-lactams was investigated, and changes in levels of expression of cell wall biosynthetic genes were identified. Finally, we validated these screens in vivo using the MT1616 transposon mutant, which lacks a functional acyl-transferase gene. Mice infected with the mutant responded to β-lactam treatment with a 100-fold decrease in bacillary lung burden over 4 weeks, while the numbers of organisms in the lungs of mice infected with wild-type bacilli proliferated. These findings reveal a road map of genes required for β-lactam resistance and validate synthetic lethality screening as a promising tool for repurposing existing classes of licensed, safe, well-characterized antimicrobials against tuberculosis. PMID:25227469

  1. ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency

    PubMed Central

    Mohni, Kareem N.; Kavanaugh, Gina M.; Cortez, David

    2014-01-01

    The DNA damage response kinase ATR and its effector kinase CHEK1 are required for cancer cells to survive oncogene-induced replication stress. ATR inhibitors exhibit synthetic lethal interactions with deficiencies in the DNA damage response enzymes ATM and XRCC1 and with overexpression of the cell cycle kinase Cyclin E. Here we report a systematic screen to identify synthetic lethal interactions with ATR-pathway targeted drugs, rationalized by their predicted therapeutic utility in the oncology clinic. We found that reduced function in the ATR pathway itself provided the strongest synthetic lethal interaction. In addition, we found that loss of the structure specific-endonuclease ERCC1-XPF (ERCC4) is synthetic lethal with ATR pathway inhibitors. ERCC1-deficient cells exhibited elevated levels of DNA damage, which was increased further by ATR inhibition. When treated with ATR or CHEK1 inhibitors, ERCC1-deficient cells arrested in S phase and failed to complete cell cycle transit even after drug removal. Notably, triple-negative breast cancer cells and non-small cell lung cancer cells depleted of ERCC1 exhibited increased sensitivity to ATR-pathway targeted drugs. Overall, we concluded that ATR pathway-targeted drugs may offer particular utility in cancers with reduced ATR pathway function or reduced levels of ERCC4 activity. PMID:24662920

  2. Analysis of Synthetic Polymers.

    ERIC Educational Resources Information Center

    Smith, Charles G.; And Others

    1989-01-01

    Reviews techniques for the characterization and analysis of synthetic polymers, copolymers, and blends. Includes techniques for structure determination, separation, and quantitation of additives and residual monomers; determination of molecular weight; and the study of thermal properties including degradation mechanisms. (MVL)

  3. Composite synthetic lethal identification of membrane traffic inhibitors

    PubMed Central

    Duncan, Mara C.; Ho, David G.; Huang, Jing; Jung, Michael E.; Payne, Gregory S.

    2007-01-01

    Small molecule inhibitors provide powerful tools to characterize highly dynamic and complex eukaryotic cell pathways such as those mediating membrane traffic. However, a lack of easy and generalizable assays has constrained identification of novel inhibitors despite availability of diverse chemical libraries. Here, we report a facile growth-based strategy in yeast to screen for pathway-specific inhibitors. The approach uses well characterized synthetic genetic growth defects to guide design of cells genetically sensitized for inhibition of chosen pathways. With this strategy, we identified a family of piperazinyl phenylethanone compounds as inhibitors of traffic between the trans-Golgi network (TGN) and endosomes that depends on the clathrin adaptor complex AP-1. The compounds did not significantly alter other trafficking pathways involving the TGN or endosomes, indicating specificity. Compound treatment also altered localization of AP-1 in mammalian cells. These previously uncharacterized inhibitors will be useful for future studies of clathrin-mediated transport in yeast, and potentially in other organisms. Furthermore, the easily automated technology should be adaptable for identification of inhibitors of other cellular processes. PMID:17404221

  4. SynLethDB: synthetic lethality database toward discovery of selective and sensitive anticancer drug targets.

    PubMed

    Guo, Jing; Liu, Hui; Zheng, Jie

    2016-01-01

    Synthetic lethality (SL) is a type of genetic interaction between two genes such that simultaneous perturbations of the two genes result in cell death or a dramatic decrease of cell viability, while a perturbation of either gene alone is not lethal. SL reflects the biologically endogenous difference between cancer cells and normal cells, and thus the inhibition of SL partners of genes with cancer-specific mutations could selectively kill cancer cells but spare normal cells. Therefore, SL is emerging as a promising anticancer strategy that could potentially overcome the drawbacks of traditional chemotherapies by reducing severe side effects. Researchers have developed experimental technologies and computational prediction methods to identify SL gene pairs on human and a few model species. However, there has not been a comprehensive database dedicated to collecting SL pairs and related knowledge. In this paper, we propose a comprehensive database, SynLethDB (http://histone.sce.ntu.edu.sg/SynLethDB/), which contains SL pairs collected from biochemical assays, other related databases, computational predictions and text mining results on human and four model species, i.e. mouse, fruit fly, worm and yeast. For each SL pair, a confidence score was calculated by integrating individual scores derived from different evidence sources. We also developed a statistical analysis module to estimate the druggability and sensitivity of cancer cells upon drug treatments targeting human SL partners, based on large-scale genomic data, gene expression profiles and drug sensitivity profiles on more than 1000 cancer cell lines. To help users access and mine the wealth of the data, we developed other practical functionalities, such as search and filtering, orthology search, gene set enrichment analysis. Furthermore, a user-friendly web interface has been implemented to facilitate data analysis and interpretation. With the integrated data sets and analytics functionalities, SynLethDB would

  5. Identification of essential genes and synthetic lethal gene combinations in Escherichia coli K-12.

    PubMed

    Mori, Hirotada; Baba, Tomoya; Yokoyama, Katsushi; Takeuchi, Rikiya; Nomura, Wataru; Makishi, Kazuichi; Otsuka, Yuta; Dose, Hitomi; Wanner, Barry L

    2015-01-01

    Here we describe the systematic identification of single genes and gene pairs, whose knockout causes lethality in Escherichia coli K-12. During construction of precise single-gene knockout library of E. coli K-12, we identified 328 essential gene candidates for growth in complex (LB) medium. Upon establishment of the Keio single-gene deletion library, we undertook the development of the ASKA single-gene deletion library carrying a different antibiotic resistance. In addition, we developed tools for identification of synthetic lethal gene combinations by systematic construction of double-gene knockout mutants. We introduce these methods herein. PMID:25636612

  6. High throughput synthetic lethality screen reveals a tumorigenic role of adenylate cyclase in fumarate hydratase-deficient cancer cells

    PubMed Central

    2014-01-01

    Background Synthetic lethality is an appealing technique for selectively targeting cancer cells which have acquired molecular changes that distinguish them from normal cells. High-throughput RNAi-based screens have been successfully used to identify synthetic lethal pathways with well-characterized tumor suppressors and oncogenes. The recent identification of metabolic tumor suppressors suggests that the concept of synthetic lethality can be applied to selectively target cancer metabolism as well. Results Here, we perform a high-throughput RNAi screen to identify synthetic lethal genes with fumarate hydratase (FH), a metabolic tumor suppressor whose loss-of-function has been associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Our unbiased screen identified synthetic lethality between FH and several genes in heme metabolism, in accordance with recent findings. Furthermore, we identified an enrichment of synthetic lethality with adenylate cyclases. The effects were validated in an embryonic kidney cell line (HEK293T) and in HLRCC-patient derived cells (UOK262) via both genetic and pharmacological inhibition. The reliance on adenylate cyclases in FH-deficient cells is consistent with increased cyclic-AMP levels, which may act to regulate cellular energy metabolism. Conclusions The identified synthetic lethality of FH with adenylate cyclases suggests a new potential target for treating HLRCC patients. PMID:24568598

  7. MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition

    PubMed Central

    Horiuchi, Dai; Kusdra, Leonard; Huskey, Noelle E.; Chandriani, Sanjay; Lenburg, Marc E.; Gonzalez-Angulo, Ana Maria; Creasman, Katelyn J.; Bazarov, Alexey V.; Smyth, James W.; Davis, Sarah E.; Yaswen, Paul; Mills, Gordon B.; Esserman, Laura J.

    2012-01-01

    Estrogen, progesterone, and HER2 receptor-negative triple-negative breast cancers encompass the most clinically challenging subtype for which targeted therapeutics are lacking. We find that triple-negative tumors exhibit elevated MYC expression, as well as altered expression of MYC regulatory genes, resulting in increased activity of the MYC pathway. In primary breast tumors, MYC signaling did not predict response to neoadjuvant chemotherapy but was associated with poor prognosis. We exploit the increased MYC expression found in triple-negative breast cancers by using a synthetic-lethal approach dependent on cyclin-dependent kinase (CDK) inhibition. CDK inhibition effectively induced tumor regression in triple-negative tumor xenografts. The proapoptotic BCL-2 family member BIM is up-regulated after CDK inhibition and contributes to this synthetic-lethal mechanism. These results indicate that aggressive breast tumors with elevated MYC are uniquely sensitive to CDK inhibitors. PMID:22430491

  8. KRAS mutant NSCLC, a new opportunity for the synthetic lethality therapeutic approach.

    PubMed

    de Castro Carpeño, Javier; Belda-Iniesta, Cristóbal

    2013-04-01

    K-RAS accounts for 90% of RAS mutations in lung adenocarcinomas, the most commonly mutated oncogene in NSCLC, with mutations detected in about 25% of all tumors. Direct inhibition of KRAS has proven clinically challenging. So far, no successful targeted therapy has been developed and remains an elusive target for cancer therapy. Despite significant efforts, currently there are no drugs directly targeting mutated KRAS. Thus, new strategies have emerged for targeting RAS including the use of synthetic lethality. A specific knowledge of individual tumor molecular abnormalities that result in oncogene-specific "synthetic lethal" interactions will allow the rationale to combine promising targeted therapies for KRAS-mutated NSCLC. In this article, we review the new approach based on testing drugs or combinations of agents that work downstream of activated K-RAS. PMID:25806225

  9. Epigenetic synthetic lethality in ovarian clear cell carcinoma: EZH2 and ARID1A mutations

    PubMed Central

    Bitler, Benjamin G; Aird, Katherine M; Zhang, Rugang

    2016-01-01

    The components of the Switch/Sucrose non-fermentable (SWI/SNF) complex are mutated in approximately 20% of human cancers. The A/T-rich interacting domain 1A (ARID1A) subunit has one of the highest mutation rates. Most notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas (OCCCs). We reported that inhibition of enhancer of zeste homology 2 (EZH2) is synthetically lethal in ARID1A-mutated OCCC. PMID:27308548

  10. Epigenetic synthetic lethality in ovarian clear cell carcinoma: EZH2 and ARID1A mutations.

    PubMed

    Bitler, Benjamin G; Aird, Katherine M; Zhang, Rugang

    2016-01-01

    The components of the Switch/Sucrose non-fermentable (SWI/SNF) complex are mutated in approximately 20% of human cancers. The A/T-rich interacting domain 1A (ARID1A) subunit has one of the highest mutation rates. Most notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas (OCCCs). We reported that inhibition of enhancer of zeste homology 2 (EZH2) is synthetically lethal in ARID1A-mutated OCCC. PMID:27308548

  11. Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities.

    PubMed

    Zhang, Tianyi; Liao, Yang; Hsu, Fu-Ning; Zhang, Robin; Searle, Jennifer S; Pei, Xun; Li, Xuan; Ryoo, Hyung Don; Ji, Jun-Yuan; Du, Wei

    2014-05-01

    Inactivation of the Rb tumor suppressor can lead to increased cell proliferation or cell death depending on specific cellular context. Therefore, identification of the interacting pathways that modulate the effect of Rb loss will provide novel insights into the roles of Rb in cancer development and promote new therapeutic strategies. Here, we identify a novel synthetic lethal interaction between Rb inactivation and deregulated Wg/Wnt signaling through unbiased genetic screens. We show that a weak allele of axin, which deregulates Wg signaling and increases cell proliferation without obvious effects on cell fate specification, significantly alters metabolic gene expression, causes hypersensitivity to metabolic stress induced by fasting, and induces synergistic apoptosis with mutation of fly Rb ortholog, rbf. Furthermore, hyperactivation of Wg signaling by other components of the Wg pathway also induces synergistic apoptosis with rbf. We show that hyperactivated Wg signaling significantly increases TORC1 activity and induces excessive energy stress with rbf mutation. Inhibition of TORC1 activity significantly suppressed synergistic cell death induced by hyperactivated Wg signaling and rbf inactivation, which is correlated with decreased energy stress and decreased induction of apoptotic regulator expression. Finally the synthetic lethality between Rb and deregulated Wnt signaling is conserved in mammalian cells and that inactivation of Rb and APC induces synergistic cell death through a similar mechanism. These results suggest that elevated TORC1 activity and metabolic stress underpin the evolutionarily conserved synthetic lethal interaction between hyperactivated Wnt signaling and inactivated Rb tumor suppressor. PMID:24809668

  12. CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours

    PubMed Central

    Costa-Cabral, Sara; Brough, Rachel; Konde, Asha; Aarts, Marieke; Campbell, James; Marinari, Eliana; Riffell, Jenna; Bardelli, Alberto; Torrance, Christopher; Lord, Christopher J.; Ashworth, Alan

    2016-01-01

    Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent kinase, CDK1. This was discovered using parallel siRNA screens in KRAS mutant and wild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and pancreatic tumour cell models. This established that the KRAS/CDK1 synthetic lethality applies in tumour cells with either amino acid position 12 (p.G12V, pG12D, p.G12S) or amino acid position 13 (p.G13D) KRAS mutations and can also be replicated in vivo in a xenograft model using a small molecule CDK1 inhibitor. Mechanistically, CDK1 inhibition caused a reduction in the S-phase fraction of KRAS mutant cells, an effect also characterised by modulation of Rb, a master control of the G1/S checkpoint. Taken together, these observations suggest that the KRAS/CDK1 interaction is a robust synthetic lethal effect worthy of further investigation. PMID:26881434

  13. Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities.

    PubMed

    Sanjiv, Kumar; Hagenkort, Anna; Calderón-Montaño, José Manuel; Koolmeister, Tobias; Reaper, Philip M; Mortusewicz, Oliver; Jacques, Sylvain A; Kuiper, Raoul V; Schultz, Niklas; Scobie, Martin; Charlton, Peter A; Pollard, John R; Berglund, Ulrika Warpman; Altun, Mikael; Helleday, Thomas

    2016-01-12

    ATR and CHK1 maintain cancer cell survival under replication stress and inhibitors of both kinases are currently undergoing clinical trials. As ATR activity is increased after CHK1 inhibition, we hypothesized that this may indicate an increased reliance on ATR for survival. Indeed, we observe that replication stress induced by the CHK1 inhibitor AZD7762 results in replication catastrophe and apoptosis, when combined with the ATR inhibitor VE-821 specifically in cancer cells. Combined treatment with ATR and CHK1 inhibitors leads to replication fork arrest, ssDNA accumulation, replication collapse, and synergistic cell death in cancer cells in vitro and in vivo. Inhibition of CDK reversed replication stress and synthetic lethality, demonstrating that regulation of origin firing by ATR and CHK1 explains the synthetic lethality. In conclusion, this study exemplifies cancer-specific synthetic lethality between two proteins in the same pathway and raises the prospect of combining ATR and CHK1 inhibitors as promising cancer therapy. PMID:26748709

  14. Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities

    PubMed Central

    Sanjiv, Kumar; Hagenkort, Anna; Calderón-Montaño, José Manuel; Koolmeister, Tobias; Reaper, Philip M.; Mortusewicz, Oliver; Jacques, Sylvain A.; Kuiper, Raoul V.; Schultz, Niklas; Scobie, Martin; Charlton, Peter A.; Pollard, John R.; Berglund, Ulrika Warpman; Altun, Mikael; Helleday, Thomas

    2015-01-01

    Summary ATR and CHK1 maintain cancer cell survival under replication stress and inhibitors of both kinases are currently undergoing clinical trials. As ATR activity is increased after CHK1 inhibition, we hypothesized that this may indicate an increased reliance on ATR for survival. Indeed, we observe that replication stress induced by the CHK1 inhibitor AZD7762 results in replication catastrophe and apoptosis, when combined with the ATR inhibitor VE-821 specifically in cancer cells. Combined treatment with ATR and CHK1 inhibitors leads to replication fork arrest, ssDNA accumulation, replication collapse, and synergistic cell death in cancer cells in vitro and in vivo. Inhibition of CDK reversed replication stress and synthetic lethality, demonstrating that regulation of origin firing by ATR and CHK1 explains the synthetic lethality. In conclusion, this study exemplifies cancer-specific synthetic lethality between two proteins in the same pathway and raises the prospect of combining ATR and CHK1 inhibitors as promising cancer therapy. PMID:26748709

  15. Targeting EZH2 methyltransferase activity in ARID1A mutated cancer cells is synthetic lethal

    PubMed Central

    Biter, Benjamin G.; Aird, Katherine M.; Garipov, Azat; Li, Hua; Amatangelo, Michael; Kossenkov, Andrew V.; Schultz, David C.; Liu, Qin; Shih, Ie-Ming; Conejo-Garcia, Jose R.; Speicher, David W.; Zhang, Rugang

    2015-01-01

    ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently has no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated ovarian cancer cells. ARID1A mutational status correlates with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct ARID1A/EZH2 target, which is upregulated by EZH2 inhibition and contributes to the observed synthetic lethality by inhibiting PI3K/AKT signaling. Significantly, EZH2 inhibition causes regression of ARID1A mutated ovarian tumors in vivo. Together, these data demonstrate for the first time a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers. PMID:25686104

  16. RADical response puts an exceptional responder in CHKmate: a synthetic lethal curative response to DNA-damaging chemotherapy?

    PubMed Central

    Peng, Guang; Woodman, Scott E.; Mills, Gordon B.

    2014-01-01

    Summary In this issue of Cancer Discovery, AI-Ahmadie and colleagues identify a somatic mutation in the Rad50 gene as a likely contributing factor to an unusual curative response to systemic combination therapy employing the DNA-damaging agent, irinotecan, and a checkpoint kinase 1(Chk1) inhibitor in a patient with recurrent, metastatic small-cell cancer. This study highlights the importance of in-depth analysis of exceptional responders to chemo and targeted therapy in early phase clinical trials and opens new avenues for developing cancer genome-based combination therapy to improve the efficacy of traditional chemotherapy through synthetically lethal interactions. PMID:25185187

  17. KRAS mutant NSCLC, a new opportunity for the synthetic lethality therapeutic approach

    PubMed Central

    Belda-Iniesta, Cristóbal

    2013-01-01

    K-RAS accounts for 90% of RAS mutations in lung adenocarcinomas, the most commonly mutated oncogene in NSCLC, with mutations detected in about 25% of all tumors. Direct inhibition of KRAS has proven clinically challenging. So far, no successful targeted therapy has been developed and remains an elusive target for cancer therapy. Despite significant efforts, currently there are no drugs directly targeting mutated KRAS. Thus, new strategies have emerged for targeting RAS including the use of synthetic lethality. A specific knowledge of individual tumor molecular abnormalities that result in oncogene-specific “synthetic lethal” interactions will allow the rationale to combine promising targeted therapies for KRAS-mutated NSCLC. In this article, we review the new approach based on testing drugs or combinations of agents that work downstream of activated K-RAS. PMID:25806225

  18. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells.

    PubMed

    Scholl, Claudia; Fröhling, Stefan; Dunn, Ian F; Schinzel, Anna C; Barbie, David A; Kim, So Young; Silver, Serena J; Tamayo, Pablo; Wadlow, Raymond C; Ramaswamy, Sridhar; Döhner, Konstanze; Bullinger, Lars; Sandy, Peter; Boehm, Jesse S; Root, David E; Jacks, Tyler; Hahn, William C; Gilliland, D Gary

    2009-05-29

    An alternative to therapeutic targeting of oncogenes is to perform "synthetic lethality" screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with "undruggable" genetic alterations. PMID:19490892

  19. A Synthetic Lethal Screen Identifies a Role for Lin-44/Wnt in C. elegans Embryogenesis

    PubMed Central

    Hartin, Samantha N.; Hudson, Martin L.; Yingling, Curtis; Ackley, Brian D.

    2015-01-01

    Background The C. elegans proteins PTP-3/LAR-RPTP and SDN-1/Syndecan are conserved cell adhesion molecules. Loss-of-function (LOF) mutations in either ptp-3 or sdn-1 result in low penetrance embryonic developmental defects. Work from other systems has shown that syndecans can function as ligands for LAR receptors in vivo. We used double mutant analysis to test whether ptp-3 and sdn-1 function in a linear genetic pathway during C. elegans embryogenesis. Results We found animals with LOF in both sdn-1 and ptp-3 exhibited a highly penetrant synthetic lethality (SynLet), with only a small percentage of animals surviving to adulthood. Analysis of the survivors demonstrated that these animals had a synergistic increase in the penetrance of embryonic developmental defects. Together, these data strongly suggested PTP-3 and SDN-1 function in parallel during embryogenesis. We subsequently used RNAi to knockdown ~3,600 genes predicted to encode secreted and/or transmembrane molecules to identify genes that interacted with ptp-3 or sdn-1. We found that the Wnt ligand, lin-44, was SynLet with sdn-1, but not ptp-3. We used 4-dimensional time-lapse analysis to characterize the interaction between lin-44 and sdn-1. We found evidence that loss of lin-44 caused defects in the polarization and migration of endodermal precursors during gastrulation, a previously undescribed role for lin-44 that is strongly enhanced by the loss of sdn-1. Conclusions PTP-3 and SDN-1 function in compensatory pathways during C. elegans embryonic and larval development, as simultaneous loss of both genes has dire consequences for organismal survival. The Wnt ligand lin-44 contributes to the early stages of gastrulation in parallel to sdn-1, but in a genetic pathway with ptp-3. Overall, the SynLet phenotype provides a robust platform to identify ptp-3 and sdn-1 interacting genes, as well as other genes that function in development, yet might be missed in traditional forward genetic screens. PMID:25938228

  20. Using Gene Essentiality and Synthetic Lethality Information to Correct Yeast and CHO Cell Genome-Scale Models

    PubMed Central

    Chowdhury, Ratul; Chowdhury, Anupam; Maranas, Costas D.

    2015-01-01

    Essentiality (ES) and Synthetic Lethality (SL) information identify combination of genes whose deletion inhibits cell growth. This information is important for both identifying drug targets for tumor and pathogenic bacteria suppression and for flagging and avoiding gene deletions that are non-viable in biotechnology. In this study, we performed a comprehensive ES and SL analysis of two important eukaryotic models (S. cerevisiae and CHO cells) using a bilevel optimization approach introduced earlier. Information gleaned from this study is used to propose specific model changes to remedy inconsistent with data model predictions. Even for the highly curated Yeast 7.11 model we identified 50 changes (metabolic and GPR) leading to the correct prediction of an additional 28% of essential genes and 36% of synthetic lethals along with a 53% reduction in the erroneous identification of essential genes. Due to the paucity of mutant growth phenotype data only 12 changes were made for the CHO 1.2 model leading to an additional correctly predicted 11 essential and eight non-essential genes. Overall, we find that CHO 1.2 was 76% less accurate than the Yeast 7.11 metabolic model in predicting essential genes. Based on this analysis, 14 (single and double deletion) maximally informative experiments are suggested to improve the CHO cell model by using information from a mouse metabolic model. This analysis demonstrates the importance of single and multiple knockout phenotypes in assessing and improving model reconstructions. The advent of techniques such as CRISPR opens the door for the global assessment of eukaryotic models. PMID:26426067

  1. Using Gene Essentiality and Synthetic Lethality Information to Correct Yeast and CHO Cell Genome-Scale Models.

    PubMed

    Chowdhury, Ratul; Chowdhury, Anupam; Maranas, Costas D

    2015-01-01

    Essentiality (ES) and Synthetic Lethality (SL) information identify combination of genes whose deletion inhibits cell growth. This information is important for both identifying drug targets for tumor and pathogenic bacteria suppression and for flagging and avoiding gene deletions that are non-viable in biotechnology. In this study, we performed a comprehensive ES and SL analysis of two important eukaryotic models (S. cerevisiae and CHO cells) using a bilevel optimization approach introduced earlier. Information gleaned from this study is used to propose specific model changes to remedy inconsistent with data model predictions. Even for the highly curated Yeast 7.11 model we identified 50 changes (metabolic and GPR) leading to the correct prediction of an additional 28% of essential genes and 36% of synthetic lethals along with a 53% reduction in the erroneous identification of essential genes. Due to the paucity of mutant growth phenotype data only 12 changes were made for the CHO 1.2 model leading to an additional correctly predicted 11 essential and eight non-essential genes. Overall, we find that CHO 1.2 was 76% less accurate than the Yeast 7.11 metabolic model in predicting essential genes. Based on this analysis, 14 (single and double deletion) maximally informative experiments are suggested to improve the CHO cell model by using information from a mouse metabolic model. This analysis demonstrates the importance of single and multiple knockout phenotypes in assessing and improving model reconstructions. The advent of techniques such as CRISPR opens the door for the global assessment of eukaryotic models. PMID:26426067

  2. Towards a compendium of essential genes – From model organisms to synthetic lethality in cancer cells

    PubMed Central

    Zhan, Tianzuo; Boutros, Michael

    2016-01-01

    Abstract Essential genes are defined by their requirement to sustain life in cells or whole organisms. The systematic identification of essential gene sets not only allows insights into the fundamental building blocks of life, but may also provide novel therapeutic targets in oncology. The discovery of essential genes has been tightly linked to the development and deployment of various screening technologies. Here, we describe how gene essentiality was addressed in different eukaryotic model organisms, covering a range of organisms from yeast to mouse. We describe how increasing knowledge of evolutionarily divergent genomes facilitate identification of gene essentiality across species. Finally, the impact of gene essentiality and synthetic lethality on cancer research and the clinical translation of screening results are highlighted. PMID:26627871

  3. Inhibition of the Polyamine Synthesis Pathway Is Synthetically Lethal with Loss of Argininosuccinate Synthase 1.

    PubMed

    Locke, Matthew; Ghazaly, Essam; Freitas, Marta O; Mitsinga, Mikaella; Lattanzio, Laura; Lo Nigro, Cristiana; Nagano, Ai; Wang, Jun; Chelala, Claude; Szlosarek, Peter; Martin, Sarah A

    2016-08-01

    Argininosuccinate synthase 1 (ASS1) is the rate-limiting enzyme for arginine biosynthesis. ASS1 expression is lost in a range of tumor types, including 50% of malignant pleural mesotheliomas. Starving ASS1-deficient cells of arginine with arginine blockers such as ADI-PEG20 can induce selective lethality and has shown great promise in the clinical setting. We have generated a model of ADI-PEG20 resistance in mesothelioma cells. This resistance is mediated through re-expression of ASS1 via demethylation of the ASS1 promoter. Through coordinated transcriptomic and metabolomic profiling, we have shown that ASS1-deficient cells have decreased levels of acetylated polyamine metabolites, together with a compensatory increase in the expression of polyamine biosynthetic enzymes. Upon arginine deprivation, polyamine metabolites are decreased in the ASS1-deficient cells and in plasma isolated from ASS1-deficient mesothelioma patients. We identify a synthetic lethal dependence between ASS1 deficiency and polyamine metabolism, which could potentially be exploited for the treatment of ASS1-negative cancers. PMID:27452468

  4. Synthetic antibodies with a human framework that protect mice from lethal Sudan ebolavirus challenge.

    PubMed

    Chen, Gang; Koellhoffer, Jayne F; Zak, Samantha E; Frei, Julia C; Liu, Nina; Long, Hua; Ye, Wei; Nagar, Kaajal; Pan, Guohua; Chandran, Kartik; Dye, John M; Sidhu, Sachdev S; Lai, Jonathan R

    2014-10-17

    The ebolaviruses cause severe and rapidly progressing hemorrhagic fever. There are five ebolavirus species; although much is known about Zaire ebolavirus (EBOV) and its neutralization by antibodies, little is known about Sudan ebolavirus (SUDV), which is emerging with increasing frequency. Here we describe monoclonal antibodies containing a human framework that potently inhibit infection by SUDV and protect mice from lethal challenge. The murine antibody 16F6, which binds the SUDV envelope glycoprotein (GP), served as the starting point for design. Sequence and structural alignment revealed similarities between 16F6 and YADS1, a synthetic antibody with a humanized scaffold. A focused phage library was constructed and screened to impart 16F6-like recognition properties onto the YADS1 scaffold. A panel of 17 antibodies were characterized and found to have a range of neutralization potentials against a pseudotype virus infection model. Neutralization correlated with GP binding as determined by ELISA. Two of these clones, E10 and F4, potently inhibited authentic SUDV and conferred protection and memory immunity in mice from lethal SUDV challenge. E10 and F4 were further shown to bind to the same epitope on GP as 16F6 with comparable affinities. These antibodies represent strong immunotherapeutic candidates for treatment of SUDV infection. PMID:25140871

  5. Identification of synthetic lethality of PLK1 inhibition and microtubule-destabilizing drugs.

    PubMed

    Hugle, M; Belz, K; Fulda, S

    2015-12-01

    Polo-like kinase 1 (PLK1) is frequently overexpressed in cancer, which correlates with poor prognosis. Therefore, we investigated PLK1 as therapeutic target using rhabdomyosarcoma (RMS) as a model. Here, we identify a novel synthetic lethal interaction of PLK1 inhibitors and microtubule-destabilizing drugs in preclinical RMS models and elucidate the underlying molecular mechanisms of this synergism. PLK1 inhibitors (i.e., BI 2536 and BI 6727) synergistically induce apoptosis together with microtubule-destabilizing drugs (i.e., vincristine (VCR), vinblastine (VBL) and vinorelbine (VNR)) in several RMS cell lines (combination index <0.9) including a patient-derived primary RMS culture. Importantly, PLK1 inhibitors and VCR cooperate to significantly suppress RMS growth in two in vivo models, including a mouse xenograft model, without causing additive toxicity. In addition, no toxicity was observed in non-malignant fibroblast or myoblast cultures. Mechanistically, BI 2536/VCR co-treatment triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by BAX/BAK activation, production of reactive oxygen species (ROS) and activation of caspase-dependent or caspase-independent effector pathways. This conclusion is supported by data showing that BI 2536/VCR-induced apoptosis is significantly inhibited by preventing cells to enter mitosis, by overexpression of BCL-2 or a non-degradable MCL-1 mutant, by BAK knockdown, ROS scavengers, caspase inhibition or endonuclease G silencing. This identification of a novel synthetic lethality of PLK1 inhibitors and microtubule-destabilizing drugs has important implications for developing PLK1 inhibitor-based combination treatments. PMID:26024389

  6. Cell line name recognition in support of the identification of synthetic lethality in cancer from text

    PubMed Central

    Kaewphan, Suwisa; Van Landeghem, Sofie; Ohta, Tomoko; Van de Peer, Yves; Ginter, Filip; Pyysalo, Sampo

    2016-01-01

    Motivation: The recognition and normalization of cell line names in text is an important task in biomedical text mining research, facilitating for instance the identification of synthetically lethal genes from the literature. While several tools have previously been developed to address cell line recognition, it is unclear whether available systems can perform sufficiently well in realistic and broad-coverage applications such as extracting synthetically lethal genes from the cancer literature. In this study, we revisit the cell line name recognition task, evaluating both available systems and newly introduced methods on various resources to obtain a reliable tagger not tied to any specific subdomain. In support of this task, we introduce two text collections manually annotated for cell line names: the broad-coverage corpus Gellus and CLL, a focused target domain corpus. Results: We find that the best performance is achieved using NERsuite, a machine learning system based on Conditional Random Fields, trained on the Gellus corpus and supported with a dictionary of cell line names. The system achieves an F-score of 88.46% on the test set of Gellus and 85.98% on the independently annotated CLL corpus. It was further applied at large scale to 24 302 102 unannotated articles, resulting in the identification of 5 181 342 cell line mentions, normalized to 11 755 unique cell line database identifiers. Availability and implementation: The manually annotated datasets, the cell line dictionary, derived corpora, NERsuite models and the results of the large-scale run on unannotated texts are available under open licenses at http://turkunlp.github.io/Cell-line-recognition/. Contact: sukaew@utu.fi PMID:26428294

  7. KEAP1-dependent synthetic lethality induced by AKT and TXNRD1 inhibitors in lung cancer

    PubMed Central

    Dai, Bingbing; Yoo, Suk-Yuong; Bartholomeusz, Geoffrey; Graham, Ryan A.; Majidi, Mourad; Yan, Shaoyu; Meng, Jieru; Ji, Lin; Coombes, Kevin; Minna, John D.; Fang, Bingliang; Roth, Jack A.

    2013-01-01

    Intrinsic resistance to agents targeting phosphatidylinositol-3-kinase (PI3K)/AKT pathway is one of the major challenges in cancer treatment with such agents. The objective of this study is to identify the genes or pathways that can be targeted to overcome the resistance of non-small cell lung cancer to the AKT inhibitor, MK2206, which is currently being evaluated in phase I and II clinical trials. Using a genome-wide small interfering RNA (siRNA) library screening and biological characterization we identified that inhibition of Thioredoxin Reductase-1 (TXNRD1), one of the key anti-oxidant enzymes, with siRNAs or its inhibitor, Auranofin, sensitized non-small cell lung cancer cells to MK2206 treatment in vitro and in vivo. We found that simultaneous inhibition of TXNRD1 and AKT pathways induced robust reactive oxygen species (ROS) production, which was involved in c-Jun N-terminal Kinase (JNK, MAPK8) activation and cell apoptosis. Furthermore we found that the synthetic lethality interaction between the TXNRD1 and AKT pathways occurred through the KEAP1/NRF2 cellular antioxidant pathway. Lastly, we found that synthetic lethality induced by TXNRD1 and AKT inhibitors relied on wild type KEAP1 function. Our study indicates that targeting the interaction between AKT and TXNRD1 antioxidant pathways with MK2206 and Auranofin, a FDA approved drug, is a rational strategy to treat lung cancer and that KEAP1 mutation status may offer a predicative biomarker for such combination approaches. PMID:23824739

  8. A screen for dynein synthetic lethals in Aspergillus nidulans identifies spindle assembly checkpoint genes and other genes involved in mitosis.

    PubMed Central

    Efimov, V P; Morris, N R

    1998-01-01

    Cytoplasmic dynein is a ubiquitously expressed microtubule motor involved in vesicle transport, mitosis, nuclear migration, and spindle orientation. In the filamentous fungus Aspergillus nidulans, inactivation of cytoplasmic dynein, although not lethal, severely impairs nuclear migration. The role of dynein in mitosis and vesicle transport in this organism is unclear. To investigate the complete range of dynein function in A. nidulans, we searched for synthetic lethal mutations that significantly reduced growth in the absence of dynein but had little effect on their own. We isolated 19 sld (synthetic lethality without dynein) mutations in nine different genes. Mutations in two genes exacerbate the nuclear migration defect seen in the absence of dynein. Mutations in six other genes, including sldA and sldB, show a strong synthetic lethal interaction with a mutation in the mitotic kinesin bimC and, thus, are likely to play a role in mitosis. Mutations in sldA and sldB also confer hypersensitivity to the microtubule-destabilizing drug benomyl. sldA and sldB were cloned by complementation of their mutant phenotypes using an A. nidulans autonomously replicating vector. Sequencing revealed homology to the spindle assembly checkpoint genes BUB1 and BUB3 from Saccharomyces cerevisiae. Genetic interaction between dynein and spindle assembly checkpoint genes, as well as other mitotic genes, indicates that A. nidulans dynein plays a role in mitosis. We suggest a model for dynein motor action in A. nidulans that can explain dynein involvement in both mitosis and nuclear distribution. PMID:9584089

  9. Synthetic lethal interactions suggest a role for the Saccharomyces cerevisiae Rtf1 protein in transcription elongation.

    PubMed Central

    Costa, P J; Arndt, K M

    2000-01-01

    Strong evidence indicates that transcription elongation by RNA polymerase II (pol II) is a highly regulated process. Here we present genetic results that indicate a role for the Saccharomyces cerevisiae Rtf1 protein in transcription elongation. A screen for synthetic lethal mutations was carried out with an rtf1 deletion mutation to identify factors that interact with Rtf1 or regulate the same process as Rtf1. The screen uncovered mutations in SRB5, CTK1, FCP1, and POB3. These genes encode an Srb/mediator component, a CTD kinase, a CTD phosphatase, and a protein involved in the regulation of transcription by chromatin structure, respectively. All of these gene products have been directly or indirectly implicated in transcription elongation, indicating that Rtf1 may also regulate this process. In support of this view, we show that RTF1 functionally interacts with genes that encode known elongation factors, including SPT4, SPT5, SPT16, and PPR2. We also show that a deletion of RTF1 causes sensitivity to 6-azauracil and mycophenolic acid, phenotypes correlated with a transcription elongation defect. Collectively, our results suggest that Rtf1 may function as a novel transcription elongation factor in yeast. PMID:11014804

  10. In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment

    PubMed Central

    Li, Jian; Zhou, Nan; Cai, Peiling; Bao, Jinku

    2016-01-01

    Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (−86.8) and amber score (−51.42). Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was −177.28 kJ/mol while that of olaparib was −159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development. PMID:26907257

  11. ATM and MET kinases are synthetic lethal with non-genotoxic activation of p53

    PubMed Central

    Sullivan, Kelly D.; Padilla-Just, Nuria; Henry, Ryan E.; Porter, Christopher C.; Kim, Jihye; Tentler, John J.; Eckhardt, S. Gail; Tan, Aik Choon; DeGregori, James; Espinosa, Joaquín M.

    2012-01-01

    The p53 tumor suppressor orchestrates alternative stress responses including cell cycle arrest and apoptosis, but the mechanisms defining cell fate upon p53 activation are poorly understood. Several small molecule activators of p53 have been developed, including Nutlin-3, but their therapeutic potential is limited by the fact that they induce reversible cell cycle arrest in most cancer cell types. We report here the results of a ‘Synthetic Lethal with Nutlin-3’ genome-wide shRNA screen, which revealed that the ATM and MET kinases govern cell fate choice upon p53 activation. Genetic or pharmacological interference with ATM or MET activity converts the cellular response from cell cycle arrest into apoptosis in diverse cancer cell types without affecting expression of key p53 target genes. ATM and MET inhibitors enable Nutlin-3 to kill tumor spheroids. These results identify novel pathways controlling the cellular response to p53 activation and aid in the design of p53-based therapies. PMID:22660439

  12. In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment.

    PubMed

    Li, Jian; Zhou, Nan; Cai, Peiling; Bao, Jinku

    2016-01-01

    Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (-86.8) and amber score (-51.42). Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was -177.28 kJ/mol while that of olaparib was -159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development. PMID:26907257

  13. Synthetic lethality between CCNE1 amplification and loss of BRCA1.

    PubMed

    Etemadmoghadam, Dariush; Weir, Barbara A; Au-Yeung, George; Alsop, Kathryn; Mitchell, Gillian; George, Joshy; Davis, Sally; D'Andrea, Alan D; Simpson, Kaylene; Hahn, William C; Bowtell, David D L

    2013-11-26

    High-grade serous ovarian cancers (HGSCs) are characterized by a high frequency of TP53 mutations, BRCA1/2 inactivation, homologous recombination dysfunction, and widespread copy number changes. Cyclin E1 (CCNE1) gene amplification has been reported to occur independently of BRCA1/2 mutation, and it is associated with primary treatment failure and reduced patient survival. Insensitivity of CCNE1-amplified tumors to platinum cross-linking agents may be partly because of an intact BRCA1/2 pathway. Both BRCA1/2 dysfunction and CCNE1 amplification are known to promote genomic instability and tumor progression. These events may be mutually exclusive, because either change provides a path to tumor development, with no selective advantage to having both mutations. Using data from a genome-wide shRNA synthetic lethal screen, we show that BRCA1 and members of the ubiquitin pathway are selectively required in cancers that harbor CCNE1 amplification. Furthermore, we show specific sensitivity of CCNE1-amplified tumor cells to the proteasome inhibitor bortezomib. These findings provide an explanation for the observed mutual exclusivity of CCNE1 amplification and BRCA1/2 loss in HGSC and suggest a unique therapeutic approach for treatment-resistant CCNE1-amplified tumors. PMID:24218601

  14. Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy

    PubMed Central

    Warkentin, Alexander A; Lopez, Michael S; Lasater, Elisabeth A; Lin, Kimberly; He, Bai-Liang; Leung, Anskar YH; Smith, Catherine C; Shah, Neil P; Shokat, Kevan M

    2014-01-01

    Activating mutations in FLT3 confer poor prognosis for individuals with acute myeloid leukemia (AML). Clinically active investigational FLT3 inhibitors can achieve complete remissions but their utility has been hampered by acquired resistance and myelosuppression attributed to a ‘synthetic lethal toxicity’ arising from simultaneous inhibition of FLT3 and KIT. We report a novel chemical strategy for selective FLT3 inhibition while avoiding KIT inhibition with the staurosporine analog, Star 27. Star 27 maintains potency against FLT3 in proliferation assays of FLT3-transformed cells compared with KIT-transformed cells, shows no toxicity towards normal human hematopoiesis at concentrations that inhibit primary FLT3-mutant AML blast growth, and is active against mutations that confer resistance to clinical inhibitors. As a more complete understanding of kinase networks emerges, it may be possible to define anti-targets such as KIT in the case of AML to allow improved kinase inhibitor design of clinical agents with enhanced efficacy and reduced toxicity. DOI: http://dx.doi.org/10.7554/eLife.03445.001 PMID:25531068

  15. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase.

    PubMed

    Frezza, Christian; Zheng, Liang; Folger, Ori; Rajagopalan, Kartik N; MacKenzie, Elaine D; Jerby, Livnat; Micaroni, Massimo; Chaneton, Barbara; Adam, Julie; Hedley, Ann; Kalna, Gabriela; Tomlinson, Ian P M; Pollard, Patrick J; Watson, Dave G; Deberardinis, Ralph J; Shlomi, Tomer; Ruppin, Eytan; Gottlieb, Eyal

    2011-09-01

    Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients. PMID:21849978

  16. Chemogenetic profiling identifies RAD17 as synthetically lethal with checkpoint kinase inhibition

    PubMed Central

    Shen, John Paul; Srivas, Rohith; Gross, Andrew; Li, Jianfeng; Jaehnig, Eric J.; Sun, Su Ming; Bojorquez-Gomez, Ana; Licon, Katherine; Sivaganesh, Vignesh; Xu, Jia L.; Klepper, Kristin; Yeerna, Huwate; Pekin, Daniel; Qiu, Chu Ping; van Attikum, Haico; Sobol, Robert W.; Ideker, Trey

    2015-01-01

    Chemical inhibitors of the checkpoint kinases have shown promise in the treatment of cancer, yet their clinical utility may be limited by a lack of molecular biomarkers to identify specific patients most likely to respond to therapy. To this end, we screened 112 known tumor suppressor genes for synthetic lethal interactions with inhibitors of the CHEK1 and CHEK2 checkpoint kinases. We identified eight interactions, including the Replication Factor C (RFC)-related protein RAD17. Clonogenic assays in RAD17 knockdown cell lines identified a substantial shift in sensitivity to checkpoint kinase inhibition (3.5-fold) as compared to RAD17 wild-type. Additional evidence for this interaction was found in a large-scale functional shRNA screen of over 100 genotyped cancer cell lines, in which CHEK1/2 mutant cell lines were unexpectedly sensitive to RAD17 knockdown. This interaction was widely conserved, as we found that RAD17 interacts strongly with checkpoint kinases in the budding yeast Saccharomyces cerevisiae. In the setting of RAD17 knockdown, CHEK1/2 inhibition was found to be synergistic with inhibition of WEE1, another pharmacologically relevant checkpoint kinase. Accumulation of the DNA damage marker γH2AX following chemical inhibition or transient knockdown of CHEK1, CHEK2 or WEE1 was magnified by knockdown of RAD17. Taken together, our data suggest that CHEK1 or WEE1 inhibitors are likely to have greater clinical efficacy in tumors with RAD17 loss-of-function. PMID:26437225

  17. Chemogenetic profiling identifies RAD17 as synthetically lethal with checkpoint kinase inhibition.

    PubMed

    Shen, John Paul; Srivas, Rohith; Gross, Andrew; Li, Jianfeng; Jaehnig, Eric J; Sun, Su Ming; Bojorquez-Gomez, Ana; Licon, Katherine; Sivaganesh, Vignesh; Xu, Jia L; Klepper, Kristin; Yeerna, Huwate; Pekin, Daniel; Qiu, Chu Ping; van Attikum, Haico; Sobol, Robert W; Ideker, Trey

    2015-11-01

    Chemical inhibitors of the checkpoint kinases have shown promise in the treatment of cancer, yet their clinical utility may be limited by a lack of molecular biomarkers to identify specific patients most likely to respond to therapy. To this end, we screened 112 known tumor suppressor genes for synthetic lethal interactions with inhibitors of the CHEK1 and CHEK2 checkpoint kinases. We identified eight interactions, including the Replication Factor C (RFC)-related protein RAD17. Clonogenic assays in RAD17 knockdown cell lines identified a substantial shift in sensitivity to checkpoint kinase inhibition (3.5-fold) as compared to RAD17 wild-type. Additional evidence for this interaction was found in a large-scale functional shRNA screen of over 100 genotyped cancer cell lines, in which CHEK1/2 mutant cell lines were unexpectedly sensitive to RAD17 knockdown. This interaction was widely conserved, as we found that RAD17 interacts strongly with checkpoint kinases in the budding yeast Saccharomyces cerevisiae. In the setting of RAD17 knockdown, CHEK1/2 inhibition was found to be synergistic with inhibition of WEE1, another pharmacologically relevant checkpoint kinase. Accumulation of the DNA damage marker γH2AX following chemical inhibition or transient knockdown of CHEK1, CHEK2 or WEE1 was magnified by knockdown of RAD17. Taken together, our data suggest that CHEK1 or WEE1 inhibitors are likely to have greater clinical efficacy in tumors with RAD17 loss-of-function. PMID:26437225

  18. Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies

    PubMed Central

    Steckel, Michael; Molina-Arcas, Miriam; Weigelt, Britta; Marani, Michaela; Warne, Patricia H; Kuznetsov, Hanna; Kelly, Gavin; Saunders, Becky; Howell, Michael; Downward, Julian; Hancock, David C

    2012-01-01

    Oncogenic mutations in RAS genes are very common in human cancer, resulting in cells with well-characterized selective advantages, but also less well-understood vulnerabilities. We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells, but not by derivatives lacking this oncogene. Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells. Cancer cells expressing oncogenic KRAS were found to be highly dependent on the transcription factor GATA2 and the DNA replication initiation regulator CDC6. Extending this analysis using a collection of drugs with known targets, we found that cancer cells with mutant KRAS showed selective addiction to proteasome function, as well as synthetic lethality with topoisomerase inhibition. Combination targeting of these functions caused improved killing of KRAS mutant cells relative to wild-type cells. These observations suggest novel targets and new ways of combining existing therapies for optimal effect in RAS mutant cancers, which are traditionally seen as being highly refractory to therapy. PMID:22613949

  19. Differential regulation and synthetic lethality of exclusive RB1 and CDKN2A mutations in lung cancer.

    PubMed

    Kim, Nayoung; Song, Mee; Kim, Somin; Seo, Yujeong; Kim, Yonghwan; Yoon, Sukjoon

    2016-01-01

    Genetic alterations in lung cancer are distinctly represented in non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). Mutation of the RB1 and CDKN2A genes, which are tightly associated with cell cycle regulation, is exclusive to SCLC and NSCLC cells, respectively. Through the systematic analysis of transcriptome and proteome datasets for 318 cancer cell lines, we characterized differential gene expression and protein regulation in RB1-mutant SCLC and CDKN2A-mutant NSCLC. Many of the genes and proteins associated with RB1-mutant SCLC cell lines belong to functional categories of gene expression and transcription, whereas those associated with CDKN2A-mutant NSCLC cell lines were enriched in gene sets of the extracellular matrix and focal adhesion. These results indicate that the loss of RB1 and CDKN2A function induces distinctively different signaling cascades in SCLC and NSCLC cells. In addition, knockdown of the RB1 gene in CKDN2A-mutant cell lines (and vice versa) synergistically inhibits cancer cell proliferation. The present study on the exclusive role of RB1 and CDKN2A mutations in lung cancer subtypes demonstrates a synthetic lethal strategy for cancer regulation. PMID:26647789

  20. Synthetic lethal targeting of PTEN-deficient cancer cells using selective disruption of polynucleotide kinase/phosphatase.

    PubMed

    Mereniuk, Todd R; El Gendy, Mohamed A M; Mendes-Pereira, Ana M; Lord, Christopher J; Ghosh, Sunita; Foley, Edan; Ashworth, Alan; Weinfeld, Michael

    2013-10-01

    A recent screen of 6,961 siRNAs to discover possible synthetic lethal partners of the DNA repair protein polynucleotide kinase/phosphatase (PNKP) led to the identification of the potent tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Here, we have confirmed the PNKP/PTEN synthetic lethal partnership in a variety of different cell lines including the PC3 prostate cancer cell line, which is naturally deficient in PTEN. We provide evidence that codepletion of PTEN and PNKP induces apoptosis. In HCT116 colon cancer cells, the loss of PTEN is accompanied by an increased background level of DNA double-strand breaks, which accumulate in the presence of an inhibitor of PNKP DNA 3'-phosphatase activity. Complementation of PC3 cells with several well-characterized mutated PTEN cDNAs indicated that the critical function of PTEN required to prevent toxicity induced by an inhibitor of PNKP is most likely associated with its cytoplasmic lipid phosphatase activity. Finally, we show that modest inhibition of PNKP in a PTEN knockout background enhances cellular radiosensitivity, suggesting that such a "synthetic sickness" approach involving the combination of PNKP inhibition with radiotherapy may be applicable to PTEN-deficient tumors. PMID:23883586

  1. Natural and glucosyl flavonoids inhibit poly(ADP-ribose) polymerase activity and induce synthetic lethality in BRCA mutant cells

    PubMed Central

    MAEDA, JUNKO; ROYBAL, ERICA J.; BRENTS, COLLEEN A.; UESAKA, MITSURU; AIZAWA, YASUSHI; KATO, TAKAMITSU A.

    2014-01-01

    Poly(ADP-ribose) polymerase (PARP) inhibitors have been proven to represent superior clinical agents targeting DNA repair mechanisms in cancer therapy. We investigated PARP inhibitory effects of the natural and synthetic flavonoids (quercetin, rutin, monoglucosyl rutin and maltooligosyl rutin) and tested the synthetic lethality in BRCA2 mutated cells. In vitro ELISA assay suggested that the flavonoids have inhibitory effects on PARP activity, but glucosyl modifications reduced the inhibitory effect. Cytotoxicity tests of Chinese hamster cells defective in BRCA2 gene (V-C8) and its parental V79 cells showed BRCA2-dependent synthetic lethality when treated with the flavonoids. BRCA2 mutated cells were three times more sensitive to the flavonoids than the wild-type and gene complemented cells. Reduced toxicity was observed in a glucosyl modification-dependent manner. The present study provides support for the clinical use of new treatment drugs, and is the beginning of the potential application of flavonoids in cancer prevention and the periodic consumption of appropriate flavonoids to reduce cancer risk in individuals carrying a mutant allele of the BRCA2 gene. PMID:24317580

  2. Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy

    PubMed Central

    Kim, Bogyou; Wang, Shangzi; Lee, Ji Min; Jeong, Yunju; Ahn, TaeJin; Son, Dae-Soon; Park, Hye Won; Yoo, Hyeon-seok; Song, Yun-Jeong; Lee, Eunjin; Oh, Young Mi; Lee, Saet Byoul; Choi, Jaehyun; Murray, Joseph C; Zhou, Yan; Song, Paul H; Kim, Kyung-Ah; Weiner, Louis M

    2014-01-01

    Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as EGFR inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by employing a siRNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the anti-tumor activity of SAIT301. Pathway analysis of these 69 genes implicated FGFR as a key regulator for anti-proliferative effects of Met targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin β3 is another potential target for combination treatment with SAIT301. Suppression of integrin β3 decreased AKT phosphorylation in SAIT301-resistant cells and restores SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis using CCLE database shows cancer cells with high levels of FGFR and integrin β3 are resistant to crizotinib treatment, suggesting FGFR and integrin β3 could be used as predictive markers for Met targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met targeting drugs. PMID:24662823

  3. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1.

    PubMed

    Oike, Takahiro; Ogiwara, Hideaki; Tominaga, Yuichi; Ito, Kentaro; Ando, Osamu; Tsuta, Koji; Mizukami, Tatsuji; Shimada, Yoko; Isomura, Hisanori; Komachi, Mayumi; Furuta, Koh; Watanabe, Shun-Ichi; Nakano, Takashi; Yokota, Jun; Kohno, Takashi

    2013-09-01

    The occurrence of inactivating mutations in SWI/SNF chromatin-remodeling genes in common cancers has attracted a great deal of interest. However, mechanistic strategies to target tumor cells carrying such mutations are yet to be developed. This study proposes a synthetic-lethality therapy for treating cancers deficient in the SWI/SNF catalytic (ATPase) subunit, BRG1/SMARCA4. The strategy relies upon inhibition of BRM/SMARCA2, another catalytic SWI/SNF subunit with a BRG1-related activity. Immunohistochemical analysis of a cohort of non-small-cell lung carcinomas (NSCLC) indicated that 15.5% (16 of 103) of the cohort, corresponding to preferentially undifferentiated tumors, was deficient in BRG1 expression. All BRG1-deficient cases were negative for alterations in known therapeutic target genes, for example, EGFR and DDR2 gene mutations, ALK gene fusions, or FGFR1 gene amplifications. RNA interference (RNAi)-mediated silencing of BRM suppressed the growth of BRG1-deficient cancer cells relative to BRG1-proficient cancer cells, inducing senescence via activation of p21/CDKN1A. This growth suppression was reversed by transduction of wild-type but not ATPase-deficient BRG1. In support of these in vitro results, a conditional RNAi study conducted in vivo revealed that BRM depletion suppressed the growth of BRG1-deficient tumor xenografts. Our results offer a rationale to develop BRM-ATPase inhibitors as a strategy to treat BRG1/SMARCA4-deficient cancers, including NSCLCs that lack mutations in presently known therapeutic target genes. PMID:23872584

  4. Systems biology-guided identification of synthetic lethal gene pairs and its potential use to discover antibiotic combinations

    PubMed Central

    Aziz, Ramy K.; Monk, Jonathan M.; Lewis, Robert M.; In Loh, Suh; Mishra, Arti; Abhay Nagle, Amrita; Satyanarayana, Chitkala; Dhakshinamoorthy, Saravanakumar; Luche, Michele; Kitchen, Douglas B.; Andrews, Kathleen A.; Fong, Nicole L.; Li, Howard J.; Palsson, Bernhard O.; Charusanti, Pep

    2015-01-01

    Mathematical models of metabolism from bacterial systems biology have proven their utility across multiple fields, for example metabolic engineering, growth phenotype simulation, and biological discovery. The usefulness of the models stems from their ability to compute a link between genotype and phenotype, but their ability to accurately simulate gene-gene interactions has not been investigated extensively. Here we assess how accurately a metabolic model for Escherichia coli computes one particular type of gene-gene interaction, synthetic lethality, and find that the accuracy rate is between 25% and 43%. The most common failure modes were incorrect computation of single gene essentiality and biological information that was missing from the model. Moreover, we performed virtual and biological screening against several synthetic lethal pairs to explore whether two-compound formulations could be found that inhibit the growth of Gram-negative bacteria. One set of molecules was identified that, depending on the concentrations, inhibits E. coli and S. enterica serovar Typhimurium in an additive or antagonistic manner. These findings pinpoint specific ways in which to improve the predictive ability of metabolic models, and highlight one potential application of systems biology to drug discovery and translational medicine. PMID:26531810

  5. A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers

    PubMed Central

    Hocke, Sandra; Guo, Yang; Job, Albert; Orth, Michael; Ziesch, Andreas; Lauber, Kirsten; De Toni, Enrico N; Gress, Thomas M.; Herbst, Andreas; Göke, Burkhard; Gallmeier, Eike

    2016-01-01

    The phosphoinositide 3-kinase-related kinase ATR represents a central checkpoint regulator and mediator of DNA-repair. Its inhibition selectively eliminates certain subsets of cancer cells in various tumor types, but the underlying genetic determinants remain enigmatic. Here, we applied a synthetic lethal screen directed against 288 DNA-repair genes using the well-defined ATR knock-in model of DLD1 colorectal cancer cells to identify potential DNA-repair defects mediating these effects. We identified a set of DNA-repair proteins, whose knockdown selectively killed ATR-deficient cancer cells. From this set, we further investigated the profound synthetic lethal interaction between ATR and POLD1. ATR-dependent POLD1 knockdown-induced cell killing was reproducible pharmacologically in POLD1-depleted DLD1 cells and a panel of other colorectal cancer cell lines by using chemical inhibitors of ATR or its major effector kinase CHK1. Mechanistically, POLD1 depletion in ATR-deficient cells caused caspase-dependent apoptosis without preceding cell cycle arrest and increased DNA-damage along with impaired DNA-repair. Our data could have clinical implications regarding tumor genotype-based cancer therapy, as inactivating POLD1 mutations have recently been identified in small subsets of colorectal and endometrial cancers. POLD1 deficiency might thus represent a predictive marker for treatment response towards ATR- or CHK1-inhibitors that are currently tested in clinical trials. PMID:26755646

  6. Synthetic predator cues impair immune function and make the biological pesticide Bti more lethal for vector mosquitoes.

    PubMed

    Op De Beeck, Lin; Janssens, Lizanne; Stoks, Robby

    2016-03-01

    The control of vector mosquitoes is one of the biggest challenges facing humankind with the use of chemical pesticides often leading to environmental impact and the evolution of resistance. Although to a lesser extent, this also holds for Bacillus thuringiensis israelensis (Bti), the most widely used biological pesticide to control mosquito populations. This raises the need for the development of integrated pest management strategies that allow the reduction of Bti concentrations without loss of the mosquito control efficiency. To this end, we tested in a laboratory experiment the combined effects of larval exposure to a sublethal Bti concentration and predation risk cues on life history and physiology of larval and adult Culex pipiens mosquitoes. Besides natural predator kairomones and prey alarm cues, we also tested synthetic kairomones of Notonecta predators. Neither Bti nor predation risk cues affected mortality, yet when both stressors were combined mortality increased on average by 133% compared to the treatment with only predation risk cues. This synergistic interaction was also present when Bti was combined with synthetic kairomones. This was further reflected in changes of the composite index of population performance, which suggested lowered per capita growth rates in mosquitoes exposed to Bti but only when Bti was combined with synthetic kairomones. Furthermore, predation risk cues shortened larval development time, reduced mass at metamorphosis in males, and had an immunosuppressive effect in larval and adult mosquitoes which may affect the mosquito vector competence. We provide the first demonstration that synthetic kairomones may generate similar effects on prey as natural kairomones. The identified immunosuppressive effect of synthetic kairomones and the novel lethal synergism type between a biological pesticide and synthetic predator kairomones provide an important proof of principle illustrating the potential of this combination for integrated

  7. Synthetic lethal compound combinations reveal a fundamental connection between wall teichoic acid and peptidoglycan biosyntheses in Staphylococcus aureus

    PubMed Central

    Campbell, Jennifer; Singh, Atul K.; Santa Maria, John P.; Kim, Younghoon; Brown, Stephanie; Swoboda, Jonathan G.; Mylonakis, Eleftherios; Wilkinson, Brian J.; Walker, Suzanne

    2010-01-01

    Methicillin resistance in Staphylococcus aureus depends on the production of mecA, which encodes penicillin-binding protein 2A (PBP2A), an acquired peptidoglycan transpeptidase (TP) with reduced susceptibility to beta-lactam antibiotics. PBP2A crosslinks nascent peptidoglycan when the native TPs are inhibited by beta-lactams. Although mecA expression is essential for beta-lactam resistance, it is not sufficient. Here we show that blocking the expression of wall teichoic acids (WTAs) by inhibiting the first enzyme in the pathway, TarO, sensitizes MRSA strains to beta-lactams even though the beta-lactam-resistant transpeptidase, PBP2A, is still expressed. The dramatic synergy between TarO inhibitors and beta-lactams is noteworthy not simply because strategies to overcome methicillin-resistant S. aureus (MRSA) are desperately needed, but because neither TarO nor the activities of the native TPs are essential in MRSA strains. The “synthetic lethality” of inhibiting TarO and the native TPs suggests a functional connection between ongoing WTA expression and peptidoglycan assembly in S. aureus. Indeed, transmission electron microscopy shows that S. aureus cells blocked in WTA synthesis have extensive defects in septation and cell separation, indicating dysregulated cell wall assembly and degradation. Our studies imply that WTAs play a fundamental role in S. aureus cell division and raise the possibility that synthetic lethal compound combinations may have therapeutic utility for overcoming antibiotic resistant bacterial infections. PMID:20961110

  8. Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2.

    PubMed

    Mahadevan, Daruka; Morales, Carla; Cooke, Laurence S; Manziello, Ann; Mount, David W; Persky, Daniel O; Fisher, Richard I; Miller, Thomas P; Qi, Wenqing

    2014-01-01

    Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼ 10-20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼ 50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy. PMID:24893165

  9. Alisertib Added to Rituximab and Vincristine Is Synthetic Lethal and Potentially Curative in Mice with Aggressive DLBCL Co-Overexpressing MYC and BCL2

    PubMed Central

    Mahadevan, Daruka; Morales, Carla; Cooke, Laurence S.; Manziello, Ann; Mount, David W.; Persky, Daniel O.; Fisher, Richard I.; Miller, Thomas P.; Qi, Wenqing

    2014-01-01

    Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼10–20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy. PMID:24893165

  10. Equation of state and fragmentation issues in computational lethality analysis

    SciTech Connect

    Trucano, T.G.

    1993-07-01

    The purpose of this report is to summarize the status of computational analysis of hypervelocity impact lethality in relatively nontechnical terms from the perspective of the author. It is not intended to be a review of the technical literature on the problems of concern. The discussion is focused by concentrating on two phenomenology areas which are of particular concern in computational impact studies. First, the material`s equation of state, specifically the treatment of expanded states of metals undergoing shock vaporization, is discussed. Second, the process of dynamic fragmentation is addressed. In both cases, the context of the discussion deals with inaccuracies and difficulties associated with numerical hypervelocity impact simulations. Laboratory experimental capabilities in hypervelocity impact for impact velocities greater than 10.0 km/s are becoming increasingly viable. This paper also gives recommendations for experimental thrusts which utilize these capabilities that will help to resolve the uncertainties in the numerical lethality studies that are pointed out in the present report.

  11. Synthetic substrates for enzyme analysis

    DOEpatents

    Bissell, E.R.; Mitchell, A.R.; Pearson, K.W.; Smith, R.E.

    1983-06-14

    Synthetic substrates are provided which may be represented as A-D. The A moiety includes an amino acid, polypeptide, or derivative. The D moiety includes 7-amino coumarin derivatives having an electron withdrawing substituent group at the 3 position carbon or fused between the 3 and 4 position carbons. No Drawings

  12. Synthetic substrates for enzyme analysis

    DOEpatents

    Bissell, Eugene R.; Mitchell, Alexander R.; Pearson, Karen W.; Smith, Robert E.

    1983-01-01

    Synthetic substrates are provided which may be represented as A-D. The A moiety thereof includes an amino acid, polypeptide, or derivative thereof. The D moiety thereof includes 7-amino coumarin derivatives having an electron withdrawing substituent group at the 3 position carbon or fused between the 3 and 4 position carbons.

  13. MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1.

    PubMed

    Romero, Octavio A; Torres-Diz, Manuel; Pros, Eva; Savola, Suvi; Gomez, Antonio; Moran, Sebastian; Saez, Carmen; Iwakawa, Reika; Villanueva, Alberto; Montuenga, Luis M; Kohno, Takashi; Yokota, Jun; Sanchez-Cespedes, Montse

    2014-03-01

    Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, amplification of L-MYC, N-MYC, and C-MYC being some of the well-established gene alterations. Here, we report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1, the latter coding for an ATPase of the switch/sucrose nonfermentable (SWI/SNF) complex. We demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to upregulate MYC targets, such as glycolysis-related genes. Finally, inactivation of the MAX dimerization protein, MGA, was also observed in both non-small cell lung cancer and SCLC. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development. PMID:24362264

  14. Identification of cetrimonium bromide and irinotecan as compounds with synthetic lethality against NDRG1 deficient prostate cancer cells

    PubMed Central

    Wissing, Michel D.; Mendonca, Janet; Kim, Eunice; Kim, Eugene; Shim, Joong S.; Kaelber, Nadine S.; Kant, Huub; Hammers, Hans; Commes, Therese; Van Diest, Paul J.; Liu, Jun O.; Kachhap, Sushant K.

    2013-01-01

    The N-myc downstream regulated gene 1 (NDRG1) has been identified as a metastasis-suppressor gene in prostate cancer (PCa). Compounds targeting PCa cells deficient in NDRG1 could potentially decrease invasion/metastasis of PCa. A cell based screening strategy was employed to identify small molecules that selectively target NDRG1 deficient PCa cells. DU-145 PCa cells rendered deficient in NDRG1 expression by a lentiviral shRNA-mediated knockdown strategy were used in the primary screen. Compounds filtered from the primary screen were further validated through proliferation and clonogenic survival assays in parental and NDRG1 knockdown PCa cells. Screening of 3360 compounds revealed irinotecan and cetrimonium bromide (CTAB) as compounds that exhibited synthetic lethality against NDRG1 deficient PCa cells. A three-dimensional (3-D) invasion assay was utilized to test the ability of CTAB to inhibit invasion of DU-145 cells. CTAB was found to remarkably decrease invasion of DU-145 cells in collagen matrix. Our results suggest that CTAB and irinotecan could be further explored for their potential clinical benefit in patients with NDRG1 deficient PCa. PMID:23377825

  15. A synthetic lethal screen identifies the Vitamin D receptor as a novel gemcitabine sensitizer in pancreatic cancer cells

    PubMed Central

    Bhattacharjee, V; Zhou, Y; Yen, TJ

    2014-01-01

    Overcoming chemoresistance of pancreatic cancer (PCa) cells should significantly extend patient survival. The current treatment modalities rely on a variety of DNA damaging agents including gemcitabine, FOLFIRINOX, and Abraxane that activate cell cycle checkpoints, which allows cells to survive these drug treaments. Indeed, these treatment regimens have only extended patient survival by a few months. The complex microenvironment of PCa tumors has been shown to complicate drug delivery thus decreasing the sensitivity of PCa tumors to chemotherapy. In this study, a genome-wide siRNA library was used to conduct a synthetic lethal screen of Panc1 cells that was treated with gemcitabine. A sublethal dose (50 nM) of the drug was used to model situations of limiting drug availability to PCa tumors in vivo. Twenty-seven validated sensitizer genes were identified from the screen including the Vitamin D receptor (VDR). Gemcitabine sensitivity was shown to be VDR dependent in multiple PCa cell lines in clonogenic survival assays. Sensitization was not achieved through checkpoint override but rather through disrupting DNA repair. VDR knockdown disrupted the cells’ ability to form phospho-γH2AX and Rad51 foci in response to gemcitabine treatment. Disruption of Rad51 foci formation, which compromises homologous recombination, was consistent with increased sensitivity of PCa cells to the PARP inhibitor Rucaparib. Thus inhibition of VDR in PCa cells provides a new way to enhance the efficacy of genotoxic drugs. PMID:25558828

  16. In vivo toxic and lethal cardiovascular effects of a synthetic polymeric 1,3-dodecylpyridinium salt in rodents

    SciTech Connect

    Grandic, Marjana; Sepcic, Kristina; Turk, Tom; Juntes, Polona; Frangez, Robert

    2011-08-15

    APS12-2 is one in a series of synthetic analogs of the polymeric alkylpyridinium salts isolated from the marine sponge Reniera sarai. As it is a potential candidate for treating non small cell lung cancer (NSCLC), we have studied its possible toxic and lethal effects in vivo. The median lethal dose (LD{sub 50}) of APS12-2 in mice was determined to be 11.5 mg/kg. Electrocardiograms, arterial blood pressure and respiratory activity were recorded under general anesthesia in untreated, pharmacologically vagotomized and artificially ventilated rats injected with APS12-2. In one group, the in vivo effects of APS12-2 were studied on nerve-evoked muscle contraction. Administration of APS12-2 at a dose of 8 mg/kg caused a progressive reduction of arterial blood pressure to a mid-circulatory value, accompanied by bradycardia, myocardial ischemia, ventricular extrasystoles, and second degree atrio-ventricular block. Similar electrocardiogram and arterial blood pressure changes caused by APS12-2 (8 mg/kg) were observed in animals pretreated with atropine and in artificially ventilated animals, indicating that hypoxia and cholinergic effects do not play a crucial role in the toxicity of APS12-2. Application of APS12-2 at sublethal doses (4 and 5.5 mg/kg) caused a decrease of arterial blood pressure, followed by an increase slightly above control values. We found that APS12-2 causes lysis of rat erythrocytes in vitro, therefore it is reasonable to expect the same effect in vivo. Indeed, hyperkalemia was observed in the blood of experimental animals. Hyperkalemia probably plays an important role in APS12-2 cardiotoxicity since no evident changes in histopathology of the heart were found. However, acute lesions were observed in the pulmonary vessels of rats after application of 8 mg/kg APS12-2. Predominant effects were dilation of interalveolar blood vessels and lysis of aggregated erythrocytes within their lumina. - Highlights: > LD{sub 50} estimated in mice (11.5 mg/kg) revealed

  17. Identification of novel synergistic targets for rational drug combinations with PI3 kinase inhibitors using siRNA synthetic lethality screening against GBM

    PubMed Central

    Kim, Yong-Wan; Liu, Ta Jen; Koul, Dimpy; Tiao, Ningyi; Feroze, Abdullah H.; Wang, Jing; Powis, Garth; Yung, W. K. Alfred

    2011-01-01

    Several small molecules that inhibit the PI3 kinase (PI3K)-Akt signaling pathway are in clinical development. Although many of these molecules have been effective in preclinical models, it remains unclear whether this strategy alone will be sufficient to interrupt the molecular events initiated and maintained by signaling along the pathways because of the activation of other pathways that compensate for the inhibition of the targeted kinase. In this study, we performed a synthetic lethality screen to identify genes or pathways whose inactivation, in combination with the PI3K inhibitors PX-866 and NVPBEZ-235, might result in a lethal phenotype in glioblastoma multiforme (GBM) cells. We screened GBM cells (U87, U251, and T98G) with a large-scale, short hairpin RNA library (GeneNet), which contains 43 800 small interfering RNA sequences targeting 8500 well-characterized human genes. To decrease off-target effects, we selected overlapping genes among the 3 cell lines that synergized with PX-866 to induce cell death. To facilitate the identification of potential targets, we used a GSE4290 dataset and The Cancer Genome Atlas GBM dataset, identifying 15 target genes overexpressed in GBM tissues. We further analyzed the selected genes using Ingenuity Pathway Analysis software and showed that the 15 genes were closely related to cancer-promoting pathways, and a highly interconnected network of aberrations along the MYC, P38MAPK, and ERK signaling pathways were identified. Our findings suggest that inhibition of these pathways might increase tumor sensitivity to PX-866 and therefore represent a potential clinical therapeutic strategy. PMID:21430111

  18. Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax.

    PubMed

    Bajpai, R; Matulis, S M; Wei, C; Nooka, A K; Von Hollen, H E; Lonial, S; Boise, L H; Shanmugam, M

    2016-07-28

    Multiple myeloma (MM) is a plasma cell malignancy that is largely incurable due to development of resistance to therapy-elicited cell death. Nutrients are intricately connected to maintenance of cellular viability in part by inhibition of apoptosis. We were interested to determine if examination of metabolic regulation of BCL-2 proteins may provide insight on alternative routes to engage apoptosis. MM cells are reliant on glucose and glutamine and withdrawal of either nutrient is associated with varying levels of apoptosis. We and others have demonstrated that glucose maintains levels of key resistance-promoting BCL-2 family member, myeloid cell leukemic factor 1 (MCL-1). Cells continuing to survive in the absence of glucose or glutamine were found to maintain expression of MCL-1 but importantly induce pro-apoptotic BIM expression. One potential mechanism for continued survival despite induction of BIM could be due to binding and sequestration of BIM to alternate pro-survival BCL-2 members. Our investigation revealed that cells surviving glutamine withdrawal in particular, enhance expression and binding of BIM to BCL-2, consequently sensitizing these cells to the BH3 mimetic venetoclax. Glutamine deprivation-driven sensitization to venetoclax can be reversed by metabolic supplementation with TCA cycle intermediate α-ketoglutarate. Inhibition of glucose metabolism with the GLUT4 inhibitor ritonavir elicits variable cytotoxicity in MM that is marginally enhanced with venetoclax treatment, however, targeting glutamine metabolism with 6-diazo-5-oxo-l-norleucine uniformly sensitized MM cell lines and relapse/refractory patient samples to venetoclax. Our studies reveal a potent therapeutic strategy of metabolically driven synthetic lethality involving targeting glutamine metabolism for sensitization to venetoclax in MM. PMID:26640142

  19. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers

    PubMed Central

    Hoffman, Gregory R.; Rahal, Rami; Buxton, Frank; Xiang, Kay; McAllister, Gregory; Frias, Elizabeth; Bagdasarian, Linda; Huber, Janina; Lindeman, Alicia; Chen, Dongshu; Romero, Rodrigo; Ramadan, Nadire; Phadke, Tanushree; Haas, Kristy; Jaskelioff, Mariela; Wilson, Boris G.; Meyer, Matthew J.; Saenz-Vash, Veronica; Zhai, Huili; Myer, Vic E.; Porter, Jeffery A.; Keen, Nicholas; McLaughlin, Margaret E.; Mickanin, Craig; Roberts, Charles W. M.; Stegmeier, Frank; Jagani, Zainab

    2014-01-01

    Defects in epigenetic regulation play a fundamental role in the development of cancer, and epigenetic regulators have recently emerged as promising therapeutic candidates. We therefore set out to systematically interrogate epigenetic cancer dependencies by screening an epigenome-focused deep-coverage design shRNA (DECODER) library across 58 cancer cell lines. This screen identified BRM/SMARCA2, a DNA-dependent ATPase of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex, as being essential for the growth of tumor cells that harbor loss of function mutations in BRG1/SMARCA4. Depletion of BRM in BRG1-deficient cancer cells leads to a cell cycle arrest, induction of senescence, and increased levels of global H3K9me3. We further demonstrate the selective dependency of BRG1-mutant tumors on BRM in vivo. Genetic alterations of the mSWI/SNF chromatin remodeling complexes are the most frequent among chromatin regulators in cancers, with BRG1/SMARCA4 mutations occurring in ∼10–15% of lung adenocarcinomas. Our findings position BRM as an attractive therapeutic target for BRG1 mutated cancers. Because BRG1 and BRM function as mutually exclusive catalytic subunits of the mSWI/SNF complex, we propose that such synthetic lethality may be explained by paralog insufficiency, in which loss of one family member unveils critical dependence on paralogous subunits. This concept of “cancer-selective paralog dependency” may provide a more general strategy for targeting other tumor suppressor lesions/complexes with paralogous subunits. PMID:24520176

  20. C. elegans ten-1 is synthetic lethal with mutations in cytoskeleton regulators, and enhances many axon guidance defective mutants

    PubMed Central

    2010-01-01

    Background Teneurins are transmembrane proteins that assist morphogenetic processes in many organisms. ten-1 is the C. elegans teneurin homolog with two transcripts, ten-1a and ten-1b, that respectively encode a long (TEN-1L) and short (TEN-1S) form of the protein. We previously isolated a C. elegans mutant where one pharyngeal neuron was frequently misplaced, and now show that it corresponds to a novel allele of ten-1. Results The novel ten-1(et5) allele is a hypomorph since its post-embryonic phenotype is weaker than the null alleles ten-1(ok641) and ten-1(tm651). ten-1 mutants have defects in all pharyngeal neurons that we examined, and in vivo reporters show that only the long form of the ten-1 gene is expressed in the pharynx, specifically in six marginal cells and the M2 neurons. Defects in the pharyngeal M2 neurons were enhanced when the ten-1(ok641) mutation was combined with mutations in the following genes: mig-14, unc-5, unc-51, unc-52 and unc-129. None of the body neurons examined show any defects in the ten-1(ok641) mutant, but genetic interaction studies reveal that ten-1(ok641) is synthetic lethal with sax-3, unc-34 and unc-73, and examination of the hypodermal cells in embryos of the ten-1(ok641) mutant point to a role of ten-1 during hypodermal cell morphogenesis. Conclusions Our results are consistent with ten-1 normally providing a function complementary to the cytoskeletal remodeling processes that occur in migrating cells or cells undergoing morphogenesis. It is possible that ten-1 influences the composition/distribution of extracellular matrix. PMID:20497576

  1. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells.

    PubMed

    Kwok, Marwan; Davies, Nicholas; Agathanggelou, Angelo; Smith, Edward; Oldreive, Ceri; Petermann, Eva; Stewart, Grant; Brown, Jeff; Lau, Alan; Pratt, Guy; Parry, Helen; Taylor, Malcolm; Moss, Paul; Hillmen, Peter; Stankovic, Tatjana

    2016-02-01

    TP53 and ataxia telangiectasia mutated (ATM) defects are associated with genomic instability, clonal evolution, and chemoresistance in chronic lymphocytic leukemia (CLL). Currently, therapies capable of providing durable remissions in relapsed/refractory TP53- or ATM-defective CLL are lacking. Ataxia telangiectasia and Rad3-related (ATR) mediates response to replication stress, the absence of which leads to collapse of stalled replication forks into chromatid fragments that require resolution through the ATM/p53 pathway. Here, using AZD6738, a novel ATR kinase inhibitor, we investigated ATR inhibition as a synthetically lethal strategy to target CLL cells with TP53 or ATM defects. Irrespective of TP53 or ATM status, induction of CLL cell proliferation upregulated ATR protein, which then became activated in response to replication stress. In TP53- or ATM-defective CLL cells, inhibition of ATR signaling by AZD6738 led to an accumulation of unrepaired DNA damage, which was carried through into mitosis because of defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe. Consequently, AZD6738 was selectively cytotoxic to both TP53- and ATM-defective CLL cell lines and primary cells. This was confirmed in vivo using primary xenograft models of TP53- or ATM-defective CLL, where treatment with AZD6738 resulted in decreased tumor load and reduction in the proportion of CLL cells with such defects. Moreover, AZD6738 sensitized TP53- or ATM-defective primary CLL cells to chemotherapy and ibrutinib. Our findings suggest that ATR is a promising therapeutic target for TP53- or ATM-defective CLL that warrants clinical investigation. PMID:26563132

  2. miR-342 overexpression results in a synthetic lethal phenotype in BRCA1-mutant HCC1937 breast cancer cells

    PubMed Central

    Crippa, Elisabetta; Folini, Marco; Pennati, Marzia; Zaffaroni, Nadia; Pierotti, Marco A.; Gariboldi, Manuela

    2016-01-01

    Expression of miR-342 has been strongly correlated with estrogen receptor (ER) status in breast cancer, where it is highest in ER-positive and lowest in triple-negative tumors. We investigated the effects of miR-342 transfection in the triple-negative breast cancer cell lines MDA-MB-231 and HCC1937, the latter carrying a germ-line BRCA1 mutation. Reconstitution of miR-342 led to caspase-dependent induction of apoptosis only in HCC1937 cells, while overexpression of wild-type BRCA1 in HCC1937 cells counteracted miR-342-mediated induction of apoptosis, suggesting that miR-342 overexpression and the lack of functional BRCA1 result in a synthetic lethal phenotype. Moreover, siRNA-mediated depletion of BRCA1 in MDA-MB-231 cells expressing the wild-type protein led to apoptosis upon transfection with miR-342. Using an in silico approach and a luciferase reporter system, we identified and functionally validated the Baculoviral IAP repeat-containing 6 gene (BIRC6), which encodes the anti-apoptotic factor Apollon/BRUCE, as a target of miR-342. In our model, BIRC6 likely acts as a determinant of the miRNA-dependent induction of apoptosis in BRCA1-mutant HCC1937 cells. Together, our findings suggest a tumor-suppressive function of miR-342 that could be exploited in the treatment of a subset of BRCA1-mutant hereditary breast cancers. PMID:26919240

  3. Synthetic Lethal Therapy for KRAS Mutant Non-small-cell Lung Carcinoma with Nanoparticle-mediated CDK4 siRNA Delivery

    PubMed Central

    Mao, Cheng-Qiong; Xiong, Meng-Hua; Liu, Yang; Shen, Song; Du, Xiao-Jiao; Yang, Xian-Zhu; Dou, Shuang; Zhang, Pei-Zhuo; Wang, Jun

    2014-01-01

    The KRAS mutation is present in ~20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in non-small-cell lung carcinomas (NSCLCs) and confers resistance to standard anticancer treatment drugs, including epidermal growth factor receptor tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between cyclin-dependent kinase 4 (CDK4) downregulation and the KRAS mutation to deliver micellar nanoparticles (MNPs) containing small interfering RNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLCs harboring the oncogenic KRAS mutation. Following MNPsiCDK4 administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLCs. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4 significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLCs via a synthetic lethal interaction between KRAS and CDK4. PMID:24496383

  4. Synthetic aperture interferometry: error analysis

    SciTech Connect

    Biswas, Amiya; Coupland, Jeremy

    2010-07-10

    Synthetic aperture interferometry (SAI) is a novel way of testing aspherics and has a potential for in-process measurement of aspherics [Appl. Opt.42, 701 (2003)].APOPAI0003-693510.1364/AO.42.000701 A method to measure steep aspherics using the SAI technique has been previously reported [Appl. Opt.47, 1705 (2008)].APOPAI0003-693510.1364/AO.47.001705 Here we investigate the computation of surface form using the SAI technique in different configurations and discuss the computational errors. A two-pass measurement strategy is proposed to reduce the computational errors, and a detailed investigation is carried out to determine the effect of alignment errors on the measurement process.

  5. Chitin synthase III: Synthetic lethal mutants and “stress related” chitin synthesis that bypasses the CSD3/CHS6 localization pathway

    PubMed Central

    Osmond, Barbara C.; Specht, Charles A.; Robbins, Phillips W.

    1999-01-01

    We screened Saccharomyces strains for mutants that are synthetically lethal with deletion of the major chitin synthase gene CHS3. In addition to finding, not surprisingly, that mutations in major cell wall-related genes such as FKS1 (glucan synthase) and mutations in any of the Golgi glycosylation complex genes (MNN9 family) are lethal in combination with chs3Δ, we found that a mutation in Srv2p, a bifunctional regulatory gene, is notably lethal in the chs3 deletion. In extending studies of fks1-chitin synthase 3 interactions, we made the surprising discovery that deletion of CSD3/CHS6, a gene normally required for Chs3p delivery and activity in vivo, was not lethal with fks1 and, in fact, that lack of Csd3p/Chs6p did not decrease the high level of stress-related chitin made in the fks1 mutant. This finding suggests that “stress response” chitin synthesis proceeds through an alternate Chs3p targeting pathway. PMID:10500155

  6. Hyper-active non-homologous end joining selects for synthetic lethality resistant and pathological Fanconi anemia hematopoietic stem and progenitor cells.

    PubMed

    Du, Wei; Amarachintha, Surya; Wilson, Andrew F; Pang, Qishen

    2016-01-01

    The prominent role of Fanconi anemia (FA) proteins involves homologous recombination (HR) repair. Poly[ADP-ribose] polymerase1 (PARP1) functions in multiple cellular processes including DNA repair and PARP inhibition is an emerging targeted therapy for cancer patients deficient in HR. Here we show that PARP1 activation in hematopoietic stem and progenitor cells (HSPCs) in response to genotoxic or oxidative stress attenuates HSPC exhaustion. Mechanistically, PARP1 controls the balance between HR and non-homologous end joining (NHEJ) in double strand break (DSB) repair by preventing excessive NHEJ. Disruption of the FA core complex skews PARP1 function in DSB repair and led to hyper-active NHEJ in Fanca(-/-) or Fancc(-/-) HSPCs. Re-expression of PARP1 rescues the hyper-active NHEJ phenotype in Brca1(-/-)Parp1(-/-) but less effective in Fanca(-/-)Parp1(-/-) cells. Inhibition of NHEJ prevents myeloid/erythroid pathologies associated with synthetic lethality. Our results suggest that hyper-active NHEJ may select for "synthetic lethality" resistant and pathological HSPCs. PMID:26916217

  7. An arf1Delta synthetic lethal screen identifies a new clathrin heavy chain conditional allele that perturbs vacuolar protein transport in Saccharomyces cerevisiae.

    PubMed Central

    Chen, C Y; Graham, T R

    1998-01-01

    ADP-ribosylation factor (ARF) is a small GTP-binding protein that is thought to regulate the assembly of coat proteins on transport vesicles. To identify factors that functionally interact with ARF, we have performed a genetic screen in Saccharomyces cerevisiae for mutations that exhibit synthetic lethality with an arf1Delta allele and defined seven genes by complementation tests (SWA1-7 for synthetically lethal with arf1Delta). Most of the swa mutants exhibit phenotypes comparable to arf1Delta mutants such as temperature-conditional growth, hypersensitivity to fluoride ions, and partial protein transport and glycosylation defects. Here, we report that swa5-1 is a new temperature-sensitive allele of the clathrin heavy chain gene (chc1-5), which carries a frameshift mutation near the 3' end of the CHC1 open reading frame. This genetic interaction between arf1 and chc1 provides in vivo evidence for a role for ARF in clathrin coat assembly. Surprisingly, strains harboring chc1-5 exhibited a significant defect in transport of carboxypeptidase Y or carboxypeptidase S to the vacuole that was not observed in other chc1 ts mutants. The kinetics of invertase secretion or transport of alkaline phosphatase to the vacuole were not significantly affected in the chc1-5 mutant, further implicating clathrin specifically in the Golgi to vacuole transport pathway for carboxypeptidase Y. PMID:9755191

  8. Differences in Expression of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Dictate Synthetic Lethality with PARP1 Inhibition.

    PubMed

    Wiegmans, Adrian P; Yap, Pei-Yi; Ward, Ambber; Lim, Yi Chieh; Khanna, Kum Kum

    2015-10-01

    The triple-negative breast cancer (TNBC) subtype represents a cancer that is highly aggressive with poor patient outcome. Current preclinical success has been gained through synthetic lethality, targeting genome instability with PARP inhibition in breast cancer cells that harbor silencing of the homologous recombination (HR) pathway. Histone deacetylase inhibitors (HDACi) are a class of drugs that mediate epigenetic changes in expression of HR pathway genes. Here, we compare the activity of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), the class I/IIa HDAC inhibitor valproic acid (VPA), and the HDAC1/2-specific inhibitor romidepsin (ROMI) for their capability to regulate DNA damage repair gene expression and in sensitizing TNBC to PARPi. We found that two of the HDACis tested, SAHA and ROMI, but not VPA, indeed inhibit HR repair and that RAD51, BARD1, and FANCD2 represent key proteins whose inhibition is required for HDACi-mediated therapy with PARP inhibition in TNBC. We also observed that restoration of BRCA1 function stabilizes the genome compared with mutant BRCA1 that results in enhanced polyploid population after combination treatment with HDACi and PARPi. Furthermore, we found that overexpression of the key HR protein RAD51 represents a mechanism for this resistance, promoting aberrant repair and the enhanced polyploidy observed. These findings highlight the key components of HR in guiding synthetic lethality with PARP inhibition and support the rationale for utilizing the novel combination of HDACi and PARPi against TNBC in the clinical setting. PMID:26294743

  9. Non-lethal sampling of walleye for stable isotope analysis: a comparison of three tissues

    USGS Publications Warehouse

    Chipps, Steven R.; VanDeHey, J.A.; Fincel, M.J.

    2012-01-01

    Stable isotope analysis of fishes is often performed using muscle or organ tissues that require sacrificing animals. Non-lethal sampling provides an alternative for evaluating isotopic composition for species of concern or individuals of exceptional value. Stable isotope values of white muscle (lethal) were compared with those from fins and scales (non-lethal) in walleye, Sander vitreus (Mitchill), from multiple systems, size classes and across a range of isotopic values. Isotopic variability was also compared among populations to determine the potential of non-lethal tissues for diet-variability analyses. Muscle-derived isotope values were enriched compared with fins and depleted relative to scales. A split-sample validation technique and linear regression found that isotopic composition of walleye fins and scales was significantly related to that in muscle tissue for both δ13C and δ15N (r2 = 0.79–0.93). However, isotopic variability was significantly different between tissue types in two of six populations for δ15N and three of six populations for δ13C. Although species and population specific, these findings indicate that isotopic measures obtained from non-lethal tissues are indicative of those obtained from muscle.

  10. Model-driven discovery of synergistic inhibitors against E. coli and S. enterica serovar Typhimurium targeting a novel synthetic lethal pair, aldA and prpC

    PubMed Central

    Aziz, Ramy K.; Khaw, Valerie L.; Monk, Jonathan M.; Brunk, Elizabeth; Lewis, Robert; Loh, Suh I.; Mishra, Arti; Nagle, Amrita A.; Satyanarayana, Chitkala; Dhakshinamoorthy, Saravanakumar; Luche, Michele; Kitchen, Douglas B.; Andrews, Kathleen A.; Palsson, Bernhard Ø.; Charusanti, Pep

    2015-01-01

    Mathematical models of biochemical networks form a cornerstone of bacterial systems biology. Inconsistencies between simulation output and experimental data point to gaps in knowledge about the fundamental biology of the organism. One such inconsistency centers on the gene aldA in Escherichia coli: it is essential in a computational model of E. coli metabolism, but experimentally it is not. Here, we reconcile this disparity by providing evidence that aldA and prpC form a synthetic lethal pair, as the double knockout could only be created through complementation with a plasmid-borne copy of aldA. Moreover, virtual and biological screening against the two proteins led to a set of compounds that inhibited the growth of E. coli and Salmonella enterica serovar Typhimurium synergistically at 100–200 μM individual concentrations. These results highlight the power of metabolic models to drive basic biological discovery and their potential use to discover new combination antibiotics. PMID:26441892

  11. Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity

    PubMed Central

    Bajrami, Ilirjana; Frankum, Jessica R.; Konde, Asha; Miller, Rowan E.; Rehman, Farah L.; Brough, Rachel; Campbell, James; Sims, David; Rafiq, Rumana; Hooper, Sean; Chen, Lina; Kozarewa, Iwanka; Assiotis, Ioannis; Fenwick, Kerry; Natrajan, Rachael; Lord, Christopher J.; Ashworth, Alan

    2016-01-01

    Small molecule inhibitors of PARP1/2 such as olaparib have been proposed to serve as a synthetic lethal therapy for cancers that harbor BRCA1 or BRCA2 mutations. Indeed, in clinical trials PARP1/2 inhibitors elicit sustained anti-tumor responses in patients with germ-line BRCA gene mutations. In hypothesizing that additional genetic determinants might direct use of these drugs, we conducted a genome-wide synthetic lethal screen for candidate olaparib sensitivity genes. In support of this hypothesis, the set of identified genes included known determinants of olaparib sensitivity, such as BRCA1, RAD51 and Fanconi’s anemia susceptibility genes. Additionally, the set included genes implicated in established networks of DNA repair, DNA cohesion and chromatin remodelling, none of which were known previously to confer sensitivity to PARP1/2 inhibition. Notably, integration of the list of candidate sensitivity genes with data from tumor DNA sequencing studies identified CDK12 deficiency as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity. In models of high-grade serous ovarian cancer (HGS-OVCa), CDK12 attenuation was sufficient to confer sensitivity to PARP1/2 inhibition, suppression of DNA repair via homologous recombination and reduced expression of BRCA1. As one of only nine genes known to be mutated in HGS-OVCa, CDK12 has properties that should confirm interest in its utility as a biomarker, particularly in ongoing clinical trials of PARP1/2 inhibitors and other agents that trigger replication fork arrest. PMID:24240700

  12. Dual inhibition of EGFR and MET induces synthetic lethality in triple-negative breast cancer cells through downregulation of ribosomal protein S6

    PubMed Central

    YI, YONG WEON; YOU, KYUSIC; BAE, EDWARD JEONG; KWAK, SAHNG-JUNE; SEONG, YEON-SUN; BAE, INSOO

    2015-01-01

    Triple-negative breast cancer (TNBC) exhibits innate resistance to the EGFR inhibition despite high level expression of EGFR. Recently, we found that the proliferation of basal-like (BL) subtype TNBC cells is synergistically inhibited by combination of EGFR and PI3K/AKT inhibitors. On the contrary, TNBC cells of mesenchymal stem-like (MSL) subtype are resistant to these combinations. To identify potential synthetic lethal interaction of compounds for treatment of MSL subtype TNBC cells, we performed MTT screening of MDA-MB-231 cells with a small library of receptor tyrosine kinase inhibitors (RTKIs) in the presence of gefitinib, an EGFR inhibitor. We identified MET inhibitors as potent RTKIs that caused synthetic lethality in combination with gefitinib in MDA-MB-231 cells. We demonstrated that combination of a MET inhibitor SU11274 with various EGFR inhibitors resulted in synergistic suppression of cell viability (in MTT assay) and cell survival (in colony formation assay) of MSL subtype TNBC cells. We further demonstrated that SU11274 alone induced G2 arrest and gefitinib/SU11274 combination sustained the SU11274-induced G2 arrest in these cells. In addition, SU11274/gefitinib combination synergistically reduced the level of ribosomal protein S6 (RPS6) in MSL subtype TNBC cells. In addition, knockdown of RPS6 itself, in both HS578T and MDA-MB-231, markedly reduced the proliferation of these cells. Taken together, our data suggest that dual targeting of EGFR and MET inhibits the proliferation of MSL subtype TNBC cells through down-regulation of RPS6. PMID:25955731

  13. Dual inhibition of EGFR and MET induces synthetic lethality in triple-negative breast cancer cells through downregulation of ribosomal protein S6.

    PubMed

    Yi, Yong Weon; You, Kyusic; Bae, Edward Jeong; Kwak, Sahng-June; Seong, Yeon-Sun; Bae, Insoo

    2015-07-01

    Triple-negative breast cancer (TNBC) exhibits innate resistance to the EGFR inhibition despite high level expression of EGFR. Recently, we found that the proliferation of basal-like (BL) subtype TNBC cells is synergistically inhibited by combination of EGFR and PI3K/AKT inhibitors. On the contrary, TNBC cells of mesenchymal stem-like (MSL) subtype are resistant to these combinations. To identify potential synthetic lethal interaction of compounds for treatment of MSL subtype TNBC cells, we performed MTT screening of MDA-MB‑231 cells with a small library of receptor tyrosine kinase inhibitors (RTKIs) in the presence of gefitinib, an EGFR inhibitor. We identified MET inhibitors as potent RTKIs that caused synthetic lethality in combination with gefitinib in MDA-MB‑231 cells. We demonstrated that combination of a MET inhibitor SU11274 with various EGFR inhibitors resulted in synergistic suppression of cell viability (in MTT assay) and cell survival (in colony formation assay) of MSL subtype TNBC cells. We further demonstrated that SU11274 alone induced G2 arrest and gefitinib/SU11274 combination sustained the SU11274-induced G2 arrest in these cells. In addition, SU11274/gefitinib combination synergistically reduced the level of ribosomal protein S6 (RPS6) in MSL subtype TNBC cells. In addition, knockdown of RPS6 itself, in both HS578T and MDA-MB‑231, markedly reduced the proliferation of these cells. Taken together, our data suggest that dual targeting of EGFR and MET inhibits the proliferation of MSL subtype TNBC cells through downregulation of RPS6. PMID:25955731

  14. Synthetic Lethality Screen Identifies RPS6KA2 as Modifier of Epidermal Growth Factor Receptor Activity in Pancreatic Cancer12

    PubMed Central

    Milosevic, Nada; Kühnemuth, Benjamin; Mühlberg, Leonie; Ripka, Stefanie; Griesmann, Heidi; Lölkes, Carolin; Buchholz, Malte; Aust, Daniela; Pilarsky, Christian; Krug, Sebastian; Gress, Thomas; Michl, Patrick

    2013-01-01

    Pancreatic cancer is characterized by a high degree of resistance to chemotherapy. Epidermal growth factor receptor (EGFR) inhibition using the small-molecule inhibitor erlotinib was shown to provide a small survival benefit in a subgroup of patients. To identify kinases whose inhibition acts synergistically with erlotinib, we employed a kinome-wide small-interfering RNA (siRNA)-based loss-of-function screen in the presence of erlotinib. Of 779 tested kinases, we identified several targets whose inhibition acted synergistically lethal with EGFR inhibition by erlotinib, among them the S6 kinase ribosomal protein S6 kinase 2 (RPS6KA2)/ribosomal S6 kinase 3. Activated RPS6KA2 was expressed in approximately 40% of 123 human pancreatic cancer tissues. RPS6KA2 was shown to act downstream of EGFR/RAS/mitogen-activated protein kinase kinase (MEK)/extracellular-signal regulated kinase (ERK) signaling and was activated by EGF independently of the presence of KRAS mutations. Knockdown of RPS6KA2 by siRNA led to increased apoptosis only in the presence of erlotinib, whereas RPS6KA2 activation or overexpression rescued from erlotinib- and gemcitabine-induced apoptosis. This effect was at least in part mediated by downstream activation of ribosomal protein S6. Genetic as well as pharmacological inhibition of RPS6KA2 by the inhibitor BI-D1870 acted synergistically with erlotinib. By applying this synergistic lethality screen using a kinome-wide RNA interference-library approach, we identified RPS6KA2 as potential drug target whose inhibition synergistically enhanced the effect of erlotinib on tumor cell survival. This kinase therefore represents a promising drug candidate suitable for the development of novel inhibitors for pancreatic cancer therapy. PMID:24403857

  15. A Synthetic Vision Preliminary Integrated Safety Analysis

    NASA Technical Reports Server (NTRS)

    Hemm, Robert; Houser, Scott

    2001-01-01

    This report documents efforts to analyze a sample of aviation safety programs, using the LMI-developed integrated safety analysis tool to determine the change in system risk resulting from Aviation Safety Program (AvSP) technology implementation. Specifically, we have worked to modify existing system safety tools to address the safety impact of synthetic vision (SV) technology. Safety metrics include reliability, availability, and resultant hazard. This analysis of SV technology is intended to be part of a larger effort to develop a model that is capable of "providing further support to the product design and development team as additional information becomes available". The reliability analysis portion of the effort is complete and is fully documented in this report. The simulation analysis is still underway; it will be documented in a subsequent report. The specific goal of this effort is to apply the integrated safety analysis to SV technology. This report also contains a brief discussion of data necessary to expand the human performance capability of the model, as well as a discussion of human behavior and its implications for system risk assessment in this modeling environment.

  16. Hyper-active non-homologous end joining selects for synthetic lethality resistant and pathological Fanconi anemia hematopoietic stem and progenitor cells

    PubMed Central

    Du, Wei; Amarachintha, Surya; Wilson, Andrew F.; Pang, Qishen

    2016-01-01

    The prominent role of Fanconi anemia (FA) proteins involves homologous recombination (HR) repair. Poly[ADP-ribose] polymerase1 (PARP1) functions in multiple cellular processes including DNA repair and PARP inhibition is an emerging targeted therapy for cancer patients deficient in HR. Here we show that PARP1 activation in hematopoietic stem and progenitor cells (HSPCs) in response to genotoxic or oxidative stress attenuates HSPC exhaustion. Mechanistically, PARP1 controls the balance between HR and non-homologous end joining (NHEJ) in double strand break (DSB) repair by preventing excessive NHEJ. Disruption of the FA core complex skews PARP1 function in DSB repair and led to hyper-active NHEJ in Fanca−/− or Fancc−/− HSPCs. Re-expression of PARP1 rescues the hyper-active NHEJ phenotype in Brca1−/−Parp1−/− but less effective in Fanca−/−Parp1−/− cells. Inhibition of NHEJ prevents myeloid/erythroid pathologies associated with synthetic lethality. Our results suggest that hyper-active NHEJ may select for “synthetic lethality” resistant and pathological HSPCs. PMID:26916217

  17. Novel synthetic plasmid and Doggybone™ DNA vaccines induce neutralizing antibodies and provide protection from lethal influenza challenge in mice

    PubMed Central

    Scott, Veronica L; Patel, Ami; Villarreal, Daniel O; Hensley, Scott E; Ragwan, Edwin; Yan, Jian; Sardesai, Niranjan Y; Rothwell, Paul J; Extance, Jonathan P; Caproni, Lisa J; Weiner, David B

    2015-01-01

    Nucleic acid-based vaccines (NAVs) are a promising alternative to conventional influenza vaccines with the potential to increase influenza vaccine availability due to their simplicity in design and rapid speed of production. NAVs can also target multiple influenza antigens and control flu variants. Traditionally NAVs have been DNA plasmids however, we are continuing to explore new methods that may enhance vaccine efficacy. Recently new focus has been on RNA cassettes as NAVs. RNA vaccines combine conceptual advantages in that they focus on delivery of only the coding cassette. However, RNA vaccines have a short half-life and cause interferon-induced fevers. Here we describe a new NAV approach where we study delivery of a linear DNA cassette [Doggybone™ linear closed DNA [(dbDNA™)] produced by an enzymatic process that yields an antigen expression cassette comprising a promoter, DNA antigen, poly A tail, and telomeric ends. This focused approach has many of the advantages of plasmid DNA as well as a minimal cassette size similar to RNA strategies. For this study, we characterized the specific CD4+ and CD8+ T cell responses and determined the hemagglutination inhibition (HI) titers induced by dbDNA™ and compared the responses with those of an optimized plasmid DNA (pDNA) vaccine encoding the same H1N1 influenza A/PR/8/34 HA gene. Immunizations with the constructs resulted in similar humoral and cellular immune responses. Both constructs induced high-titer HI antibodies and fully protected animals from lethal viral challenge. The data obtained from this study provides important validation for further development of novel vector approaches. PMID:26091432

  18. Combined STAT3 and BCR-ABL1 Inhibition Induces Synthetic Lethality in Therapy-Resistant Chronic Myeloid Leukemia

    PubMed Central

    Mason, Clinton C.; Vellore, Nadeem A.; Resetca, Diana; Zabriskie, Matthew S.; Zhang, Tian Y.; Khorashad, Jamshid S.; Engar, Alexander J.; Reynolds, Kimberly R.; Anderson, David J.; Senina, Anna; Pomicter, Anthony D.; Arpin, Carolynn C.; Ahmad, Shazia; Heaton, William L.; Tantravahi, Srinivas K.; Todic, Aleksandra; Moriggl, Richard; Wilson, Derek J.; Baron, Riccardo

    2014-01-01

    Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCRABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays, and hydrogen-deuterium exchange assays establish direct engagement of STAT3 by BP-5-087 and provide a high-resolution view of the STAT3 SH2 domain/BP-5-087 interface. In primary cells from CML patients with BCR-ABL1 kinase-independent TKI resistance, BP-5-087 (1.0 μM) restored TKI sensitivity to therapy-resistant CML progenitor cells, including leukemic stem cells (LSCs). Our findings implicate STAT3 as a critical signaling node in BCR-ABL1 kinase-independent TKI resistance, and suggest that BP-5-087 has clinical utility for treating malignancies characterized by STAT3 activation. PMID:25134459

  19. Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia.

    PubMed

    Eiring, A M; Page, B D G; Kraft, I L; Mason, C C; Vellore, N A; Resetca, D; Zabriskie, M S; Zhang, T Y; Khorashad, J S; Engar, A J; Reynolds, K R; Anderson, D J; Senina, A; Pomicter, A D; Arpin, C C; Ahmad, S; Heaton, W L; Tantravahi, S K; Todic, A; Colaguori, R; Moriggl, R; Wilson, D J; Baron, R; O'Hare, T; Gunning, P T; Deininger, M W

    2015-03-01

    Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCR-ABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays and hydrogen-deuterium exchange assays establish direct engagement of STAT3 by BP-5-087 and provide a high-resolution view of the STAT3 SH2 domain/BP-5-087 interface. In primary cells from chronic myeloid leukemia (CML) patients with BCR-ABL1 kinase-independent TKI resistance, BP-5-087 (1.0 μM) restored TKI sensitivity to therapy-resistant CML progenitor cells, including leukemic stem cells. Our findings implicate STAT3 as a critical signaling node in BCR-ABL1 kinase-independent TKI resistance, and suggest that BP-5-087 has clinical utility for treating malignancies characterized by STAT3 activation. PMID:25134459

  20. Identification of unique sensitizing targets for anti-inflammatory CDDO-Me in metastatic melanoma by a large-scale synthetic lethal RNAi screening

    PubMed Central

    Ekmekcioglu, Suhendan; Grimm, Elizabeth A.

    2013-01-01

    Summary CDDO-Me has been shown to exert potent anti-inflammatory activity for chronic kidney disease and antitumor activity for several tumors, including melanoma, in early clinical trials. To improve CDDO-Me response in melanoma, we utilized a large-scale synthetic lethal RNAi screen targeting 6,000 human druggable genes to identify targets that would sensitize melanoma cells to CDDO-Me. Based on screening results, five unique genes (GNPAT, SUMO1, SPINT2, FLI1, and SSX1) significantly potentiated the growth-inhibitory effects of CDDO-Me and induced apoptosis in A375, a BRAF mutated melanoma line (P<0.001). These five genes were then individually validated as targets to potentiate CDDO-Me activity, and related downstream signaling pathways of these genes were analyzed. In addition, the levels of phosphorylated Erk1/2, Akt, GSK-2, and PRAS40 were dramatically decreased by downregulating each of these five genes separately, suggesting a set of common mediators. Our findings indicate that GNPAT, SUMO1, SPINT2, FLI1, and SSX1 play critical roles in synergy with inflammation pathways in modulating melanoma cell survival, and could serve as sensitizing targets to enhance CDDO-Me efficacy in melanoma growth control. PMID:23020131

  1. A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers

    PubMed Central

    Yamaguchi, Kosuke; Iglesias-Bartolomé, Ramiro; Wang, Zhiyong; Callejas-Valera, Juan Luis; Amornphimoltham, Panomwat; Molinolo, Alfredo A.; Cohen, Ezra E.; Califano, Joseph A.; Lippman, Scott M.; Luo, Ji; Gutkind, J. Silvio

    2016-01-01

    mTOR inhibition has emerged as a promising strategy for head and neck squamous cell carcinomas (HNSCC) treatment. However, most targeted therapies ultimately develop resistance due to the activation of adaptive survival signaling mechanisms limiting the activity of targeted agents. Thus, co-targeting key adaptive mechanisms may enable more effective cancer cell killing. Here, we performed a synthetic lethality screen using shRNA libraries to identify druggable candidates for combinatorial signal inhibition. We found that the ERK pathway was the most highly represented. Combination of rapamycin with trametinib, a MEK1/2 inhibitor, demonstrated strong synergism in HNSCC-derived cells in vitro and in vivo, including HNSCC cells expressing the HRAS and PIK3CA oncogenes. Interestingly, cleaved caspase-3 was potently induced by the combination therapy in PIK3CA+ cells in vitro and tumor xenografts. Moreover, ectopic expression of PIK3CA mutations into PIK3CA− HNSCC cells sensitized them to the pro-apoptotic activity of the combination therapy. These findings indicate that co-targeting the mTOR/ERK pathways may provide a suitable precision strategy for HNSCC treatment. Moreover, PIK3CA+ HNSCC are particularly prone to undergo apoptosis after mTOR and ERK inhibition, thereby providing a potential biomarker of predictive value for the selection of patients that may benefit from this combination therapy. PMID:26882569

  2. Loss of ypk1 function causes rapamycin sensitivity, inhibition of translation initiation and synthetic lethality in 14-3-3-deficient yeast.

    PubMed Central

    Gelperin, Daniel; Horton, Lynn; DeChant, Anne; Hensold, Jack; Lemmon, Sandra K

    2002-01-01

    14-3-3 proteins bind to phosphorylated proteins and regulate a variety of cellular activities as effectors of serine/threonine phosphorylation. To define processes requiring 14-3-3 function in yeast, mutants with increased sensitivity to reduced 14-3-3 protein levels were identified by synthetic lethal screening. One mutation was found to be allelic to YPK1, which encodes a Ser/Thr protein kinase. Loss of Ypk function causes hypersensitivity to rapamycin, similar to 14-3-3 mutations and other mutations affecting the TOR signaling pathway in yeast. Similar to treatment with rapamycin, loss of Ypk function disrupted translation, at least in part by causing depletion of eIF4G, a central adaptor protein required for cap-dependent mRNA translation initiation. In addition, Ypk1 as well as eIF4G protein levels were rapidly depleted upon nitrogen starvation, but not during glucose starvation, even though both conditions inhibit translation initiation. These results suggest that Ypk regulates translation initiation in response to nutrient signals, either through the TOR pathway or in a functionally related pathway parallel to TOR. PMID:12196392

  3. microRNA-206 impairs c-Myc-driven cancer in a synthetic lethal manner by directly inhibiting MAP3K13

    PubMed Central

    Han, Han; Chen, Yuxing; Cheng, Li; Prochownik, Edward V.; Li, Youjun

    2016-01-01

    c-Myc (Myc) is one of the most frequently dysregulated oncogenic transcription factors in human cancer. By functionally screening a microRNA (miR) library, we identified miR-206 as being a synthetic lethal in Myc over-expressing human cancer cells. miR-206 inhibited MAP3K13, which resulted in Myc protein de-stabilization, and an inhibition of anchorage-independent growth and in vivo tumorigenesis by Myc over-expressing human cancer cells. Eliminating MAP3K13 by shRNA recapitulated the effects caused by miR-206, thus supporting the idea that miR-206's effect on Myc was mediated through MAP3K13. Conversely, enforced expression of MAP3K13 stabilized Myc by promoting its N-terminal phosphorylation and enhancing its transcriptional activity. Gene expression analyses of breast cancers expressing high levels of Myc indicated that low miR-206 expression and high MAP3K13 expression correlated with poor patient survival. The critical link between miR-206 and MAP3K13 in the development of Myc over-expressing human cancers suggests potential points of therapeutic intervention for this molecular sub-category. PMID:26918941

  4. A Synthetic Lethal Interaction between Glutathione Synthesis and Mitochondrial Reactive Oxygen Species Provides a Tumor-Specific Vulnerability Dependent on STAT3

    PubMed Central

    Garama, Daniel J.; Harris, Tiffany J.; White, Christine L.; Rossello, Fernando J.; Abdul-Hay, Maher

    2015-01-01

    Increased production of mitochondrion-derived reactive oxygen species (ROS) is characteristic of a metabolic shift observed during malignant transformation. While the exact sources and roles of ROS in tumorigenesis remain to be defined, it has become clear that maintaining redox balance is critical for cancer cell proliferation and survival and, as such, may represent a vulnerability that can be exploited therapeutically. STAT3, a latent cytosolic transcription factor activated by diverse cytokines and growth factors, has been shown to exhibit an additional, nontranscriptional function in mitochondria, including modulation of electron transport chain activity. In particular, malignant transformation by Ras oncogenes exploits mitochondrial STAT3 functions. We used mass spectrometry-based metabolomics profiling to explore the biochemical basis for the STAT3 dependence of Ras transformation. We identified the gamma-glutamyl cycle, the production of glutathione, and the regulation of ROS as a mitochondrion-STAT3-dependent pathway in Ras-transformed cells. Experimental inhibition of key enzymes in the glutathione cycle resulted in the depletion of glutathione, accumulation of ROS, oxidative DNA damage, and cell death in an oncogenic Ras- and mitochondrial STAT3-dependent manner. These data uncover a synthetic lethal interaction involving glutathione production and mitochondrial ROS regulation in Ras-transformed cells that is governed by mitochondrial STAT3 and might be exploited therapeutically. PMID:26283727

  5. Computational Modeling And Analysis Of Synthetic Jets

    NASA Technical Reports Server (NTRS)

    Mittal, Rajat; Cattafesta, Lou

    2005-01-01

    In the last report we focused on the study of 3D synthetic jets of moderate jet aspect-ratio. Jets in quiescent and cross-flow cases were investigated. Since most of the synthetic jets in practical applications are found to be of large aspect ratio, the focus was shifted to studying synthetic jets of large aspect ratio. In the current year, further progress has been made by studying jets of aspect ratio 8 and infinity. Some other aspects of the jet, like the vorticity flux is looked into apart from analyzing the vortex dynamics, velocity profiles and the other dynamical characteristics of the jet which allows us to extract some insight into the effect of these modifications on the jet performance. Also, efforts were made to qualitatively validate the simulated results with the NASA Langley test cases at higher jet Reynolds number for the quiescent jet case.

  6. Evidence that synthetic lethality underlies the mutual exclusivity of oncogenic KRAS and EGFR mutations in lung adenocarcinoma

    PubMed Central

    Unni, Arun M; Lockwood, William W; Zejnullahu, Kreshnik; Lee-Lin, Shih-Queen; Varmus, Harold

    2015-01-01

    Human lung adenocarcinomas (LUAD) contain mutations in EGFR in ∼15% of cases and in KRAS in ∼30%, yet no individual adenocarcinoma appears to carry activating mutations in both genes, a finding we have confirmed by re-analysis of data from over 600 LUAD. Here we provide evidence that co-occurrence of mutations in these two genes is deleterious. In transgenic mice programmed to express both mutant oncogenes in the lung epithelium, the resulting tumors express only one oncogene. We also show that forced expression of a second oncogene in human cancer cell lines with an endogenous mutated oncogene is deleterious. The most prominent features accompanying loss of cell viability were vacuolization, other changes in cell morphology, and increased macropinocytosis. Activation of ERK, p38 and JNK in the dying cells suggests that an overly active MAPK signaling pathway may mediate the phenotype. Together, our findings indicate that mutual exclusivity of oncogenic mutations may reveal unexpected vulnerabilities and therapeutic possibilities. DOI: http://dx.doi.org/10.7554/eLife.06907.001 PMID:26047463

  7. A Synthetic Lethality Screen Using a Focused siRNA Library to Identify Sensitizers to Dasatinib Therapy for the Treatment of Epithelial Ovarian Cancer

    PubMed Central

    Pathak, Harsh B.; Zhou, Yan; Sethi, Geetika; Hirst, Jeff; Schilder, Russell J.; Golemis, Erica A.; Godwin, Andrew K.

    2015-01-01

    Molecular targeted therapies have been the focus of recent clinical trials for the treatment of patients with recurrent epithelial ovarian cancer (EOC). The majority have not fared well as monotherapies for improving survival of these patients. Poor bioavailability, lack of predictive biomarkers, and the presence of multiple survival pathways can all diminish the success of a targeted agent. Dasatinib is a tyrosine kinase inhibitor of the Src-family kinases (SFK) and in preclinical studies shown to have substantial activity in EOC. However, when evaluated in a phase 2 clinical trial for patients with recurrent or persistent EOC, it was found to have minimal activity. We hypothesized that synthetic lethality screens performed using a cogently designed siRNA library would identify second-site molecular targets that could synergize with SFK inhibition and improve dasatinib efficacy. Using a systematic approach, we performed primary siRNA screening using a library focused on 638 genes corresponding to a network centered on EGFR, HER2, and the SFK-scaffolding proteins BCAR1, NEDD9, and EFS to screen EOC cells in combination with dasatinib. We followed up with validation studies including deconvolution screening, quantitative PCR to confirm effective gene silencing, correlation of gene expression with dasatinib sensitivity, and assessment of the clinical relevance of hits using TCGA ovarian cancer data. A refined list of five candidates (CSNK2A1, DAG1, GRB2, PRKCE, and VAV1) was identified as showing the greatest potential for improving sensitivity to dasatinib in EOC. Of these, CSNK2A1, which codes for the catalytic alpha subunit of protein kinase CK2, was selected for additional evaluation. Synergistic activity of the clinically relevant inhibitor of CK2, CX-4945, with dasatinib in reducing cell proliferation and increasing apoptosis was observed across multiple EOC cell lines. This overall approach to improving drug efficacy can be applied to other targeted agents

  8. Enhanced non-homologous end joining contributes toward synthetic lethality of pathological RAD51C mutants with poly (ADP-ribose) polymerase.

    PubMed

    Somyajit, Kumar; Mishra, Anup; Jameei, Aida; Nagaraju, Ganesh

    2015-01-01

    Poly (ADP-ribose) polymerase 1 (PARP1) inhibitors are actively under clinical trials for the treatment of breast and ovarian cancers that arise due to mutations in BRCA1 and BRCA2. The RAD51 paralog RAD51C has been identified as a breast and ovarian cancer susceptibility gene. The pathological RAD51C mutants that were identified in cancer patients are hypomorphic with partial repair function. However, targeting cancer cells that express hypomorphic mutants of RAD51C is highly challenging. Here, we report that RAD51C-deficient cells can be targeted by a 'synthetic lethal' approach using PARP inhibitor and this sensitivity was attributed to accumulation of cells in the G2/M and chromosomal aberrations. In addition, spontaneous hyperactivation of PARP1 was evident in RAD51C-deficient cells. Interestingly, RAD51C-negative cells exhibited enhanced recruitment of non-homologous end joining (NHEJ) proteins onto chromatin and this accumulation correlated with increased activity of error-prone NHEJ as well as genome instability leading to cell death. Notably, inhibition of DNA-PKcs or depletion of KU70 or Ligase IV rescued this phenotype. Strikingly, stimulation of NHEJ by low dose of ionizing radiation (IR) in the PARP inhibitor-treated RAD51C-deficient cells and cells expressing pathological RAD51C mutants induced enhanced toxicity 'synergistically'. These results demonstrate that cancer cells arising due to hypomorphic mutations in RAD51C can be specifically targeted by a 'synergistic approach' and imply that this strategy can be potentially applied to cancers with hypomorphic mutations in other homologous recombination pathway genes. PMID:25292178

  9. A multifactorial analysis of factors related to lethality after treatment of perforated gastroduodenal ulcer. 1935-1985.

    PubMed Central

    Svanes, C; Salvesen, H; Espehaug, B; Søreide, O; Svanes, K

    1989-01-01

    One thousand one hundred and twenty-eight patients treated for perforated gastroduodenal ulcer during the years 1935-1985 were studied at the Haukeland University Hospital. The majority of patients (97.7%) were treated surgically. The data was analyzed by contingency tables and chi square testing, and a stepwise logistic regression analysis was performed in order to reveal interactions between variables and to elucidate time trends in lethality rates. The total postperforation lethality was 7.4%, the postsurgical death rate was 6.6%, and the death rate among conservatively treated patients was 42.3%. Lethality was significantly influenced by year of hospital admission and increased markedly with the age of the patients. For all age groups, the lethality decreased markedly with time. Treatment delay was associated with a moderate but significant increase in lethality. In patients with gastric ulcer the lethality was 3.6 times higher than in those with duodenal ulcer. The death rate was similar in the duodenal and pyloric ulcer groups. Death rate decreased with time in both stomach ulcer, duodenal, and pyloric ulcer patients. There was no sex difference and no difference between patients treated with simple suture or gastric resection. PMID:2930287

  10. Determinants of the lethality of climate-related disasters in the Caribbean Community (CARICOM): a cross-country analysis

    PubMed Central

    Andrewin, Aisha N.; Rodriguez-Llanes, Jose M.; Guha-Sapir, Debarati

    2015-01-01

    Floods and storms are climate-related hazards posing high mortality risk to Caribbean Community (CARICOM) nations. However risk factors for their lethality remain untested. We conducted an ecological study investigating risk factors for flood and storm lethality in CARICOM nations for the period 1980–2012. Lethality - deaths versus no deaths per disaster event- was the outcome. We examined biophysical and social vulnerability proxies and a decadal effect as predictors. We developed our regression model via multivariate analysis using a generalized logistic regression model with quasi-binomial distribution; removal of multi-collinear variables and backward elimination. Robustness was checked through subset analysis. We found significant positive associations between lethality, percentage of total land dedicated to agriculture (odds ratio [OR] 1.032; 95% CI: 1.013–1.053) and percentage urban population (OR 1.029, 95% CI 1.003–1.057). Deaths were more likely in the 2000–2012 period versus 1980–1989 (OR 3.708, 95% CI 1.615–8.737). Robustness checks revealed similar coefficients and directions of association. Population health in CARICOM nations is being increasingly impacted by climate-related disasters connected to increasing urbanization and land use patterns. Our findings support the evidence base for setting sustainable development goals (SDG). PMID:26153115

  11. Determinants of the lethality of climate-related disasters in the Caribbean Community (CARICOM): a cross-country analysis

    NASA Astrophysics Data System (ADS)

    Andrewin, Aisha N.; Rodriguez-Llanes, Jose M.; Guha-Sapir, Debarati

    2015-07-01

    Floods and storms are climate-related hazards posing high mortality risk to Caribbean Community (CARICOM) nations. However risk factors for their lethality remain untested. We conducted an ecological study investigating risk factors for flood and storm lethality in CARICOM nations for the period 1980-2012. Lethality - deaths versus no deaths per disaster event- was the outcome. We examined biophysical and social vulnerability proxies and a decadal effect as predictors. We developed our regression model via multivariate analysis using a generalized logistic regression model with quasi-binomial distribution; removal of multi-collinear variables and backward elimination. Robustness was checked through subset analysis. We found significant positive associations between lethality, percentage of total land dedicated to agriculture (odds ratio [OR] 1.032; 95% CI: 1.013-1.053) and percentage urban population (OR 1.029, 95% CI 1.003-1.057). Deaths were more likely in the 2000-2012 period versus 1980-1989 (OR 3.708, 95% CI 1.615-8.737). Robustness checks revealed similar coefficients and directions of association. Population health in CARICOM nations is being increasingly impacted by climate-related disasters connected to increasing urbanization and land use patterns. Our findings support the evidence base for setting sustainable development goals (SDG).

  12. Determinants of the lethality of climate-related disasters in the Caribbean Community (CARICOM): a cross-country analysis.

    PubMed

    Andrewin, Aisha N; Rodriguez-Llanes, Jose M; Guha-Sapir, Debarati

    2015-01-01

    Floods and storms are climate-related hazards posing high mortality risk to Caribbean Community (CARICOM) nations. However risk factors for their lethality remain untested. We conducted an ecological study investigating risk factors for flood and storm lethality in CARICOM nations for the period 1980-2012. Lethality--deaths versus no deaths per disaster event- was the outcome. We examined biophysical and social vulnerability proxies and a decadal effect as predictors. We developed our regression model via multivariate analysis using a generalized logistic regression model with quasi-binomial distribution; removal of multi-collinear variables and backward elimination. Robustness was checked through subset analysis. We found significant positive associations between lethality, percentage of total land dedicated to agriculture (odds ratio [OR] 1.032; 95% CI: 1.013-1.053) and percentage urban population (OR 1.029, 95% CI 1.003-1.057). Deaths were more likely in the 2000-2012 period versus 1980-1989 (OR 3.708, 95% CI 1.615-8.737). Robustness checks revealed similar coefficients and directions of association. Population health in CARICOM nations is being increasingly impacted by climate-related disasters connected to increasing urbanization and land use patterns. Our findings support the evidence base for setting sustainable development goals (SDG). PMID:26153115

  13. Analysis of the Liver Soluble Proteome from Bull Terriers Affected with Inherited Lethal Acrodermatitis

    PubMed Central

    Mouat, Michael F.; Mauldin, Elizabeth A.; Casal, Margret L.

    2012-01-01

    Lethal acrodermatitis (LAD) is a genetic disease affecting bull terrier dogs. The phenotype is similar to that for acrodermatitis enteropathica in humans, but is currently without treatment. The purpose of the research presented here is to determine the biochemical defects associated with LAD using proteomic methodologies. Two affected (male and female) and one unaffected (male) bull terrier pups were euthanized at 14 weeks of age, their livers dissected and prepared for two-dimensional gel electrophoresis (2DE) and densitometry. Approximately 200 protein spots were observed. The density of the spots within each gel was normalized to the total spot volume of the gel; only those soluble liver protein spots that were consistently different in both of the livers of the affected pups compared to the unaffected pup were excised manually and submitted for MALDI mass spectrometry. Thirteen proteins were identified as differentially expressed in the affected, compared to the unaffected, pups. The proteins were involved in numerous cellular physiological functions, including chaperones, calcium binding, and energy metabolism, as well as being associated with the inflammatory response. Of note were haptoglobin, glutamine synthetase, prohibitin and keratin 10 which exhibited at least a 4-fold level of differential expression. These data represent the first proteomic analysis of this mutation. The differentially expressed proteins that were identified may be key in understanding the etiology of LAD, and may lead to diagnostic tools for its identification within the bull terrier population. PMID:17693109

  14. Non-lethal weapons technologies--the case for independent scientific analysis.

    PubMed

    Altmann, J

    2001-01-01

    Various technologies have been proposed for non-lethal weapons (NLW), some of them credible, or at least plausible, but strong claims were made for others without evidence or references. Five such technologies are examined. For the chemical and biological examples, detailed information is lacking but the diminishing number of such claims over time and general scientific knowledge suggest that fulfilment of the promises is improbable. For acoustic weapons, a detailed study found that many of the claims are plainly untrue. In this case, even wrong values for physiological thresholds were presented. Civil and military NLW programmes in the USA put their main emphasis on simple, short-term technologies rather than exotic ones. In order to avoid dangers arising from unrealistic promises, the concept of preventive arms control should be applied to NLW. Its first step is a scientific analysis, investigating the new weapons, the propagation of their effects and the effect on the targets. Such detailed studies are needed for each proposed NLW technology. PMID:11578041

  15. Integrating ethical analysis "into the DNA" of synthetic biology.

    PubMed

    Heavey, Patrick

    2015-02-01

    Current ethical analysis tends to evaluate synthetic biology at an overview level. Synthetic biology, however, is an umbrella term that covers a variety of areas of research. These areas contain, in turn, a hierarchy of different research fields. This abstraction hierarchy-the term is borrowed from engineering-permits synthetic biologists to specialise to a very high degree. Though synthetic biology per se may create profound ethical challenges, much of the day-to-day research does not. Yet seemingly innocuous research could lead to ethically problematic results. For example, Dolly the sheep resulted from a long series of research steps, none of which presented any ethical problems. The atomic bomb was developed as a result of Einstein's uncontentions theoretical research that proved the equivalence of matter and energy. Therefore it would seem wise for ethicists to evaluate synbio research across its subfields and through its abstraction hierarchies, comparing and inter-relating the various areas of research. In addition, it would be useful if journals that publish synbio papers require an ethical statement from authors, as standard practice, so as to encourage scientists to constantly engage with ethical issues in their work. Also, this would allow an ethical snapshot of the state of the research at any given time to exist, allowing for accurate evaluation by scientists and ethicists, regulators and policymakers. PMID:25185871

  16. Preliminary Integrated Safety Analysis of Synthetic Vision Conducted

    NASA Technical Reports Server (NTRS)

    Reveley, Mary S.

    2002-01-01

    The goal of the NASA Aviation Safety Program is to develop and demonstrate technologies that could help reduce the aviation fatal accident rate by a factor of 5 by the year 2007 and by a factor of 10 by the year 2022. Integrated safety analysis of day-to-day operations and risks within those operations will provide an understanding of the Aviation Safety Program portfolio beyond what is now available. Synthetic vision is the first of the Aviation Safety Program technologies that has been analyzed by the Logistics Management Institute under a contract with the NASA Glenn Research Center. These synthetic vision analyses include both a reliability analysis and a computer simulation model.

  17. FTIR analysis and monitoring of synthetic aviation engine oils.

    PubMed

    Adams, Mike J; Romeo, Melissa J; Rawson, Paul

    2007-10-15

    Synthetic turbine oils from military aircraft engines were analysed for antioxidant content and total acid number using infrared (IR) spectroscopy. Two-dimensional IR correlation analysis was employed to investigate and interpret observed trends in the spectra, as acid was formed and antioxidant species were depleted in the oils, as a function of aging and engine wear. Principal components and partial least squares algorithms were used and compared for the development of calibration and prediction models. Transmission IR spectrometry is demonstrated to be effective for the analysis and monitoring of synthetic aviation turbine engine oils and shown to provide rapid and accurate information as compared with traditional analytical techniques and methods. PMID:19073081

  18. Analysis of new aphid lethal paralysis virus (ALPV) isolates suggests evolution of two ALPV species.

    PubMed

    Liu, Sijun; Vijayendran, Diveena; Carrillo-Tripp, Jimena; Miller, W Allen; Bonning, Bryony C

    2014-12-01

    Aphid lethal paralysis virus (ALPV; family Dicistroviridae) was first isolated from the bird cherry-oat aphid, Rhopalosiphum padi. ALPV-like virus sequences have been reported from many insects and insect predators. We identified a new isolate of ALPV (ALPV-AP) from the pea aphid, Acyrthosiphon pisum, and a new isolate (ALPV-DvV) from western corn rootworm, Diabrotica virgifera virgifera. ALPV-AP has an ssRNA genome of 9940 nt. Based on phylogenetic analysis, ALPV-AP was closely related to ALPV-AM, an ALPV isolate from honeybees, Apis mellifera, in Spain and Brookings, SD, USA. The distinct evolutionary branches suggested the existence of two lineages of the ALPV virus. One consisted of ALPV-AP and ALPV-AM, whilst all other isolates of ALPV grouped into the other lineage. The similarity of ALPV-AP and ALPV-AM was up to 88 % at the RNA level, compared with 78-79 % between ALPV-AP and other ALPV isolates. The sequence identity of proteins between ALPV-AP and ALPV-AM was 98-99 % for both ORF1 and ORF2, whilst only 85-87 % for ORF1 and 91-92 % for ORF2 between ALPV-AP and other ALPV isolates. Sequencing of RACE (rapid amplification of cDNA ends) products and cDNA clones of the virus genome revealed sequence variation in the 5' UTRs and in ORF1, indicating that ALPV may be under strong selection pressure, which could have important biological implications for ALPV host range and infectivity. Our results indicated that ALPV-like viruses infect insects in the order Coleoptera, in addition to the orders Hemiptera and Hymenoptera, and we propose that ALPV isolates be classified as two separate viral species. PMID:25170050

  19. Protection Against Lethal Sendai Virus Infection by in vivo Priming of Virus-Specific Cytotoxic T Lymphocytes with a Free Synthetic Peptide

    NASA Astrophysics Data System (ADS)

    Kast, W. Martin; Roux, Laurent; Curren, Joseph; Blom, Hendrika J. J.; Voordouw, Arie C.; Meloen, Rob H.; Kolakofsky, Daniel; Melief, Cornelis J. M.

    1991-03-01

    The only peptide of Sendai virus that is recognized by cytotoxic T lymphocytes (CTL) in B6 mice was found with (i) the use of recombinant vaccinia virus constructs containing separate genes of Sendai virus and (ii) a set of overlapping peptides completely spanning the identified nucleoprotein (NP) gene product. This immunodominant NP peptide is recognized by Sendai virus-specific CTL that are known to have therapeutic effects in vivo. By subcutaneous immunization, this peptide induced Sendai virus and NP peptide-specific CTL memory responses in vivo. Most importantly, mice that had been immunized with this peptide were protected against a lethal virus dose, indicating that viral peptides can be used as antiviral T-cell vaccines. The induction of T-cell memory by free peptide immunization potentially has wide applicability in biology and medicine, including protection against infectious disease.

  20. Synthetic aperture sonar imaging using joint time-frequency analysis

    NASA Astrophysics Data System (ADS)

    Wang, Genyuan; Xia, Xiang-Gen

    1999-03-01

    The non-ideal motion of the hydrophone usually induces the aperture error of the synthetic aperture sonar (SAS), which is one of the most important factors degrading the SAS imaging quality. In the SAS imaging, the return signals are usually nonstationary due to the non-ideal hydrophone motion. In this paper, joint time-frequency analysis (JTFA), as a good technique for analyzing nonstationary signals, is used in the SAS imaging. Based on the JTFA of the sonar return signals, a novel SAS imaging algorithm is proposed. The algorithm is verified by simulation examples.

  1. [ANALYSIS OF A LETHAL OUTCOME RISK AFTER TRAUMA IN HIV-INFECTED PATIENTS IN POLYSYSTEMIC INJURY].

    PubMed

    Guryev, S O; Solovyov, O S; Tanasiyenko, P V

    2016-02-01

    Abstract The data, concerning clinic--epidemiologic and clinic--nosological characteristic of a HIV-infected injured persons in polytrauma were adduced. There was established, that polysystemic injuries (PSI) in a HIV-infected persons occur in a younger injured patients, a trauma environment is quite a speciphic one (criminal trauma prevails), as well as mechanism of the injury occurrence (falling down is much more freqent), and the risk of a lethal outcome is determined by predominantly cranial, thoracic and abdominal components of injury. A lethal outcome occurrence risk in HIV-infected injured persons in PSI in accordance to the age signs and traumagenesis is lesser, than in a control body. It is necessary to prolong the investigations, concerning studying this phenomenon and other peculiarities of a traumatic disease in HIV-infected injured persons in polytrauma. PMID:27244924

  2. Dynamic flux balance analysis for synthetic microbial communities.

    PubMed

    Henson, Michael A; Hanly, Timothy J

    2014-10-01

    Dynamic flux balance analysis (DFBA) is an extension of classical flux balance analysis that allows the dynamic effects of the extracellular environment on microbial metabolism to be predicted and optimised. Recently this computational framework has been extended to microbial communities for which the individual species are known and genome-scale metabolic reconstructions are available. In this review, the authors provide an overview of the emerging DFBA approach with a focus on two case studies involving the conversion of mixed hexose/pentose sugar mixtures by synthetic microbial co-culture systems. These case studies illustrate the key requirements of the DFBA approach, including the incorporation of individual species metabolic reconstructions, formulation of extracellular mass balances, identification of substrate uptake kinetics, numerical solution of the coupled linear program/differential equations and model adaptation for common, suboptimal growth conditions and identified species interactions. The review concludes with a summary of progress to date and possible directions for future research. PMID:25257022

  3. Synthetic Training Data Generation for Activity Monitoring and Behavior Analysis

    NASA Astrophysics Data System (ADS)

    Monekosso, Dorothy; Remagnino, Paolo

    This paper describes a data generator that produces synthetic data to simulate observations from an array of environment monitoring sensors. The overall goal of our work is to monitor the well-being of one occupant in a home. Sensors are embedded in a smart home to unobtrusively record environmental parameters. Based on the sensor observations, behavior analysis and modeling are performed. However behavior analysis and modeling require large data sets to be collected over long periods of time to achieve the level of accuracy expected. A data generator - was developed based on initial data i.e. data collected over periods lasting weeks to facilitate concurrent data collection and development of algorithms. The data generator is based on statistical inference techniques. Variation is introduced into the data using perturbation models.

  4. Histone acetylation and gene expression analysis of sex lethal mutants in Drosophila.

    PubMed Central

    Bhadra, U; Pal-Bhadra, M; Birchler, J A

    2000-01-01

    The evolution of sex determination mechanisms is often accompanied by reduction in dosage of genes on a whole chromosome. Under these circumstances, negatively acting regulatory genes would tend to double the expression of the genome, which produces compensation of the single-sex chromosome and increases autosomal gene expression. Previous work has suggested that to reduce the autosomal expression to the female level, these dosage effects are modified by a chromatin complex specific to males, which sequesters a histone acetylase to the X. The reduced autosomal histone 4 lysine 16 (H4Lys16) acetylation results in lowered autosomal expression, while the higher acetylation on the X is mitigated by the male-specific lethal complex, preventing overexpression. In this report, we examine how mutations in the principal sex determination gene, Sex lethal (Sxl), impact the H4 acetylation and gene expression on both the X and autosomes. When Sxl expression is missing in females, we find that the sequestration occurs concordantly with reductions in autosomal H4Lys16 acetylation and gene expression on the whole. When Sxl is ectopically expressed in Sxl(M) mutant males, the sequestration is disrupted, leading to an increase in autosomal H4Lys16 acetylation and overall gene expression. In both cases we find relatively little effect upon X chromosomal gene expression. PMID:10835396

  5. Economic Deprivation as a Predictor of the Direction of Lethal Violence: An Analysis of Italian Provinces.

    PubMed

    Stack, Steven; Laubepin, Frederique; Vichi, Monica; Minelli, Giada; Lester, David; Ferracuti, Stefano; Girardi, Paolo; Pompili, Maurizio

    2016-07-01

    Research on suicide and homicide rates has neglected an integrated model seeking to explain social variation in the direction of lethal violence. The present investigation explores the association between measures of social deprivation on the relative incidence of suicide over homicide in Italian provinces. Data refer to official government sources on lethal violence rates and measures of social deprivation. The central dependent variable (SHR) is the tendency towards suicide measured as the suicide rate divided by the sum of the suicide and homicide rates. Data were available for 102 Italian provinces in the Census year 2001. The percentage of the population marked by two indicators of deprivation (low education, household population density) were negatively associated with the SHR. The results are largely consistent with a stream of previous research that connects deprivation with a relatively high probability for disadvantaged populations to direct aggression outwardly in the form of homicide rather than inwardly in the form of suicide. The present study specifies which elements of deprivation best predict the direction of violence and is the first study for the Italian context. PMID:26881819

  6. Time-frequency analysis of synthetic aperture radar signals

    SciTech Connect

    Johnston, B.

    1996-08-01

    Synthetic aperture radar (SAR) has become an important tool for remote sensing of the environment. SAR is a set of digital signal processing algorithms that are used to focus the signal returned to the radar because radar systems in themselves cannot produce the high resolution images required in remote sensing applications. To reconstruct an image, several parameters must be estimated and the quality of output image depends on the degree of accuracy of these parameters. In this thesis, we derive the fundamental SAR algorithms and concentrate on the estimation of one of its critical parameters. We show that the common technique for estimating this particular parameter can sometimes lead to erroneous results and reduced quality images. We also employ time-frequency analysis techniques to examine variations in the radar signals caused by platform motion and show how these results can be used to improve output image quality.

  7. Hypoxia Potentiates the Radiation-Sensitizing Effect of Olaparib in Human Non-Small Cell Lung Cancer Xenografts by Contextual Synthetic Lethality

    PubMed Central

    Jiang, Yanyan; Verbiest, Tom; Devery, Aoife M.; Bokobza, Sivan M.; Weber, Anika M.; Leszczynska, Katarzyna B.; Hammond, Ester M.; Ryan, Anderson J.

    2016-01-01

    synthetic killing, and that tumor hypoxia may be a potential biomarker for selecting patients who may get the greatest benefit from the addition of olaparib to radiation therapy. PMID:27020103

  8. Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma.

    PubMed

    Beck, Daniel; Zobel, Jenny; Barber, Ruth; Evans, Sian; Lezina, Larissa; Allchin, Rebecca L; Blades, Matthew; Elliott, Richard; Lord, Christopher J; Ashworth, Alan; Porter, Andrew C G; Wagner, Simon D

    2016-08-01

    We demonstrate the usefulness of synthetic lethal screening of a conditionally BCL6-deficient Burkitt lymphoma cell line, DG75-AB7, with a library of small molecules to determine survival pathways suppressed by BCL6 and suggest mechanism-based treatments for lymphoma. Lestaurtinib, a JAK2 inhibitor and one of the hits from the screen, repressed survival of BCL6-deficient cells in vitro and reduced growth and proliferation of xenografts in vivo BCL6 deficiency in DG75-AB7 induced JAK2 mRNA and protein expression and STAT3 phosphorylation. Surface IL10RA was elevated by BCL6 deficiency, and blockade of IL10RA repressed STAT3 phosphorylation. Therefore, we define an IL10RA/JAK2/STAT3 pathway each component of which is repressed by BCL6. We also show for the first time that JAK2 is a direct BCL6 target gene; BCL6 bound to the JAK2 promoter in vitro and was enriched by ChIP-seq. The place of JAK2 inhibitors in the treatment of diffuse large B-cell lymphoma has not been defined; we suggest that JAK2 inhibitors might be most effective in poor prognosis ABC-DLBCL, which shows higher levels of IL10RA, JAK2, and STAT3 but lower levels of BCL6 than GC-DLBCL and might be usefully combined with novel approaches such as inhibition of IL10RA. PMID:27268052

  9. Loss of Apm1, the μ1 Subunit of the Clathrin-Associated Adaptor-Protein-1 Complex, Causes Distinct Phenotypes and Synthetic Lethality with Calcineurin Deletion in Fission Yeast

    PubMed Central

    Kita, Ayako; Sugiura, Reiko; Shoji, Hiromi; He, Yi; Deng, Lu; Lu, Yabin; Sio, Susie O.; Takegawa, Kaoru; Sakaue, Motoyoshi; Shuntoh, Hisato; Kuno, Takayoshi

    2004-01-01

    Calcineurin is a highly conserved regulator of Ca2+ signaling in eukaryotes. In fission yeast, calcineurin is not essential for viability but is required for cytokinesis and Cl- homeostasis. In a genetic screen for mutations that are synthetically lethal with calcineurin deletion, we isolated a mutant, cis1-1/apm1-1, an allele of the apm1+ gene that encodes a homolog of the mammalian μ1A subunit of the clathrin-associated adaptor protein-1 (AP-1) complex. The cis1-1/apm1-1 mutant as well as the apm1-deleted (Δapm1) cells showed distinct phenotypes: temperature sensitivity; tacrolimus (FK506) sensitivity; and pleiotropic defects in cytokinesis, cell integrity, and vacuole fusion. Electron micrographs revealed that Δapm1 cells showed large vesicular structures associated with Golgi stacks and accumulated post-Golgi secretory vesicles. Δapm1 cells also showed the massive accumulation of the exocytic v-SNARE Syb1 in the Golgi/endosomes and a reduced secretion of acid phosphatase. These phenotypes observed in apm1 mutations were accentuated upon temperature up-shift and FK506 treatment. Notably, Apm1-GFP localized to the Golgi/endosomes, the spindle pole bodies, and the medial region. These findings suggest a role for Apm1 associated with the Golgi/endosome function, thereby affecting various cellular processes, including secretion, cytokinesis, vacuole fusion, and cell integrity and also suggest that calcineurin is involved in these events. PMID:15047861

  10. Regulation of the Gene Sex-Lethal: A Comparative Analysis of Drosophila Melanogaster and Drosophila Subobscura

    PubMed Central

    Penalva, LOF.; Sakamoto, H.; Navarro-Sabate, A.; Sakashita, E.; Granadino, B.; Segarra, C.; Sanchez, L.

    1996-01-01

    The Drosophila gene Sex-lethal (Sxl) controls the processes of sex determination and dosage compensation. A Drosophila subobscura genomic fragment containing all the exons and the late and early promotors in the Sxl gene of D. melanogaster was isolated. Early Sxl expression in D. subobscura seems to be controlled at the transcriptional level, possibly by the X:A signal. In the region upstream of the early Sxl transcription initiation site are two conserved regions suggested to be involved in the early activation of Sxl. Late Sxl expression in D. subobscura produces four transcripts in adult females and males. In males, the transcripts have an additional exon which contains three translational stop codons so that a truncated, presumably nonfunctional Sxl protein is produced. The Sxl pre-mRNA of D. subobscura lacks the poly-U sequence presented at the polypirimidine tract of the 3' splice site of the male-specific exon present in D. melanogaster. Introns 2 and 3 contain the Sxl-binding poly-U stretches, whose localization in intron 2 varies but in intron 3 is conserved. The Sxl protein is fully conserved at the amino acid level in both species. PMID:8978052

  11. Biophysical analysis of a lethal laminin alpha-1 mutation reveals altered self-interaction.

    PubMed

    Patel, Trushar R; Nikodemus, Denise; Besong, Tabot M D; Reuten, Raphael; Meier, Markus; Harding, Stephen E; Winzor, Donald J; Koch, Manuel; Stetefeld, Jörg

    2016-01-01

    Laminins are key basement membrane molecules that influence several biological activities and are linked to a number of diseases. They are secreted as heterotrimeric proteins consisting of one α, one β, and one γ chain, followed by their assembly into a polymer-like sheet at the basement membrane. Using sedimentation velocity, dynamic light scattering, and surface plasmon resonance experiments, we studied self-association of three laminin (LM) N-terminal fragments α-1 (hLM α-1N), α-5 (hLM α-5N) and β-3 (hLM β-3N) originating from the short arms of the human laminin αβγ heterotrimer. Corresponding studies of the hLM α-1N C49S mutant, equivalent to the larval lethal C56S mutant in zebrafish, have shown that this mutation causes enhanced self-association behavior, an observation that provides a plausible explanation for the inability of laminin bearing this mutation to fulfill functional roles in vivo, and hence for the deleterious pathological consequences of the mutation on lens function. PMID:26215696

  12. Development of synthetic flood damage curve by explicit costs analysis

    NASA Astrophysics Data System (ADS)

    Martina, Mario; Molinari, Daniela; Dottori, Francesco; Scorzini, Annarita

    2015-04-01

    Damage modelling is a key component in flood risk assessments. A conventional approach for estimating direct flood damages is the use of depth-damage functions. However, at present, there are few studies that describe in detail the parameters involved in the models and the hypotheses used for the development of these functions based on synthetic approaches and/or actual flood damage data. In this work a synthetic approach was adopted for the development of a damage model for residential buildings. The approach follows the loss assessment procedure usually applied by the insurance loss adjusters. Required information consisted of all those variables that are necessary to define hazard characteristics at building location, compute the exposure value of the building and the replacement costs of its components. In detail, the model requires four input tables. The hazard module includes the variables describing the features of the flood event at building location (e.g. water depth outside the building, water depth inside the basement, maximum velocity of the flood, duration of the event, contaminant and sediment load). The exposure module includes both extensive variables (e.g. foot print area, number of floors) and "vulnerability" variables, where the latter affect damage estimation in two different ways: by changing the replacement value/unit prices of the building and its components (e.g. the finishing level, building type) or by modifying the function(s) describing damage mechanisms (e.g. building structure, plant distribution). The replacement values table and the unit-price table include respectively the replacement value of the building and the unitary replacement costs of the different building components (e.g. doors and pavement replacement per square meter). The final output of the model is represented by different sets of damage functions describing all the building components (e.g. plasters, plants), depending on hazard, exposure and vulnerability

  13. Impact of insecticides on the invasive Halyomorpha halys (Hemiptera: Pentatomidae): analysis of insecticide lethality.

    PubMed

    Leskey, Tracy C; Lee, Doo-Hyung; Short, Brent D; Wright, Starker E

    2012-10-01

    The efficacy of 37 insecticide treatments against adult Halyomorpha halys (Stål) was established based on exposure to 18-h old dry insecticide residue in laboratory bioassays. Individual adult H. halys were exposed to an insecticide residue for 4.5 h and then monitored daily for survivorship over a 7-d period. The proportion of dead and moribund insects was used as an estimate of overall insecticide efficacy against H. halys immediately after the exposure period and over the 7-d trial. Among all materials evaluated, 14 insecticides exhibited increasing efficacy, in which the percentage of dead and moribund insects (used as a measure of insecticide efficacy) increased by > 10% after 7 d. By contrast, insecticide efficacy values of eight insecticides declined by > 10% (based on recovery of adults from a moribund state) over the 7-d period with most belonging to the pyrethroid class. In this study, the efficacy value of neonicotinoid, acetamiprid, showed the greatest decline from 93 to 10% over 7 d. A lethality index (scale of 0-100) was developed to compare insecticides based on quantifying the immediate and longer-term effects of insecticide exposure on H. halys. Among all materials evaluated, dimethoate, malathion, bifenthrin, methidathion, endosulfan, methomyl, chlorpyrifos, acephate, fenpropathrin, and permethrin yielded the highest values (> 75) because of a high degree of immediate mortality with very little recovery. Our results provide baseline information regarding potential of candidate insecticides against adult H. halys and highlight the need to consider longer-term effects in establishing overall efficacy ratings against this invasive species. PMID:23156170

  14. Seamless Synthetic Aperture Radar Archive for Interferometry Analysis

    NASA Astrophysics Data System (ADS)

    Baker, S.; Meertens, C. M.; Phillips, D. A.; Crosby, C.; Fielding, E. J.; Nicoll, J.; Bryson, G.; Buechler, B.; Baru, C.

    2012-12-01

    The NASA Advancing Collaborative Connections for Earth System Science (ACCESS) Seamless Synthetic Aperture Radar (SAR) Archive (SSARA) project is a 2-year collaboration between UNAVCO/WInSAR, the Alaska Satellite Facility (ASF), the Jet Propulsion Laboratory (JPL), and the San Diego Supercomputer Center (SDSC) to design and implement a seamless distributed access system for SAR data and derived data products (i.e. terrain corrected interferograms). A seamless SAR archive increases the accessibility and the utility of SAR science data to solid Earth and cryospheric science researchers. Building on the established webs services and APIs at UNAVCO and ASF, the SSARA project will provide simple web services tools to seamlessly and effectively exchange and share space- and airborne SAR metadata, archived SAR data, and on-demand derived products between the distributed archives and individual users. Development of standard formats for data products and new QC/QA definitions will be implemented to streamline data usage and enable advanced query capabilities. The new ACCESS-developed tools will help overcome the obstacles of heterogeneous archive access protocols and data formats, data provider access policy constraints, and will also enable interoperability with key information technology development systems such as the NASA/JPL QuakeSim and ARIA projects, which provide higher level resources for geodetic data processing, data assimilation and modeling, and integrative analysis for scientific research and hazards applications. The SSARA project will significantly enhance mature IT capabilities at ASF's NASA-supported DAAC, the GEO Supersites archive, supported operationally by UNAVCO, and UNAVCO's WInSAR and EarthScope SAR archives that are supported by NASA, NSF, and the USGS in close collaboration with ESA/ESRIN.

  15. Data Analysis Methods for Synthetic Polymer Mass Spectrometry: Autocorrelation

    PubMed Central

    Wallace, William E.; Guttman, Charles M.

    2002-01-01

    Autocorrelation is shown to be useful in describing the periodic patterns found in high- resolution mass spectra of synthetic polymers. Examples of this usefulness are described for a simple linear homopolymer to demonstrate the method fundamentals, a condensation polymer to demonstrate its utility in understanding complex spectra with multiple repeating patterns on different mass scales, and a condensation copolymer to demonstrate how it can elegantly and efficiently reveal unexpected phenomena. It is shown that using autocorrelation to determine where the signal devolves into noise can be useful in determining molecular mass distributions of synthetic polymers, a primary focus of the NIST synthetic polymer mass spectrometry effort. The appendices describe some of the effects of transformation from time to mass space when time-of-flight mass separation is used, as well as the effects of non-trivial baselines on the autocorrelation function.

  16. MYC, Metabolic Synthetic Lethality, and Cancer.

    PubMed

    Hsieh, Annie L; Dang, Chi V

    2016-01-01

    The MYC oncogene plays a pivotal role in the development and progression of human cancers. It encodes a transcription factor that has broad reaching effects on many cellular functions, most importantly in driving cell growth through regulation of genes involved in ribosome biogenesis, metabolism, and cell cycle. Upon binding DNA with its partner MAX, MYC recruits factors that release paused RNA polymerases to drive transcription and amplify gene expression. At physiologic levels of MYC, occupancy of high-affinity DNA-binding sites drives 'house-keeping' metabolic genes and those involved in ribosome and mitochondrial biogenesis for biomass accumulation. At high oncogenic levels of MYC, invasion of low-affinity sites and enhancer sequences alter the transcriptome and cause metabolic imbalances, which activates stress response and checkpoints such as p53. Loss of checkpoints unleashes MYC's full oncogenic potential to couple metabolism with neoplastic cell growth and division. Cells that overexpress MYC, however, are vulnerable to metabolic perturbations that provide potential new avenues for cancer therapy. PMID:27557535

  17. Experimental Analysis of Impinging Single and Twin Circular Synthetic Jets

    NASA Astrophysics Data System (ADS)

    Cardone, Gennaro; Greco, Carlo Salvatore; Castrillo, Giusy; Astarita, Tommaso; Experimental Thermo-Fluid-Dynamics Research Team

    2015-11-01

    The behavior of impinging single synthetic jet and twin circular synthetic jets in phase opposition is experimentally investigated by using Particle Image Velocimetry (PIV) at Reynolds and Strouhal numbers equal to 5100 and 0.024, respectively. Different inter-axes distances for the twin configuration and several nozzle-to-plate distances have been investigated. The time-averaged behavior of the all velocity components are reported and discussed. Their distributions, near the impinging plate, are described for both the synthetic jet configurations and for all the nozzle-to-plate distances. At low nozzle-to-plate distance (H/D <4) the axial velocity profile near the impinging plate shows a double peak with a minimum on the jet axis. Instead, at high nozzle-to-plate distance (H/D >6), the axial velocity profile is bell-shaped. This is ascribed to the adverse pressure gradient strength and the potential core-like region extension. Indeed, the turbulence distribution shows a region characterized by low values, resembling the potential core region of continuous jets. Comparing the two synthetic jet configurations, a higher centerline velocity and a smaller jet width have been found for the twin case.

  18. SAMPLING AND ANALYSIS OF BUTADIENE AT A SYNTHETIC RUBBER PLANT

    EPA Science Inventory

    Butadiene emission samples were collected from the process vent stream of a plant manufacturing synthetic rubber from styrene and butadiene. Samples were collected by modification of the evacuated container sampling procedure, outlined in Section 7.1.1 of EPA Method 18. On-site a...

  19. What Are Reasons for the Large Gender Differences in the Lethality of Suicidal Acts? An Epidemiological Analysis in Four European Countries

    PubMed Central

    Heinrichs, Katherina; Székely, András; Tóth, Mónika Ditta; Coyne, James; Quintão, Sónia; Arensman, Ella; Coffey, Claire; Maxwell, Margaret; Värnik, Airi; van Audenhove, Chantal; McDaid, David; Sarchiapone, Marco; Schmidtke, Armin; Genz, Axel; Gusmão, Ricardo; Hegerl, Ulrich

    2015-01-01

    Background In Europe, men have lower rates of attempted suicide compared to women and at the same time a higher rate of completed suicides, indicating major gender differences in lethality of suicidal behaviour. The aim of this study was to analyse the extent to which these gender differences in lethality can be explained by factors such as choice of more lethal methods or lethality differences within the same suicide method or age. In addition, we explored gender differences in the intentionality of suicide attempts. Methods and Findings Methods. Design: Epidemiological study using a combination of self-report and official data. Setting: Mental health care services in four European countries: Germany, Hungary, Ireland, and Portugal. Data basis: Completed suicides derived from official statistics for each country (767 acts, 74.4% male) and assessed suicide attempts excluding habitual intentional self-harm (8,175 acts, 43.2% male). Main Outcome Measures and Data Analysis. We collected data on suicidal acts in eight regions of four European countries participating in the EU-funded “OSPI-Europe”-project (www.ospi-europe.com). We calculated method-specific lethality using the number of completed suicides per method * 100 / (number of completed suicides per method + number of attempted suicides per method). We tested gender differences in the distribution of suicidal acts for significance by using the χ2-test for two-by-two tables. We assessed the effect sizes with phi coefficients (φ). We identified predictors of lethality with a binary logistic regression analysis. Poisson regression analysis examined the contribution of choice of methods and method-specific lethality to gender differences in the lethality of suicidal acts. Findings Main Results Suicidal acts (fatal and non-fatal) were 3.4 times more lethal in men than in women (lethality 13.91% (regarding 4106 suicidal acts) versus 4.05% (regarding 4836 suicidal acts)), the difference being significant for the

  20. Analysis of Parent Synthetic Cannabinoids in Blood and Urinary Metabolites by Liquid Chromatography Tandem Mass Spectrometry.

    PubMed

    Knittel, Jessica L; Holler, Justin M; Chmiel, Jeffrey D; Vorce, Shawn P; Magluilo, Joseph; Levine, Barry; Ramos, Gerardo; Bosy, Thomas Z

    2016-04-01

    Synthetic cannabinoids emerged on the designer drug market in recent years due to their ability to produce cannabis-like effects without the risk of detection by traditional drug testing techniques such as immunoassay and gas chromatography-mass spectrometry. As government agencies work to schedule existing synthetic cannabinoids, new, unregulated and structurally diverse compounds continue to be developed and sold. Synthetic cannabinoids undergo extensive metabolic conversion. Consequently, both blood and urine specimens may play an important role in the forensic analysis of synthetic cannabinoids. It has been observed that structurally similar synthetic cannabinoids follow common metabolic pathways, which often produce metabolites with similar metabolic transformations. Presented are two validated quantitative methods for extracting and identifying 15 parent synthetic cannabinoids in blood, 17 synthetic cannabinoid metabolites in urine and the qualitative identification of 2 additional parent compounds. The linear range for most synthetic cannabinoid compounds monitored was 0.1-10 ng/mL with the limit of detection between 0.01 and 0.5 ng/mL. Selectivity, specificity, accuracy, precision, recovery and matrix effect were also examined and determined to be acceptable for each compound. The validated methods were used to analyze a compilation of synthetic cannabinoid investigative cases where both blood and urine specimens were submitted. The study suggests a strong correlation between the metabolites detected in urine and the parent compounds found in blood. PMID:26792810

  1. [Analysis of a synthetic onion aroma (author's transl)].

    PubMed

    Ledl, F

    1975-02-01

    A complex mixture of compounds possessing an intensive aroma of onions is obtained, when propionaldehyde, propionaldehyde and acetaldehyde are treated with hydrogen sulfide and ammonia. Dihydrodithiazines, diethyltrithiolane, diethyl-methyl-1,3-dithiine and in small quantities diethyltetrathiane, dimethylthiophene, dipropyldisulfide, dipropenylsulfide, alkylpyridines, and the condensation products of aldehydes can be proved by the GC-MS-technic. The compositions of the synthetic onion aroma corresponds slightly with the composition of the natural onion aroma. PMID:1224790

  2. Screening and analysis of genes expressed upon infection of broad bean with Clover yellow vein virus causing lethal necrosis.

    PubMed

    Nakahara, Kenji S; Kitazawa, Hiroaki; Atsumi, Go; Choi, Sun Hee; Suzuki, Yuji; Uyeda, Ichiro

    2011-01-01

    Clover yellow vein virus (ClYVV) causes lethal systemic necrosis in legumes, including broad bean (Vicia faba) and pea (Pisum sativum). To identify host genes involved in necrotic symptom expression after ClYVV infection, we screened cDNA fragments in which expression was changed in advance of necrotic symptom expression in broad bean (V. faba cv. Wase) using the differential display technique and secondarily with Northern blot analysis. Expression changes were confirmed in 20 genes, and the six that exhibited the most change were analyzed further. These six genes included a gene that encodes a putative nitrate-induced NOI protein (VfNOI), and another was homologous to an Arabidopsis gene that encodes a glycine- and proline-rich protein GPRP (VfGPRP). We recently reported that necrotic symptom development in ClYVV-infected pea is associated with expression of salicylic acid (SA)-dependent pathogenesis-related (PR) proteins and requires SA-dependent host responses. Interestingly, VfNOI and VfGPRP expression was correlated with that of the putative SA-dependent PR proteins in ClYVV-infected broad bean. However, broad bean infected with a recombinant ClYVV expressing the VfGPRP protein showed weaker symptoms and less viral multiplication than that infected with ClYVV expressing the GFP protein. These results imply that VfGPRP plays a role in defense against ClYVV rather than in necrotic symptom expression. PMID:21767375

  3. Quantitative proteomics analysis of zebrafish exposed to sub-lethal dosages of β-methyl-amino-L-alanine (BMAA)

    PubMed Central

    Frøyset, Ann Kristin; Khan, Essa Ahsan; Fladmark, Kari Espolin

    2016-01-01

    The non-protein amino acid β-methylamino-L-alanine (BMAA) is a neurotoxin present in microalgae and shown to accumulate in the food web. BMAA has been linked to the complex neurodegenerative disorder of Guam and to increased incidents sporadic ALS. Two main neurotoxic routes are suggested; an excitotoxic by acting as an agonist towards glutamate receptors and a metabolic by misincorporating into cellular proteins. We have used zebrafish, an increasingly used model for neurodegenerative diseases, to further identify signaling components involved in BMAA-induced toxicity. Zebrafish embryos were exposed to sub-lethal dosages of BMAA and a label-free proteomics analysis was conducted on larvae 4 days post fertilization. The exposed larvae showed no developmental abnormalities, but a reduced heart rate and increased expression of GSK3 isoforms. Search towards a reviewed database containing 2968 entries identified 480 proteins. Only 17 of these were regulated 2-fold or more in the exposed larvae. Seven of these proteins could be associated to glutamate receptor signaling and recycling. The remaining nine have all been linked to disturbance in protein homeostasis, reactive oxygen species (ROS) development or neuronal cell death. We also found that BMAA influenced the endocannabinoid system by up-regulation of fatty acid amide hydrolase (FAAH) and that FAAH inhibitor URB597 reduced the BMAA effect on heart rate and GSK3 expression. PMID:27404450

  4. Quantitative proteomics analysis of zebrafish exposed to sub-lethal dosages of β-methyl-amino-L-alanine (BMAA).

    PubMed

    Frøyset, Ann Kristin; Khan, Essa Ahsan; Fladmark, Kari Espolin

    2016-01-01

    The non-protein amino acid β-methylamino-L-alanine (BMAA) is a neurotoxin present in microalgae and shown to accumulate in the food web. BMAA has been linked to the complex neurodegenerative disorder of Guam and to increased incidents sporadic ALS. Two main neurotoxic routes are suggested; an excitotoxic by acting as an agonist towards glutamate receptors and a metabolic by misincorporating into cellular proteins. We have used zebrafish, an increasingly used model for neurodegenerative diseases, to further identify signaling components involved in BMAA-induced toxicity. Zebrafish embryos were exposed to sub-lethal dosages of BMAA and a label-free proteomics analysis was conducted on larvae 4 days post fertilization. The exposed larvae showed no developmental abnormalities, but a reduced heart rate and increased expression of GSK3 isoforms. Search towards a reviewed database containing 2968 entries identified 480 proteins. Only 17 of these were regulated 2-fold or more in the exposed larvae. Seven of these proteins could be associated to glutamate receptor signaling and recycling. The remaining nine have all been linked to disturbance in protein homeostasis, reactive oxygen species (ROS) development or neuronal cell death. We also found that BMAA influenced the endocannabinoid system by up-regulation of fatty acid amide hydrolase (FAAH) and that FAAH inhibitor URB597 reduced the BMAA effect on heart rate and GSK3 expression. PMID:27404450

  5. Integrated clinical, whole-genome, and transcriptome analysis of multisampled lethal metastatic prostate cancer

    PubMed Central

    Bova, G. Steven; Kallio, Heini M.L.; Annala, Matti; Kivinummi, Kati; Högnäs, Gunilla; Häyrynen, Sergei; Rantapero, Tommi; Kivinen, Virpi; Isaacs, William B.; Tolonen, Teemu; Nykter, Matti; Visakorpi, Tapio

    2016-01-01

    We report the first combined analysis of whole-genome sequence, detailed clinical history, and transcriptome sequence of multiple prostate cancer metastases in a single patient (A21). Whole-genome and transcriptome sequence was obtained from nine anatomically separate metastases, and targeted DNA sequencing was performed in cancerous and noncancerous foci within the primary tumor specimen removed 5 yr before death. Transcriptome analysis revealed increased expression of androgen receptor (AR)-regulated genes in liver metastases that harbored an AR p.L702H mutation, suggesting a dominant effect by the mutation despite being present in only one of an estimated 16 copies per cell. The metastases harbored several alterations to the PI3K/AKT pathway, including a clonal truncal mutation in PIK3CG and present in all metastatic sites studied. The list of truncal genomic alterations shared by all metastases included homozygous deletion of TP53, hemizygous deletion of RB1 and CHD1, and amplification of FGFR1. If the patient were treated today, given this knowledge, the use of second-generation androgen-directed therapies, cessation of glucocorticoid administration, and therapeutic inhibition of the PI3K/AKT pathway or FGFR1 receptor could provide personalized benefit. Three previously unreported truncal clonal missense mutations (ABCC4 p.R891L, ALDH9A1 p.W89R, and ASNA1 p.P75R) were expressed at the RNA level and assessed as druggable. The truncal status of mutations may be critical for effective actionability and merit further study. Our findings suggest that a large set of deeply analyzed cases could serve as a powerful guide to more effective prostate cancer basic science and personalized cancer medicine clinical trials. PMID:27148588

  6. Integrated clinical, whole-genome, and transcriptome analysis of multisampled lethal metastatic prostate cancer.

    PubMed

    Bova, G Steven; Kallio, Heini M L; Annala, Matti; Kivinummi, Kati; Högnäs, Gunilla; Häyrynen, Sergei; Rantapero, Tommi; Kivinen, Virpi; Isaacs, William B; Tolonen, Teemu; Nykter, Matti; Visakorpi, Tapio

    2016-05-01

    We report the first combined analysis of whole-genome sequence, detailed clinical history, and transcriptome sequence of multiple prostate cancer metastases in a single patient (A21). Whole-genome and transcriptome sequence was obtained from nine anatomically separate metastases, and targeted DNA sequencing was performed in cancerous and noncancerous foci within the primary tumor specimen removed 5 yr before death. Transcriptome analysis revealed increased expression of androgen receptor (AR)-regulated genes in liver metastases that harbored an AR p.L702H mutation, suggesting a dominant effect by the mutation despite being present in only one of an estimated 16 copies per cell. The metastases harbored several alterations to the PI3K/AKT pathway, including a clonal truncal mutation in PIK3CG and present in all metastatic sites studied. The list of truncal genomic alterations shared by all metastases included homozygous deletion of TP53, hemizygous deletion of RB1 and CHD1, and amplification of FGFR1. If the patient were treated today, given this knowledge, the use of second-generation androgen-directed therapies, cessation of glucocorticoid administration, and therapeutic inhibition of the PI3K/AKT pathway or FGFR1 receptor could provide personalized benefit. Three previously unreported truncal clonal missense mutations (ABCC4 p.R891L, ALDH9A1 p.W89R, and ASNA1 p.P75R) were expressed at the RNA level and assessed as druggable. The truncal status of mutations may be critical for effective actionability and merit further study. Our findings suggest that a large set of deeply analyzed cases could serve as a powerful guide to more effective prostate cancer basic science and personalized cancer medicine clinical trials. PMID:27148588

  7. A population-based analysis of clustering identifies a strong genetic contribution to lethal prostate cancer

    PubMed Central

    Nelson, Quentin; Agarwal, Neeraj; Stephenson, Robert; Cannon-Albright, Lisa A.

    2013-01-01

    Background: Prostate cancer is a common and often deadly cancer. Decades of study have yet to identify genes that explain much familial prostate cancer. Traditional linkage analysis of pedigrees has yielded results that are rarely validated. We hypothesize that there are rare segregating variants responsible for high-risk prostate cancer pedigrees, but recognize that within-pedigree heterogeneity is responsible for significant noise that overwhelms signal. Here we introduce a method to identify homogeneous subsets of prostate cancer, based on cancer characteristics, which show the best evidence for an inherited contribution. Methods: We have modified an existing method, the Genealogical Index of Familiality (GIF) used to show evidence for significant familial clustering. The modification allows a test for excess familial clustering of a subset of prostate cancer cases when compared to all prostate cancer cases. Results: Consideration of the familial clustering of eight clinical subsets of prostate cancer cases compared to the expected familial clustering of all prostate cancer cases identified three subsets of prostate cancer cases with evidence for familial clustering significantly in excess of expected. These subsets include prostate cancer cases diagnosed before age 50 years, prostate cancer cases with body mass index (BMI) greater than or equal to 30, and prostate cancer cases for whom prostate cancer contributed to death. Conclusions: This analysis identified several subsets of prostate cancer cases that cluster significantly more than expected when compared to all prostate cancer familial clustering. A focus on high-risk prostate cancer cases or pedigrees with these characteristics will reduce noise and could allow identification of the rare predisposition genes or variants responsible. PMID:23970893

  8. Fentanyl-Laced 'Norco' Is Lethal, Report Warns

    MedlinePlus

    ... fullstory_160158.html Fentanyl-Laced 'Norco' Is Lethal, Report Warns New street drug combines two synthetic opioids ... imprint and were beige instead of white. The report was published online July 27 in the journal ...

  9. Geomorphological analysis and prioritization of sub-watersheds using Snyder's synthetic unit hydrograph method

    NASA Astrophysics Data System (ADS)

    Singh, Nivedita; Singh, K. K.

    2014-11-01

    The present study makes an attempt to prioritize sub-watersheds based on Snyder's synthetic unit hydrograph method. Snyder's method of synthetic unit hydrograph calculates peak discharge and lag time of the unit hydrograph for each sub-watersheds. Compound values of ranking are calculated from assigned rankings to parameters, viz. peak discharge and lag time. Depending on the range of the compound values sub-watersheds are classified as high, medium and low soil-erosive sub-watersheds. The priorities obtained from Snyder's synthetic unit hydrograph method are compared with the methods of morphometric analysis and land use/land cover analysis. On comparison of priorities for Dangri River watershed, Panchkula District, Haryana (India), among the three methods it was found that the sub-watershed (SW1) has the same priority. Among all the three methods, Snyder's synthetic unit hydrograph is a better method, as it is easier to use and less data intensive.

  10. Seamless Synthetic Aperture Radar Archive for Interferometry Analysis

    NASA Astrophysics Data System (ADS)

    Baker, S.; Baru, C.; Bryson, G.; Buechler, B.; Crosby, C.; Fielding, E.; Meertens, C.; Nicoll, J.; Youn, C.

    2014-11-01

    The NASA Advancing Collaborative Connections for Earth System Science (ACCESS) seamless synthetic aperture radar (SAR) archive (SSARA) project is a collaboration between UNAVCO, the Alaska Satellite Facility (ASF), the Jet Propulsion Laboratory (JPL), and OpenTopography at the San Diego Supercomputer Center (SDSC) to design and implement a seamless distributed access system for SAR data and derived interferometric SAR (InSAR) data products. A unified application programming interface (API) has been created to search the SAR archives at ASF and UNAVCO, 30 and 90-m SRTM DEM data available through OpenTopography, and tropospheric data from the NASA OSCAR project at JPL. The federated query service provides users a single access point to search for SAR granules, InSAR pairs, and corresponding DEM and tropospheric data products from the four archives, as well as the ability to search and download pre-processed InSAR products from ASF and UNAVCO.

  11. Synthetic plant defense elicitors

    PubMed Central

    Bektas, Yasemin; Eulgem, Thomas

    2015-01-01

    To defend themselves against invading pathogens plants utilize a complex regulatory network that coordinates extensive transcriptional and metabolic reprogramming. Although many of the key players of this immunity-associated network are known, the details of its topology and dynamics are still poorly understood. As an alternative to forward and reverse genetic studies, chemical genetics-related approaches based on bioactive small molecules have gained substantial popularity in the analysis of biological pathways and networks. Use of such molecular probes can allow researchers to access biological space that was previously inaccessible to genetic analyses due to gene redundancy or lethality of mutations. Synthetic elicitors are small drug-like molecules that induce plant defense responses, but are distinct from known natural elicitors of plant immunity. While the discovery of some synthetic elicitors had already been reported in the 1970s, recent breakthroughs in combinatorial chemical synthesis now allow for inexpensive high-throughput screens for bioactive plant defense-inducing compounds. Along with powerful reverse genetics tools and resources available for model plants and crop systems, comprehensive collections of new synthetic elicitors will likely allow plant scientists to study the intricacies of plant defense signaling pathways and networks in an unparalleled fashion. As synthetic elicitors can protect crops from diseases, without the need to be directly toxic for pathogenic organisms, they may also serve as promising alternatives to conventional biocidal pesticides, which often are harmful for the environment, farmers and consumers. Here we are discussing various types of synthetic elicitors that have been used for studies on the plant immune system, their modes-of-action as well as their application in crop protection. PMID:25674095

  12. The VG/GA strain of Newcastle disease virus: Mucosal immunity, protection against lethal challenge and molecular analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The VG/GA strain of Newcastle disease virus (NDV) isolated from the intestine of healthy turkeys has been proposed to replicate in the respiratory and intestinal tract of chickens. In this study, the virus distribution, the mucosal and systemic immune response, the efficacy against lethal challenge...

  13. An analysis of foliage induced azimuthal synthetic pattern distortions

    NASA Astrophysics Data System (ADS)

    Toups, M. F.

    1992-05-01

    Phase and amplitude fluctuations induced by wave propagation through foliage limit the ability of a synthetic aperture radar (SAR) system to image a target under foliage. One-way measurements of these fluctuations were done using the NASA/JPL C-, L-, UHF band SAR during the Lincoln Laboratory July 1990 Foliage Penetration Experiment. In this experiment, single-frequency CW signal sources, 'tone generators', were placed in the open and under foliage in order to measure one-way propagation. Three tone generator sites located under trees and one tone generator site in the open were utilized. Tone generators at the open site were used as controls. At each site, six tone generators were deployed, one for each frequency and polarization utilized by the NASA/JPL SAR system. The statistical properties of the phase and amplitude fluctuations induced by the foliage are determined for each tone generator site, frequency, and polarization. The effect of these amplitude and phase fluctuations on the ability of a SAR system to image a target *bscured by foliage is shown. These results are compared with the measured ground truth for each tone generator site. The ground truth measured during the experiment includes foliage densities, moisture contents, and permittivities.

  14. Perspective - synthetic DEMs: A vital underpinning for the quantitative future of landform analysis?

    NASA Astrophysics Data System (ADS)

    Hillier, J. K.; Sofia, G.; Conway, S. J.

    2015-12-01

    Physical processes, including anthropogenic feedbacks, sculpt planetary surfaces (e.g. Earth's). A fundamental tenet of geomorphology is that the shapes created, when combined with other measurements, can be used to understand those processes. Artificial or synthetic digital elevation models (DEMs) might be vital in progressing further with this endeavour in two ways. First, synthetic DEMs can be built (e.g. by directly using governing equations) to encapsulate the processes, making predictions from theory. A second, arguably underutilised, role is to perform checks on accuracy and robustness that we dub "synthetic tests". Specifically, synthetic DEMs can contain a priori known, idealised morphologies that numerical landscape evolution models, DEM-analysis algorithms, and even manual mapping can be assessed against. Some such tests, for instance examining inaccuracies caused by noise, are moderately commonly employed, whilst others are much less so. Derived morphological properties, including metrics and mapping (manual and automated), are required to establish whether or not conceptual models represent reality well, but at present their quality is typically weakly constrained (e.g. by mapper inter-comparison). Relatively rare examples illustrate how synthetic tests can make strong "absolute" statements about landform detection and quantification; for example, 84 % of valley heads in the real landscape are identified correctly. From our perspective, it is vital to verify such statistics quantifying the properties of landscapes as ultimately this is the link between physics-driven models of processes and morphological observations that allows quantitative hypotheses to be tested. As such the additional rigour possible with this second usage of synthetic DEMs feeds directly into a problem central to the validity of much of geomorphology. Thus, this note introduces synthetic tests and DEMs and then outlines a typology of synthetic DEMs along with their benefits

  15. Analysis of Eisenia fetida earthworm responses to sub-lethal C60 nanoparticle exposure using (1)H-NMR based metabolomics.

    PubMed

    Lankadurai, Brian P; Nagato, Edward G; Simpson, André J; Simpson, Myrna J

    2015-10-01

    The enhanced production and environmental release of Buckminsterfullerene (C60) nanoparticles will likely increase the exposure and risk to soil dwelling organisms. We used (1)H NMR-based metabolomics to investigate the response of Eisenia fetida earthworms to sub-lethal C60 nanoparticle exposure in both contact and soil tests. Principal component analysis of (1)H NMR data showed clear separation between controls and exposed earthworms after just 2 days of exposure, however as exposure time increased the separation decreased in soil but increased in contact tests suggesting potential adaptation during soil exposure. The amino acids leucine, valine, isoleucine and phenylalanine, the nucleoside inosine, and the sugars glucose and maltose emerged as potential bioindicators of exposure to C60 nanoparticles. The significant responses observed in earthworms using NMR-based metabolomics after exposure to very low concentrations of C60 nanoparticles suggests the need for further investigations to better understand and predict their sub-lethal toxicity. PMID:26024814

  16. End-to-end automated microfluidic platform for synthetic biology: from design to functional analysis

    DOE PAGESBeta

    Linshiz, Gregory; Jensen, Erik; Stawski, Nina; Bi, Changhao; Elsbree, Nick; Jiao, Hong; Kim, Jungkyu; Mathies, Richard; Keasling, Jay D.; Hillson, Nathan J.

    2016-02-02

    Synthetic biology aims to engineer biological systems for desired behaviors. The construction of these systems can be complex, often requiring genetic reprogramming, extensive de novo DNA synthesis, and functional screening. Here, we present a programmable, multipurpose microfluidic platform and associated software and apply the platform to major steps of the synthetic biology research cycle: design, construction, testing, and analysis. We show the platform’s capabilities for multiple automated DNA assembly methods, including a new method for Isothermal Hierarchical DNA Construction, and for Escherichia coli and Saccharomyces cerevisiae transformation. The platform enables the automated control of cellular growth, gene expression induction, andmore » proteogenic and metabolic output analysis. Finally, taken together, we demonstrate the microfluidic platform’s potential to provide end-to-end solutions for synthetic biology research, from design to functional analysis.« less

  17. Application of non-lethal stable isotope analysis to assess feeding patterns of juvenile pallid sturgeon Scaphirhynchus albus: A comparison of tissue types and sample preservation methods

    USGS Publications Warehouse

    Andvik, R.T.; VanDeHey, J.A.; Fincel, M.J.; French, William E.; Bertrand, K.N.; Chipps, S.R.; Klumb, R.A.; Graeb, B.D.S.

    2010-01-01

    Traditional techniques for stable isotope analysis (SIA) generally require sacrificing animals to collect tissue samples; this can be problematic when studying diets of endangered species such as the pallid sturgeon Scaphirhynchus albus. Our objectives were to (i) determine if pectoral fin tissue (non-lethal) could be a substitute for muscle tissue (lethal) in SIA of juvenile pallid sturgeon, and (ii) evaluate the influence of preservation techniques on stable isotope values. In the laboratory, individual juvenile pallid sturgeon were held for up to 186 day and fed chironomids, fish, or a commercially available pellet diet. Significant, positive relationships (r2 ??? 0.8) were observed between fin and muscle tissues for both ??15N and ??13C; in all samples isotopes were enriched in fins compared to muscle tissue. Chironomid and fish based diets of juvenile pallid sturgeon were distinguishable for fast growing fish (0.3 mm day-1) using stable ??15N and ??13C isotopes. Frozen and preserved fin tissue ??15N isotopes were strongly related (r2 = 0.89) but ??13C isotopes were weakly related (r2 = 0.16). Therefore, freezing is recommended for preservation of fin clips to avoid the confounding effect of enrichment by ethanol. This study demonstrates the utility of a non-lethal technique to assess time integrated food habits of juvenile pallid sturgeon and should be applicable to other threatened or endangered species. ?? 2010 Blackwell Verlag, Berlin.

  18. Integrated In Silico Analysis of Pathway Designs for Synthetic Photo-Electro-Autotrophy

    PubMed Central

    Noor, Elad; van der Oost, John; de Vos, Willem M.; Kengen, Servé W. M.; Martins dos Santos, Vitor A. P.

    2016-01-01

    The strong advances in synthetic biology enable the engineering of novel functions and complex biological features in unprecedented ways, such as implementing synthetic autotrophic metabolism into heterotrophic hosts. A key challenge for the sustainable production of fuels and chemicals entails the engineering of synthetic autotrophic organisms that can effectively and efficiently fix carbon dioxide by using sustainable energy sources. This challenge involves the integration of carbon fixation and energy uptake systems. A variety of carbon fixation pathways and several types of photosystems and other energy uptake systems can be chosen and, potentially, modularly combined to design synthetic autotrophic metabolism. Prior to implementation, these designs can be evaluated by the combination of several computational pathway analysis techniques. Here we present a systematic, integrated in silico analysis of photo-electro-autotrophic pathway designs, consisting of natural and synthetic carbon fixation pathways, a proton-pumping rhodopsin photosystem for ATP regeneration and an electron uptake pathway. We integrated Flux Balance Analysis of the heterotrophic chassis Escherichia coli with kinetic pathway analysis and thermodynamic pathway analysis (Max-min Driving Force). The photo-electro-autotrophic designs are predicted to have a limited potential for anaerobic, autotrophic growth of E. coli, given the relatively low ATP regenerating capacity of the proton pumping rhodopsin photosystems and the high ATP maintenance of E. coli. If these factors can be tackled, our analysis indicates the highest growth potential for the natural reductive tricarboxylic acid cycle and the synthetic pyruvate synthase–pyruvate carboxylate -glyoxylate bicycle. Both carbon fixation cycles are very ATP efficient, while maintaining fast kinetics, which also results in relatively low estimated protein costs for these pathways. Furthermore, the synthetic bicycles are highly thermodynamic

  19. ROUND ROBIN ANALYSIS OF ALCOHOL AND CARBONYL SYNTHETIC EXHAUST SAMPLES

    EPA Science Inventory

    Recent changes in regulatory practices have brought about a need for speciated analysis of the volatile organic components of vehicle exhaust. he purpose of this study was to allow interested laboratories to participate in a Round Robin so that each could assess their speciation ...

  20. Synthetical Reliability Analysis Model of CNC Software System

    NASA Astrophysics Data System (ADS)

    Xu, Yue; Xia, Yinjie; Wan, Yi

    CNC technology is the core of advanced manufacturing technology, and CNC software system is the very important part of numerical control system. The entire CNC system will not work normally, once the potential failure makes the software invalid. As to the current study of CNC sysytem, in use of the FAULT glitch tree, established a glitch tree for the CNC system; find the minimum cut sets with Fussed method and then according to the probability of several common glitches, make quantitative analysis in the reliability of the CNC system so that scientific ways can be provided for the reliability design, maintenance and management of the CNC system.

  1. Unsteady flow and heat transfer analysis of an impinging synthetic jet

    NASA Astrophysics Data System (ADS)

    Bazdidi-Tehrani, Farzad; Karami, Mahdi; Jahromi, Mehdi

    2011-11-01

    The present paper focuses on the analysis of unsteady flow and heat transfer regarding an axisymmetric impinging synthetic jet on a constant heat flux disc. Synthetic jet is a zero net mass flux jet that provides an unsteady flow without any external source of fluid. Present results are validated against the available experimental data showing that the SST/ k - ω turbulence model is more accurate and reliable than the standard and low- Re k - ɛ models for predicting heat transfer from an impinging synthetic jet. It is found that the time-averaged Nusselt number enhances as the nozzle-to-plate distance is increased. As the oscillation frequency in the range of 16-400 Hz is increased, the heat transfer is enhanced. It is shown that the instantaneous Nu distribution along the wall is influenced mainly by the interaction of produced vortex ring and wall boundary layer. Also, the fluctuation level of Nu decreases as the frequency is raised.

  2. 1H NMR-Based Metabolomic Analysis of Sub-Lethal Perfluorooctane Sulfonate Exposure to the Earthworm, Eisenia fetida, in Soil.

    PubMed

    Lankadurai, Brian P; Furdui, Vasile I; Reiner, Eric J; Simpson, André J; Simpson, Myrna J

    2013-01-01

    1H NMR-based metabolomics was used to measure the response of Eisenia fetida earthworms after exposure to sub-lethal concentrations of perfluorooctane sulfonate (PFOS) in soil. Earthworms were exposed to a range of PFOS concentrations (five, 10, 25, 50, 100 or 150 mg/kg) for two, seven and fourteen days. Earthworm tissues were extracted and analyzed by 1H NMR. Multivariate statistical analysis of the metabolic response of E. fetida to PFOS exposure identified time-dependent responses that were comprised of two separate modes of action: a non-polar narcosis type mechanism after two days of exposure and increased fatty acid oxidation after seven and fourteen days of exposure. Univariate statistical analysis revealed that 2-hexyl-5-ethyl-3-furansulfonate (HEFS), betaine, leucine, arginine, glutamate, maltose and ATP are potential indicators of PFOS exposure, as the concentrations of these metabolites fluctuated significantly. Overall, NMR-based metabolomic analysis suggests elevated fatty acid oxidation, disruption in energy metabolism and biological membrane structure and a possible interruption of ATP synthesis. These conclusions obtained from analysis of the metabolic profile in response to sub-lethal PFOS exposure indicates that NMR-based metabolomics is an excellent discovery tool when the mode of action (MOA) of contaminants is not clearly defined. PMID:24958147

  3. 1H NMR-Based Metabolomic Analysis of Sub-Lethal Perfluorooctane Sulfonate Exposure to the Earthworm, Eisenia fetida, in Soil

    PubMed Central

    Lankadurai, Brian P.; Furdui, Vasile I.; Reiner, Eric J.; Simpson, André J.; Simpson, Myrna J.

    2013-01-01

    1H NMR-based metabolomics was used to measure the response of Eisenia fetida earthworms after exposure to sub-lethal concentrations of perfluorooctane sulfonate (PFOS) in soil. Earthworms were exposed to a range of PFOS concentrations (five, 10, 25, 50, 100 or 150 mg/kg) for two, seven and fourteen days. Earthworm tissues were extracted and analyzed by 1H NMR. Multivariate statistical analysis of the metabolic response of E. fetida to PFOS exposure identified time-dependent responses that were comprised of two separate modes of action: a non-polar narcosis type mechanism after two days of exposure and increased fatty acid oxidation after seven and fourteen days of exposure. Univariate statistical analysis revealed that 2-hexyl-5-ethyl-3-furansulfonate (HEFS), betaine, leucine, arginine, glutamate, maltose and ATP are potential indicators of PFOS exposure, as the concentrations of these metabolites fluctuated significantly. Overall, NMR-based metabolomic analysis suggests elevated fatty acid oxidation, disruption in energy metabolism and biological membrane structure and a possible interruption of ATP synthesis. These conclusions obtained from analysis of the metabolic profile in response to sub-lethal PFOS exposure indicates that NMR-based metabolomics is an excellent discovery tool when the mode of action (MOA) of contaminants is not clearly defined. PMID:24958147

  4. Performance analysis of improved methodology for incorporation of spatial/spectral variability in synthetic hyperspectral imagery

    NASA Astrophysics Data System (ADS)

    Scanlan, Neil W.; Schott, John R.; Brown, Scott D.

    2003-12-01

    Synthetic imagery has traditionally been used to support sensor design by enabling design engineers to pre-evaluate image products during the design and development stages. Increasingly exploitation analysts are looking to synthetic imagery as a way to develop and test exploitation algorithms before image data are available from new sensors. Even when sensors are available, synthetic imagery can significantly aid in algorithm development by providing a wide range of "ground truthed" images with varying illumination, atmospheric, viewing and scene conditions. One limitation of synthetic data is that the background variability is often too bland. It does not exhibit the spatial and spectral variability present in real data. In this work, four fundamentally different texture modeling algorithms will first be implemented as necessary into the Digital Imaging and Remote Sensing Image Generation (DIRSIG) model environment. Two of the models to be tested are variants of a statistical Z-Score selection model, while the remaining two involve a texture synthesis and a spectral end-member fractional abundance map approach, respectively. A detailed comparative performance analysis of each model will then be carried out on several texturally significant regions of the resultant synthetic hyperspectral imagery. The quantitative assessment of each model will utilize a set of three peformance metrics that have been derived from spatial Gray Level Co-Occurrence Matrix (GLCM) analysis, hyperspectral Signal-to-Clutter Ratio (SCR) measures, and a new concept termed the Spectral Co-Occurrence Matrix (SCM) metric which permits the simultaneous measurement of spatial and spectral texture. Previous research efforts on the validation and performance analysis of texture characterization models have been largely qualitative in nature based on conducting visual inspections of synthetic textures in order to judge the degree of similarity to the original sample texture imagery. The quantitative

  5. Performance analysis of improved methodology for incorporation of spatial/spectral variability in synthetic hyperspectral imagery

    NASA Astrophysics Data System (ADS)

    Scanlan, Neil W.; Schott, John R.; Brown, Scott D.

    2004-01-01

    Synthetic imagery has traditionally been used to support sensor design by enabling design engineers to pre-evaluate image products during the design and development stages. Increasingly exploitation analysts are looking to synthetic imagery as a way to develop and test exploitation algorithms before image data are available from new sensors. Even when sensors are available, synthetic imagery can significantly aid in algorithm development by providing a wide range of "ground truthed" images with varying illumination, atmospheric, viewing and scene conditions. One limitation of synthetic data is that the background variability is often too bland. It does not exhibit the spatial and spectral variability present in real data. In this work, four fundamentally different texture modeling algorithms will first be implemented as necessary into the Digital Imaging and Remote Sensing Image Generation (DIRSIG) model environment. Two of the models to be tested are variants of a statistical Z-Score selection model, while the remaining two involve a texture synthesis and a spectral end-member fractional abundance map approach, respectively. A detailed comparative performance analysis of each model will then be carried out on several texturally significant regions of the resultant synthetic hyperspectral imagery. The quantitative assessment of each model will utilize a set of three peformance metrics that have been derived from spatial Gray Level Co-Occurrence Matrix (GLCM) analysis, hyperspectral Signal-to-Clutter Ratio (SCR) measures, and a new concept termed the Spectral Co-Occurrence Matrix (SCM) metric which permits the simultaneous measurement of spatial and spectral texture. Previous research efforts on the validation and performance analysis of texture characterization models have been largely qualitative in nature based on conducting visual inspections of synthetic textures in order to judge the degree of similarity to the original sample texture imagery. The quantitative

  6. Analysis of the full-length genome sequence of papaya lethal yellowing virus (PLYV), determined by deep sequencing, confirms its classification in the genus Sobemovirus.

    PubMed

    Pereira, Alvaro J; Alfenas-Zerbini, Poliane; Cascardo, Renan S; Andrade, Eduardo C; Murilo Zerbini, F

    2012-10-01

    Papaya lethal yellowing virus (PLYV) causes an economically important disease in papayas in northeastern Brazil. Based on biological and molecular properties, PLYV has been tentatively assigned to the genus Sobemovirus. We report the sequence of the full-length genome of a PLYV isolate from Brazil, determined by deep sequencing. The PLYV genome is 4,145 nt long and contains four ORFs, with an arrangement identical to that of sobemoviruses. The polyprotein and CP display significant sequence identity with the corresponding proteins of other sobemoviruses. Pairwise comparisons and phylogenetic analysis based on complete nucleotide sequences confirm the classification of PLYV in the genus Sobemovirus. PMID:22743825

  7. Structure-Based Systematic Isolation of Conditional-Lethal Mutations in the Single Yeast Calmodulin Gene

    PubMed Central

    Ohya, Y.; Botstein, D.

    1994-01-01

    Conditional-lethal mutations of the single calmodulin gene in Saccharomyces cerevisiae have been very difficult to isolate by random and systematic methods, despite the fact that deletions cause recessive lethality. We report here the isolation of numerous conditional-lethal mutants that were recovered by systematically altering phenylalanine residues. The phenylalanine residues of calmodulin were implicated in function both by structural studies of calmodulin bound to target peptides and by their extraordinary conservation in evolution. Seven single and 26 multiple Phe -> Ala mutations were constructed. Mutant phenotypes were examined in a haploid cmd1 disrupted strain under three conditions: single copy, low copy, and overexpressed. Whereas all but one of the single mutations caused no obvious phenotype, most of the multiple mutations caused obvious growth phenotypes. Five were lethal, 6 were lethal only in synthetic medium, 13 were temperature-sensitive lethal and 2 had no discernible phenotypic consequences. Overexpression of some of the mutant genes restored the phenotype to nearly wild type. Several temperature-sensitive calmodulin mutations were suppressed by elevated concentration of CaCl(2) in the medium. Mutant calmodulin protein was detected at normal levels in extracts of most of the lethal mutant cells, suggesting that the deleterious phenotypes were due to loss of the calmodulin function and not protein instability. Analysis of diploid strains heterozygous for all combinations of cmd1-ts alleles revealed four intragenic complementation groups. The contributions of individual phe->ala changes to mutant phenotypes support the idea of internal functional redundancy in the symmetrical calmodulin protein molecule. These results suggest that the several phenylalanine residues in calmodulin are required to different extents in different combinations in order to carry out each of the several essential tasks. PMID:7896089

  8. Clinical parameters, postmortem analysis and estimation of lethal dose in victims of a massive intoxication with diethylene glycol.

    PubMed

    Ferrari, Luis A; Giannuzzi, Leda

    2005-10-01

    could be observed. The lethal dose for human beings estimated in this work ranged from 0.014 to 0.170 mg DEG/kg body weight. This is a lower lethal dose than reported in a separate incident in Haiti. These results may contribute to the understanding of DEG's metabolic pathway and provides data from lethal doses in humans. PMID:15979833

  9. Application of non-lethal stable isotope analysis to assess feeding patterns of juvenile pallid sturgeon Scaphirhynchus albus: a comparison of tissue types and sample preservation methods

    USGS Publications Warehouse

    Andvik, R.T.; VanDeHey, J.A.; Fincel, M.J.; French, William E.; Bertrand, K.N.; Chipps, Steven R.; Klumb, R.A.; Graeb, B.D.S.

    2010-01-01

    Traditional techniques for stable isotope analysis (SIA) generally require sacrificing animals to collect tissue samples; this can be problematic when studying diets of endangered species such as the pallid sturgeon Scaphirhynchus albus. Our objectives were to (i) determine if pectoral fin tissue (non-lethal) could be a substitute for muscle tissue (lethal) in SIA of juvenile pallid sturgeon, and (ii) evaluate the influence of preservation techniques on stable isotope values. In the laboratory, individual juvenile pallid sturgeon were held for up to 186 day and fed chironomids, fish, or a commercially available pellet diet. Significant, positive relationships (r² ≥ 0.8) were observed between fin and muscle tissues for both δ15N and δ13C; in all samples isotopes were enriched in fins compared to muscle tissue. Chironomid and fish based diets of juvenile pallid sturgeon were distinguishable for fast growing fish (0.3 mm day−1) using stable δ15N and δ13C isotopes. Frozen and preserved fin tissue δ15N isotopes were strongly related (r2 = 0.89) but δ13C isotopes were weakly related (r2 = 0.16). Therefore, freezing is recommended for preservation of fin clips to avoid the confounding effect of enrichment by ethanol. This study demonstrates the utility of a non-lethal technique to assess time integrated food habits of juvenile pallid sturgeon and should be applicable to other threatened or endangered species.

  10. [Evaluation of the diagnostic usefulness for ultrasonographic and echocardiographic lethal markers in fetal pulmonary hypoplasia. Analysis of 11 cases].

    PubMed

    Kieszek, S; Kaczmarek, P; Czichos, E; Respondek, M

    1996-07-01

    Results of ultrasonographic and echocardiographic studies of 11 fetuses were analysed retrospectively in relation to their pulmonary hypoplasia. Congenital malformations, quality of hydramnios and echocardiographical measurements of fetal chest were estimated. The best symptoms of pulmonary hypoplasia were: oligo/ahydramnios, absence of fetal breathing movements and malformations in fetal chest cavity (diaphragmatic hernia, cardiomegaly, hydrothorax). Systemic malformations were present in each case. The measurements such as CC, CA, HA, (CA-HA) x 100/CA were not accurate enough and we did not find any statistical differences between the control and the studied group. Finding several factors predisposing to lung hypoplasia means that its lethal form may be present in fetus. PMID:9138996

  11. Perspective - Synthetic DEMs: A vital underpinning for the quantitative future of landform analysis?

    NASA Astrophysics Data System (ADS)

    Hillier, John K.; Sofia, Giulia; Conway, Susan

    2015-04-01

    Physical processes, including anthropogenic feedbacks, sculpt planetary surfaces (e.g., Earth's). A fundamental tenet of Geomorphology is that the shapes created, when combined with other measurements, can be used to understand those processes. Morphological data, including metrics and mapping (manual and automated), are a key resource in this endeavour. However, how good are these data that analyses rely on? Artificial or synthetic DEMs are widely used to examine the distortions of 'noise' (e.g., on topographic parameters), but only rarely to make strong 'absolute' statements about landform detection and quantification; e.g., 84% of the river channels in the real landscape are found, or 47% of all actual drumlins H > 3 m are mapped. In theory synthetic DEMs a priori containing known, idealised components can give such absolute conclusions regarding effectiveness if they can be constructed so as to represent well the actual landscapes. So, do we need good realistic synthetic DEMs, how can we best construct them, and what for? From our perspective, they are vital to verify the statistics that will link physics-driven models of processes to morphological observations, allowing quantitative hypotheses to be formulated and tested. We will outline current approaches, and some speculations about the future, but we are seeking a discussion on how best to construct realistic synthetic DEMs and proceed with uncertainty-aware landscape analysis to examine physical processes.

  12. Fractal image analysis - Application to the topography of Oregon and synthetic images.

    NASA Technical Reports Server (NTRS)

    Huang, Jie; Turcotte, Donald L.

    1990-01-01

    Digitized topography for the state of Oregon has been used to obtain maps of fractal dimension and roughness amplitude. The roughness amplitude correlates well with variations in relief and is a promising parameter for the quantitative classification of landforms. The spatial variations in fractal dimension are low and show no clear correlation with different tectonic settings. For Oregon the mean fractal dimension from a two-dimensional spectral analysis is D = 2.586, and for a one-dimensional spectral analysis the mean fractal dimension is D = 1.487, which is close to the Brown noise value D = 1.5. Synthetic two-dimensional images have also been generated for a range of D values. For D = 2.6, the synthetic image has a mean one-dimensional spectral fractal dimension D = 1.58, which is consistent with the results for Oregon. This approach can be easily applied to any digitzed image that obeys fractal statistics.

  13. Coal liquefaction processes and development requirements analysis for synthetic fuels production

    NASA Technical Reports Server (NTRS)

    1980-01-01

    Focus of the study is on: (1) developing a technical and programmatic data base on direct and indirect liquefaction processes which have potential for commercialization during the 1980's and beyond, and (2) performing analyses to assess technology readiness and development trends, development requirements, commercial plant costs, and projected synthetic fuel costs. Numerous data sources and references were used as the basis for the analysis results and information presented.

  14. Synthetic fuels and the environment: an environmental and regulatory impacts analysis

    SciTech Connect

    1980-06-01

    Since July 1979 when DOE/EV-0044 report Environmental Analysis of Synthetic Liquid fuels was published the synthetic fuels program proposals of the Administration have undergone significant modifications. The program year for which the development goal of 1.5 million barrels per day is to be reached has been changed from 1990 to 1995. The program plan is now proposed to have two stages to ensure, among other things, better environmental protection: an initial stage emphasizing applied research and development (R and D), including environmental research, followed by a second stage that would accelerate deployment of those synthetic fuel technologies then judged most ready for rapid deployment and economic operation within the environmental protection requirements. These program changes have significantly expanded the scope of technologies to be considered in this environmental analysis and have increased the likelihood that accelerated environmental R and D efforts will be successful in solving principal environmental and worker safety concerns for most technologies prior to the initiation of the second stage of the accelerated deployment plan. Information is presented under the following section headings: summary; study description; the technologies and their environmental concerns (including, coal liquefaction and gasification, oil shale production, biomass and urban waste conversion); regulatory and institutional analyses; and environmental impacts analysis (including air and water quaility analyses, impacts of carbon dioxide and acid rain, water availability, solid and hazardous wastes, coal mining environmental impacts, transportation issues, community growth and change, and regional impacts). Additional information is presented in seventeen appendixes. (JGB)

  15. Rapid in vivo analysis of synthetic promoters for plant pathogen phytosensing

    PubMed Central

    2011-01-01

    Background We aimed to engineer transgenic plants for the purpose of early detection of plant pathogen infection, which was accomplished by employing synthetic pathogen inducible promoters fused to reporter genes for altered phenotypes in response to the pathogen infection. Toward this end, a number of synthetic promoters consisting of inducible regulatory elements fused to a red fluorescent protein (RFP) reporter were constructed for use in phytosensing. Results For rapid analysis, an Agrobacterium-mediated transient expression assay was evaluated, then utilized to assess the inducibility of each synthetic promoter construct in vivo. Tobacco (Nicotiana tabacum cv. Xanthi) leaves were infiltrated with Agrobacterium harboring the individual synthetic promoter-reporter constructs. The infiltrated tobacco leaves were re-infiltrated with biotic (bacterial pathogens) or abiotic (plant defense signal molecules salicylic acid, ethylene and methyl jasmonate) agents 24 and 48 hours after initial agroinfiltration, followed by RFP measurements at relevant time points after treatment. These analyses indicated that the synthetic promoter constructs were capable of conferring the inducibility of the RFP reporter in response to appropriate phytohormones and bacterial pathogens, accordingly. Conclusions These observations demonstrate that the Agrobacterium-mediated transient expression is an efficient method for in vivo assays of promoter constructs in less than one week. Our results provide the opportunity to gain further insights into the versatility of the expression system as a potential tool for high-throughput in planta expression screening prior to generating stably transgenic plants for pathogen phytosensing. This system could also be utilized for temporary phytosensing; e.g., not requiring stably transgenic plants. PMID:22093754

  16. Functional analysis of endoplasmic reticulum glucosyltransferase (UGGT): Synthetic chemistry's initiative in glycobiology.

    PubMed

    Ito, Yukishige; Takeda, Yoichi; Seko, Akira; Izumi, Masayuki; Kajihara, Yasuhiro

    2015-05-01

    UGGT1 is called as a folding sensor protein that recognizes misfolded glycoproteins and selectively glucosylates high-mannose-type glycans on the proteins. However, conventional approaches using naturally occurring glycoproteins is not optimum in performing precise analysis of the unique properties of UGGT1. We have demonstrated that high-mannose-type glycans, in which various hydrophobic aglycons were introduced, act as good substrates for UGGT1 and are useful analytical tools for its characterization. Moreover, we found that UGGT2, an isoform UGGT1, is also capable of glucosylating these synthetic substrates. Our strategy stemmed on synthetic chemistry has been further strengthened by total synthesis of homogeneous glycoproteins in correctly folded as well as in intentionally misfolded forms. PMID:25481681

  17. Quantitative Analysis of Cis-Regulatory Element Activity Using Synthetic Promoters in Transgenic Plants.

    PubMed

    Benn, Geoffrey; Dehesh, Katayoon

    2016-01-01

    Synthetic promoters, introduced stably or transiently into plants, are an invaluable tool for the identification of functional regulatory elements and the corresponding transcription factor(s) that regulate the amplitude, spatial distribution, and temporal patterns of gene expression. Here, we present a protocol describing the steps required to identify and characterize putative cis-regulatory elements. These steps include application of computational tools to identify putative elements, construction of a synthetic promoter upstream of luciferase, identification of transcription factors that regulate the element, testing the functionality of the element introduced transiently and/or stably into the species of interest followed by high-throughput luciferase screening assays, and subsequent data processing and statistical analysis. PMID:27557758

  18. Analysis and optimization of a synthetic milkweed floral attractant for mosquitoes.

    PubMed

    Otienoburu, Philip E; Ebrahimi, Babak; Phelan, P Larry; Foster, Woodbridge A

    2012-07-01

    A pentane extract of flowers of common milkweed, Asclepias syriaca (Asclepiadaceae), elicited significant orientation from both male and female Culex pipiens in a dual-port flight olfactometer. Analysis of the extract by gas chromatography-mass spectrometry revealed six major constituents in order of relative abundance: benzaldehyde, (E)-β-ocimene, phenylacetaldehyde, benzyl alcohol, nonanal, and (E)-2-nonenal. Although not all were collected from the headspace profile of live flowers, a synthetic blend of these six compounds, when presented to mosquitoes in the same levels and proportions that occur in the extract, elicited a response comparable to the extract. Subtractive behavioral bioassays demonstrated that a three-component blend consisting of benzaldehyde, phenylacetaldehyde, and (E)-2-nonenal was as attractive as the full blend. These findings suggest the potential use of synthetic floral-odor blends for monitoring or control of both male and female disease-vectoring mosquitoes. PMID:22711028

  19. Metabolomics Analysis Identifies D-Alanine-D-alanine Ligase as the Primary Lethal Target of D-cycloserine in Mycobacteria

    PubMed Central

    Halouska, Steven; Fenton, Robert J.; Zinniel, Denise K.; Marshall, Darrell D.; Barletta, Raúl G.; Powers, Robert

    2014-01-01

    D-cycloserine is an effective second line antibiotic used as a last resort to treat multi (MDR)- and extensively (XDR)- drug resistant strains of Mycobacterium tuberculosis. D-cycloserine interferes with the formation of peptidoglycan biosynthesis by competitive inhibition of Alanine racemase (Alr) and D-Alanine-D-alanine ligase (Ddl). Although, the two enzymes are known to be inhibited, the in vivo lethal target is still unknown. Our NMR metabolomics work has revealed that Ddl is the primary target of DCS, as cell growth is inhibited when the production of D-alanyl-D-alanine is halted. It is shown that inhibition of Alr may contribute indirectly by lowering the levels of D-alanine thus allowing DCS to outcompete D-alanine for Ddl binding. The NMR data also supports the possibility of a transamination reaction to produce D-alanine from pyruvate and glutamate, thereby bypassing Alr inhibition. Furthermore, the inhibition of peptidoglycan synthesis results in a cascading effect on cellular metabolism as there is a shift toward the catabolic routes to compensate for accumulation of peptidoglycan precursors. PMID:24303782

  20. Fiber optic evaporation analysis of environmental parameters and of synthetic urine samples

    NASA Astrophysics Data System (ADS)

    Preter, Eyal; Katzman, Moshe; Oren, Ziv; Ronen, Maria; Gerber, Doron; Zadok, Avi

    2015-09-01

    The evaporation rate of water droplets is evaluated as a function of temperature and relative humidity using a fiber-optic sensor. Either parameter may be monitored when the other is known, with uncertainties of 0.5 deg. C or 1.5% relative humidity. Further, the sensor is used in the analysis of negative control synthetic solutions, made to mimic human urine. Samples of binary mixtures of the solution with water at different volume ratios are categorized using correlation analysis of the recorded evaporation dynamics, with 87% success. The results represent an important first step towards potential use of the sensor in point-of-care diagnostics.

  1. Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder.

    PubMed

    Mortier, G R; Weis, M; Nuytinck, L; King, L M; Wilkin, D J; De Paepe, A; Lachman, R S; Rimoin, D L; Eyre, D R; Cohn, D H

    2000-04-01

    Achondrogenesis II-hypochondrogenesis and severe spondyloepiphyseal dysplasia congenita (SEDC) are lethal forms of dwarfism caused by dominant mutations in the type II collagen gene (COL2A1). To identify the underlying defect in seven cases with this group of conditions, we used the combined strategy of cartilage protein analysis and COL2A1 mutation analysis. Overmodified type II collagen and the presence of type I collagen was found in the cartilage matrix of all seven cases. Five patients were heterozygous for a nucleotide change that predicted a glycine substitution in the triple helical domain (G313S, G517V, G571A, G910C, G943S). In all five cases, analysis of cartilage type II collagen suggested incorporation of the abnormal alpha1(II) chain in the extracellular collagen trimers. The G943S mutation has been reported previously in another unrelated patient with a strikingly similar phenotype, illustrating the possible specific effect of the mutation. The radiographically less severely affected patient was heterozygous for a 4 bp deletion in the splice donor site of intron 35, likely to result in aberrant splicing. One case was shown to be heterozygous for a single nucleotide change predicted to result in a T1191N substitution in the carboxy-propeptide of the proalpha1(II) collagen chain. Study of the clinical, radiographic, and morphological features of the seven cases supports evidence for a phenotypic continuum between achondrogenesis II-hypochondrogenesis and lethal SEDC and suggests a relationship between the amount of type I collagen in the cartilage and the severity of the phenotype. PMID:10745044

  2. A high-throughput pipeline for the production of synthetic antibodies for analysis of ribonucleoprotein complexes.

    PubMed

    Na, Hong; Laver, John D; Jeon, Jouhyun; Singh, Fateh; Ancevicius, Kristin; Fan, Yujie; Cao, Wen Xi; Nie, Kun; Yang, Zhenglin; Luo, Hua; Wang, Miranda; Rissland, Olivia; Westwood, J Timothy; Kim, Philip M; Smibert, Craig A; Lipshitz, Howard D; Sidhu, Sachdev S

    2016-04-01

    Post-transcriptional regulation of mRNAs plays an essential role in the control of gene expression. mRNAs are regulated in ribonucleoprotein (RNP) complexes by RNA-binding proteins (RBPs) along with associated protein and noncoding RNA (ncRNA) cofactors. A global understanding of post-transcriptional control in any cell type requires identification of the components of all of its RNP complexes. We have previously shown that these complexes can be purified by immunoprecipitation using anti-RBP synthetic antibodies produced by phage display. To develop the large number of synthetic antibodies required for a global analysis of RNP complex composition, we have established a pipeline that combines (i) a computationally aided strategy for design of antigens located outside of annotated domains, (ii) high-throughput antigen expression and purification in Escherichia coli, and (iii) high-throughput antibody selection and screening. Using this pipeline, we have produced 279 antibodies against 61 different protein components of Drosophila melanogaster RNPs. Together with those produced in our low-throughput efforts, we have a panel of 311 antibodies for 67 RNP complex proteins. Tests of a subset of our antibodies demonstrated that 89% immunoprecipitate their endogenous target from embryo lysate. This panel of antibodies will serve as a resource for global studies of RNP complexes in Drosophila. Furthermore, our high-throughput pipeline permits efficient production of synthetic antibodies against any large set of proteins. PMID:26847261

  3. Amphetamine binding to synthetic melanin and scatchard analysis of binding data.

    PubMed

    Gautam, Lata; Scott, Karen S; Cole, Michael D

    2005-01-01

    Previous research into drug-hair binding shows that hair color affects drug-hair binding. There are no structural disparities in hair of different colors other than the type and content of melanin present. For this reason, this investigation focuses on synthetic eumelanin as a site for drug interaction using amphetamine as the candidate drug. The binding study was carried out at room temperature. The interaction between synthetic eumelanin and amphetamine was monitored using UV-Vis spectrophotometry at 257.2 nm. As the molecular weight of melanin is unknown, the number of binding sites could not be calculated directly. Hence the ratio of the number of mumoles of drug bound and the dry weight of melanin in mug was considered. Equilibrium was reached when approximately 32% of the drug was bound to melanin. Hence this study proves that amphetamine binds to synthetic eumelanin in vitro. Data interpretation using Scatchard analysis yielded a curvilinear plot with upward concavity indicating multiple binding sites on melanin and negative cooperativity. PMID:16105258

  4. Synthetic environments

    NASA Astrophysics Data System (ADS)

    Lukes, George E.; Cain, Joel M.

    1996-02-01

    The Advanced Distributed Simulation (ADS) Synthetic Environments Program seeks to create robust virtual worlds from operational terrain and environmental data sources of sufficient fidelity and currency to interact with the real world. While some applications can be met by direct exploitation of standard digital terrain data, more demanding applications -- particularly those support operations 'close to the ground' -- are well-served by emerging capabilities for 'value-adding' by the user working with controlled imagery. For users to rigorously refine and exploit controlled imagery within functionally different workstations they must have a shared framework to allow interoperability within and between these environments in terms of passing image and object coordinates and other information using a variety of validated sensor models. The Synthetic Environments Program is now being expanded to address rapid construction of virtual worlds with research initiatives in digital mapping, softcopy workstations, and cartographic image understanding. The Synthetic Environments Program is also participating in a joint initiative for a sensor model applications programer's interface (API) to ensure that a common controlled imagery exploitation framework is available to all researchers, developers and users. This presentation provides an introduction to ADS and the associated requirements for synthetic environments to support synthetic theaters of war. It provides a technical rationale for exploring applications of image understanding technology to automated cartography in support of ADS and related programs benefitting from automated analysis of mapping, earth resources and reconnaissance imagery. And it provides an overview and status of the joint initiative for a sensor model API.

  5. Estimation of the synthetic routes of seized methamphetamines using GC-MS and multivariate analysis.

    PubMed

    Choe, Sanggil; Lee, Jaesin; Choi, Hyeyoung; Park, Yujin; Lee, Heesang; Jo, Jiyeong; Park, Yonghoon; Kim, Eunmi; Pyo, Jaesung; Lee, Hun Joo; Kim, Suncheun

    2016-02-01

    One hundred and twenty six seized methamphetamine (MA) samples were analyzed using GC-MS. All the peaks that appeared in the chromatograms were investigated and 61 impurities including n-octacosane (internal standard) were identified. Among them, 37 impurities were already known or newly identified by comparing with commercial library entries and 18 impurities were detected for the first time. To estimate the synthetic routes of MA samples, route specific impurities had to be selected for each method. Two naphthalenes, 1,3-dimethyl-2-phenylnaphthalene and 1-benzyl-3-methylnaphthalene were selected as Nagai route specific impurities and three diasteromers, UK-19.62(58_165_178) I, UK-19.95(58_165_178) II, UK-20.49(58_165_178) III were also selected not only for their high frequency detection only in Nagai samples but also for the high principal component analysis (PCA) correlation values. For the Emde route, N,N-dimethyl-3,4-diphenylhexane-2,5-diamine and N-methyl-1-{4-[2-(methylamino)propyl]phenyl}-1-phenylpropan-2-amine were selected as route specific impurities, and N,N-di(β-phenylisopropyl)amine I (DPIA I), N,N-di(β-phenylisopropyl)amine II (DPIA II), N,N-di(β-phenylisopropyl)methylamine I (DPIMA I) and N,N-di(β-phenylisopropyl)methylamine II (DPIMA II) were selected for the Leuckart route. With these route specific impurities, synthetic routes could be identified for 78 of the 126 samples. The 61 impurities were registered in AMDIS target component library and the GC-MS data were deconvoluted. After AMDIS deconvolution, a matrix file was composed and then multivariate analyses were performed to estimate the synthetic route for unknown samples. The unsupervised methods, hierarchical clustering analysis (HCA) and PCA clustered the samples according to the closeness between samples. Two classification functions were obtained from discriminant analysis (DA) and the synthetic routes of the unknown samples were predicted using these two functions. PMID:26765094

  6. Analysis of mechanical strength to fixing the femoral neck fracture in synthetic bone type Asnis

    PubMed Central

    Freitas, Anderson; Lula, Welder Fernandes; de Oliveira, Jonathan Sampaio; Maciel, Rafael Almeida; Souto, Diogo Ranier de Macedo; Godinho, Patrick Fernandes

    2014-01-01

    OBJECTIVE: To analyze the results of biomechanical assays of fixation of Pauwels type III femoral neck fracture in synthetic bone, using 7.5mm cannulated screws in inverted triangle formation, in relation to the control group. METHODS: Ten synthetic bones were used, from a domestic brand, divided into two groups: test and control. In the test group, a 70° tilt osteotomy of the femoral neck was fixated using three cannulated screws in inverted triangle formation. The resistance of this fixation and its rotational deviation were analyzed at 5mm displacement (phase 1) and 10mm displacement (phase 2). The control group was tested in its integrity until the fracture of the femoral neck occurred. The Mann-Whitney test was used for group analysis and comparison. RESULTS: The values in the test group in phase 1, in samples 1-5, showed a mean of 579N and SD =77N. Rotational deviations showed a mean of 3.33°, SD = 2.63°. In phase 2, the mean was 696N and SD =106N. The values of the maximum load in the control group had a mean of 1329N and SD=177N. CONCLUSION: The analysis of mechanical strength between the groups determined a statistically significant lower value in the test group. Level of Evidence III, Control Case. PMID:25246851

  7. Analysis coherent signal processing methods in synthetic aperture radar on small-scale viewing angles under voluntary movement aircraft

    NASA Astrophysics Data System (ADS)

    Anikin, Sergey N.; Vishentsev, Mihail V.; Stukalova, Anna S.

    2007-02-01

    In the article realize analysis the coherent processing method which uses to form synthetic aperture antenna on a board of aircraft. The factors, which send for distortion radar image on small-scale viewing angle during high-intensity maneuvering velocity shown for considering method of synthesizing aperture antenna. A synthetic aperture antenna software model was designing and analyzing. Some results of research of the coherent processing methods for receiving earth's imagery are shown.

  8. Quantitative wake analysis of a freely swimming fish using 3D synthetic aperture PIV

    NASA Astrophysics Data System (ADS)

    Mendelson, Leah; Techet, Alexandra H.

    2015-07-01

    Synthetic aperture PIV (SAPIV) is used to quantitatively analyze the wake behind a giant danio ( Danio aequipinnatus) swimming freely in a seeded quiescent tank. The experiment is designed with minimal constraints on animal behavior to ensure that natural swimming occurs. The fish exhibits forward swimming and turning behaviors at speeds between 0.9 and 1.5 body lengths/second. Results show clearly isolated and linked vortex rings in the wake structure, as well as the thrust jet coming off of a visual hull reconstruction of the fish body. As a benchmark for quantitative analysis of volumetric PIV data, the vortex circulation and impulse are computed using methods consistent with those applied to planar PIV data. Volumetric momentum analysis frameworks are discussed for linked and asymmetric vortex structures, laying a foundation for further volumetric studies of swimming hydrodynamics with SAPIV. Additionally, a novel weighted refocusing method is presented as an improvement to SAPIV reconstruction.

  9. Proteomic analysis of differentiating neuroblastoma cells treated with sub-lethal neurite inhibitory concentrations of diazinon: Identification of novel biomarkers of effect

    SciTech Connect

    Harris, W.; Sachana, M.; Flaskos, J.; Hargreaves, A.J.

    2009-10-15

    In previous work we showed that sub-lethal levels of diazinon inhibited neurite outgrowth in differentiating N2a neuroblastoma cells. Western blotting analysis targeted at proteins involved in axon growth and stress responses, revealed that such exposure led to a reduction in the levels of neurofilament heavy chain, microtubule associated protein 1 B (MAP 1B) and HSP-70. The aim of this study was to apply the approach of 2 dimensional polyacrylamide gel electrophoresis and mass spectrometry to identify novel biomarkers of effect. A number of proteins were found to be up-regulated compared to the control on silver-stained gels. These were classified in to 3 main groups of proteins: cytosolic factors, chaperones and the actin-binding protein cofilin, all of which are involved in cell differentiation, survival or metabolism. The changes observed for cofilin were further confirmed by quantitative Western blotting analysis with anti-actin and anti-cofilin antibodies. Indirect immunofluorescence staining with the same antibodies indicated that the microfilament network was disrupted in diazinon-treated cells. Our data suggest that microfilament organisation is disrupted by diazinon exposure, which may be related to increased cofilin expression.

  10. [Analysis of 5S rDNA changes in synthetic allopolyploids Triticum x Aegilops].

    PubMed

    Shcherban', A B; Sergeeva, E M; Badaeva, E D; Salina, E A

    2008-01-01

    By the example of three synthetic allopolyploids: Aegilops sharonensis x Ae. umbellulata (2n =28), Triticum urartu x Ae. tauschii (2n =28), T. dicoccoides x Ae. tauschii (2n =42) the 5S rDNA changes at the early stage of allopolyploidization were investigated. Using fluorescent in situ hybridization (FISH), the quantitative changes affecting the separate loci of one of the parental genomes were revealed in plants of S3 generation of each hybrid combination. Souther hybridization with genomic DNA of allopolyploid T. urartu x Ae. tauschii (TMU38 x TQ27) revealed lower intensity of the fragments from Ae. tauschii compared with the T. urartu fragments. It may be confirmation of the reduction of signal on 1D chromosome that was revealed in this hybrid using FISH. Both appearance of a new 5S rDNA fragments and full disappearance of fragments from parental species were not showed by Southern hybridization, as well as PCR-analysis of 5-15 plants of S2-S3 generations. The changes were not found under comparison of primary structure of nine 5S rDNA sequences of allopolyploid TMU38 x TQ27 with analogous sequences from parental species genomes. The observable similarity by FISH results of one of the studied synthetic allopolyploids with natural allopolyploid of similar genome composition indicates the early formation of unique for each allopolyploid 5S rDNA organization. PMID:18856060

  11. Nuclear Test Depth Determination with Synthetic Modelling: Global Analysis from PNEs to DPRK-2016

    NASA Astrophysics Data System (ADS)

    Rozhkov, Mikhail; Stachnik, Joshua; Baker, Ben; Epiphansky, Alexey; Bobrov, Dmitry

    2016-04-01

    Seismic event depth determination is critical for the event screening process at the International Data Center, CTBTO. A thorough determination of the event depth can be conducted mostly through additional special analysis because the IDC's Event Definition Criteria is based, in particular, on depth estimation uncertainties. This causes a large number of events in the Reviewed Event Bulletin to have depth constrained to the surface making the depth screening criterion not applicable. Further it may result in a heavier workload to manually distinguish between subsurface and deeper crustal events. Since the shape of the first few seconds of signal of very shallow events is very sensitive to the depth phases, cross correlation between observed and theoretic seismograms can provide a basis for the event depth estimation, and so an expansion to the screening process. We applied this approach mostly to events at teleseismic and partially regional distances. The approach was found efficient for the seismic event screening process, with certain caveats related mostly to poorly defined source and receiver crustal models which can shift the depth estimate. An adjustable teleseismic attenuation model (t*) for synthetics was used since this characteristic is not known for most of the rays we studied. We studied a wide set of historical records of nuclear explosions, including so called Peaceful Nuclear Explosions (PNE) with presumably known depths, and recent DPRK nuclear tests. The teleseismic synthetic approach is based on the stationary phase approximation with hudson96 program, and the regional modelling was done with the generalized ray technique by Vlastislav Cerveny modified to account for the complex source topography. The software prototype is designed to be used for the Expert Technical Analysis at the IDC. With this, the design effectively reuses the NDC-in-a-Box code and can be comfortably utilized by the NDC users. The package uses Geotool as a front-end for data

  12. Synthetic Aperture Radar Interferometry for Digital Elevation Model of Kuwait Desert - Analysis of Errors

    NASA Astrophysics Data System (ADS)

    Jassar, H. K. Al; Rao, K. S.

    2012-07-01

    Using different combinations of 29 Advanced Synthetic Aperture Radar (ASAR) images, 43 Digital Elevations Models (DEM) were generated adopting SAR Interferometry (InSAR) technique. Due to sand movement in desert terrain, there is a poor phase correlation between different SAR images. Therefore, suitable methodology for generating DEMs of Kuwait desert terrain using InSAR technique were worked out. Time series analysis was adopted to derive the best DEM out of 43 DEMs. The problems related to phase de-correlation over desert terrain are discussed. Various errors associated with the DEM generation are discussed which include atmospheric effects, penetration into soil medium, sand movement. The DEM of Shuttle Radar Topography Mission (SRTM) is used as a reference. The noise levels of DEM of SRTM are presented.

  13. Fourier analysis of parallel inexact Block-Jacobi splitting with transport synthetic acceleration in slab geometry

    SciTech Connect

    Rosa, M.; Warsa, J. S.; Chang, J. H.

    2006-07-01

    A Fourier analysis is conducted for the discrete-ordinates (SN) approximation of the neutron transport problem solved with Richardson iteration (Source Iteration) and Richardson iteration preconditioned with Transport Synthetic Acceleration (TSA), using the Parallel Block-Jacobi (PBJ) algorithm. Both 'traditional' TSA (TTSA) and a 'modified' TSA (MTSA), in which only the scattering in the low order equations is reduced by some non-negative factor {beta} and < 1, are considered. The results for the un-accelerated algorithm show that convergence of the PBJ algorithm can degrade. The PBJ algorithm with TTSA can be effective provided the {beta} parameter is properly tuned for a given scattering ratio c, but is potentially unstable. Compared to TTSA, MTSA is less sensitive to the choice of {beta}, more effective for the same computational effort (c'), and it is unconditionally stable. (authors)

  14. Critical analysis on nanostructured CoFeB synthetic orthogonal ferrimagnet

    SciTech Connect

    Chen, Y. S.; Lin, J. G.; Cheng, Chih-Wei; Chern, G.

    2014-09-21

    Critical analysis on the magnetic properties of synthetic ferrimagnet (SyF), Ta/MgO/CoFeB/Ru/CoFeB/MgO/Ta, is demonstrated via both static and dynamic techniques. With the Ru thickness being 2.3 nm, the coupling between two CoFeB layers becomes orthogonal, which can be used for spin-transfer-torque nano-oscillator (STNO). The fitting of angular dependent ferromagnetic resonance (FMR) allows the precise determination of magnetic anisotropy of each CoFeB layer, the relative magnetizations and the exchange field near the frequency of STNO applications. In addition, the mechanism of resonance broadening at out-of-plane direction is identified to be magnetic inhomogeneity by fitting the angular dependent linewidth of FMR spectra, which provides indispensable information for the future design of STNO devices.

  15. Synthetic graph generation for data-intensive HPC benchmarking: Scalability, analysis and real-world application

    SciTech Connect

    Powers, Sarah S.; Lothian, Joshua

    2014-12-01

    The benchmarking effort within the Extreme Scale Systems Center at Oak Ridge National Laboratory seeks to provide High Performance Computing benchmarks and test suites of interest to the DoD sponsor. The work described in this report is a part of the effort focusing on graph generation. A previously developed benchmark, SystemBurn, allows the emulation of a broad spectrum of application behavior profiles within a single framework. To complement this effort, similar capabilities are desired for graph-centric problems. This report described the in-depth analysis of the generated synthetic graphs' properties at a variety of scales using different generator implementations and examines their applicability to replicating real world datasets.

  16. Analysis of wideband forward looking synthetic aperture radar for sensing land mines

    NASA Astrophysics Data System (ADS)

    Kovvali, Narayan; Carin, Lawrence

    2004-08-01

    Signal processing algorithms are considered for the analysis of wideband, forward looking synthetic aperture radar data and for sensing metal and plastic land mines, with principal application to unpaved roads. Simple prescreening algorithms are considered for reduction of the search space required for a subsequent classifier. The classifier employs features based on viewing the target at multiple ranges, with classification implemented via a support vector machine and a relevance vector machine (RVM). Concerning classifier training, we consider cases for which training is performed on both mine and nonmine (clutter) data. In addition, motivated by the fact that the clutter statistics may vary significantly between the training and testing data, we also consider RVM implementation when we only train on mine data.

  17. Genomewide Clonal Analysis of Lethal Mutations in the Drosophila melanogaster Eye: Comparison of the X Chromosome and Autosomes

    PubMed Central

    Call, Gerald B.; Olson, John M.; Chen, Jiong; Villarasa, Nikki; Ngo, Kathy T.; Yabroff, Allison M.; Cokus, Shawn; Pellegrini, Matteo; Bibikova, Elena; Bui, Chris; Cespedes, Albert; Chan, Cheryl; Chan, Stacy; Cheema, Amrita K.; Chhabra, Akanksha; Chitsazzadeh, Vida; Do, Minh-Tu; Fang, Q. Angela; Folick, Andrew; Goodstein, Gelsey L.; Huang, Cheng R.; Hung, Tony; Kim, Eunha; Kim, William; Kim, Yulee; Kohan, Emil; Kuoy, Edward; Kwak, Robert; Lee, Eric; Lee, JiEun; Lin, Henry; Liu, H-C. Angela; Moroz, Tatiana; Prasad, Tharani; Prashad, Sacha L.; Patananan, Alexander N.; Rangel, Alma; Rosselli, Desiree; Sidhu, Sohrab; Sitz, Daniel; Taber, Chelsea E.; Tan, Jingwen; Topp, Kasey; Tran, PhuongThao; Tran, Quynh-Minh; Unkovic, Mary; Wells, Maggie; Wickland, Jessica; Yackle, Kevin; Yavari, Amir; Zaretsky, Jesse M.; Allen, Christopher M.; Alli, Latifat; An, Ju; Anwar, Abbas; Arevalo, Sonia; Ayoub, Danny; Badal, Shawn S.; Baghdanian, Armonde; Baghdanian, Arthur H.; Baumann, Sara A.; Becerra, Vivian N.; Chan, Hei J.; Chang, Aileen E.; Cheng, Xibin A.; Chin, Mabel; Chong, Fleurette; Crisostomo, Carlyn; Datta, Sanjit; Delosreyes, Angela; Diep, Francie; Ekanayake, Preethika; Engeln, Mark; Evers, Elizabeth; Farshidi, Farzin; Fischer, Katrina; Formanes, Arlene J.; Gong, Jun; Gupta, Riju; Haas, Blake E.; Hahm, Vicky; Hsieh, Michael; Hui, James Z.; Iao, Mei L.; Jin, Sophia D.; Kim, Angela Y.; Kim, Lydia S-H.; King, Megan; Knudsen-Robbins, Chloe; Kohanchi, David; Kovshilovskaya, Bogdana; Ku, Amy; Kung, Raymond W.; Landig, Mark E. L.; Latterman, Stephanie S.; Lauw, Stephanie S.; Lee, Daniel S.; Lee, Joann S.; Lei, Kai C.; Leung, Lesley L.; Lerner, Renata; Lin, Jian-ya; Lin, Kathleen; Lim, Bryon C.; Lui, Crystal P. Y.; Liu, Tiffany Q.; Luong, Vincent; Makshanoff, Jacob; Mei, An-Chi; Meza, Miguel; Mikhaeil, Yara A.; Moarefi, Majid; Nguyen, Long H.; Pai, Shekhar S.; Pandya, Manish; Patel, Aadit R.; Picard, Paul D.; Safaee, Michael M.; Salame, Carol; Sanchez, Christian; Sanchez, Nina; Seifert, Christina C.; Shah, Abhishek; Shilgevorkyan, Oganes H.; Singh, Inderroop; Soma, Vanessa; Song, Junia J.; Srivastava, Neetika; Sta.Ana, Jennifer L.; Sun, Christie; Tan, Diane; Teruya, Alison S.; Tikia, Robyn; Tran, Trinh; Travis, Emily G.; Trinh, Jennifer D.; Vo, Diane; Walsh, Thomas; Wong, Regan S.; Wu, Katherine; Wu, Ya-Whey; Yang, Nkau X. V.; Yeranosian, Michael; Yu, James S.; Zhou, Jennifer J.; Zhu, Ran X.; Abrams, Anna; Abramson, Amanda; Amado, Latiffe; Anderson, Jenny; Bashour, Keenan; Beyer, Elsa; Bookatz, Allen; Brewer, Sarah; Buu, Natalie; Calvillo, Stephanie; Cao, Joseph; Chan, Amy; Chan, Jenny; Chang, Aileen; Chang, Daniel; Chang, Yuli; Chen, YiBing; Choi, Joo; Chou, Jeyling; Dang, Peter; Datta, Sumit; Davarifar, Ardy; Deravanesian, Artemis; Desai, Poonam; Fabrikant, Jordan; Farnad, Shahbaz; Fu, Katherine; Garcia, Eddie; Garrone, Nick; Gasparyan, Srpouhi; Gayda, Phyllis; Go, Sherrylene; Goffstein, Chad; Gonzalez, Courtney; Guirguis, Mariam; Hassid, Ryan; Hermogeno, Brenda; Hong, Julie; Hong, Aria; Hovestreydt, Lindsay; Hu, Charles; Huff, Devon; Jamshidian, Farid; Jen, James; Kahen, Katrin; Kao, Linda; Kelley, Melissa; Kho, Thomas; Kim, Yein; Kim, Sarah; Kirkpatrick, Brian; Langenbacher, Adam; Laxamana, Santino; Lee, Janet; Lee, Chris; Lee, So-Youn; Lee, ToHang S.; Lee, Toni; Lewis, Gemma; Lezcano, Sheila; Lin, Peter; Luu, Thanh; Luu, Julie; Marrs, Will; Marsh, Erin; Marshall, Jamie; Min, Sarah; Minasian, Tanya; Minye, Helena; Misra, Amit; Morimoto, Miles; Moshfegh, Yasaman; Murray, Jessica; Nguyen, Kha; Nguyen, Cynthia; Nodado, Ernesto; O'Donahue, Amanda; Onugha, Ndidi; Orjiakor, Nneka; Padhiar, Bhavin; Paul, Eric; Pavel-Dinu, Mara; Pavlenko, Alex; Paz, Edwin; Phaklides, Sarah; Pham, Lephong; Poulose, Preethi; Powell, Russell; Pusic, Aya; Ramola, Divi; Regalia, Kirsten; Ribbens, Meghann; Rifai, Bassel; Saakyan, Manyak; Saarikoski, Pamela; Segura, Miriam; Shadpour, Farnaz; Shemmassian, Aram; Singh, Ramnik; Singh, Vivek; Skinner, Emily; Solomin, Daniel; Soneji, Kosha; Spivey, Kristin; Stageberg, Erika; Stavchanskiy, Marina; Tekchandani, Leena; Thai, Leo; Thiyanaratnam, Jayantha; Tong, Maurine; Toor, Aneet; Tovar, Steve; Trangsrud, Kelly; Tsang, Wah-Yung; Uemura, Marc; Vollmer, Emily; Weiss, Emily; Wood, Damien; Wu, Joy; Wu, Sophia; Wu, Winston; Xu, Qing; Yamauchi, Yuki; Yarosh, Will; Yee, Laura; Yen, George; Banerjee, Utpal

    2007-01-01

    Using a large consortium of undergraduate students in an organized program at the University of California, Los Angeles (UCLA), we have undertaken a functional genomic screen in the Drosophila eye. In addition to the educational value of discovery-based learning, this article presents the first comprehensive genomewide analysis of essential genes involved in eye development. The data reveal the surprising result that the X chromosome has almost twice the frequency of essential genes involved in eye development as that found on the autosomes. PMID:17720911

  18. Gene expression analysis of host innate immune responses in the central nervous system following lethal CVS-11 infection in mice.

    PubMed

    Sugiura, Naoko; Uda, Akihiko; Inoue, Satoshi; Kojima, Daisuke; Hamamoto, Noriko; Kaku, Yoshihiro; Okutani, Akiko; Noguchi, Akira; Park, Chun-Ho; Yamada, Akio

    2011-01-01

    The central nervous system (CNS) tissue of mice infected with the CVS-11 strain of rabies virus (RABV) was subjected to gene expression analysis using microarray and canonical pathway analyses. Genes associated with innate immunity as well as inflammatory responses were significantly up-regulated, corroborating with the previous findings obtained using attenuated viruses that did not induce a fatal outcome in infected mice. Histopathological examination showed that neurons in the cerebellum had undergone apoptosis. Although the extent of Fas ligand up-regulation was not so prominent, perforin and granzyme genes were highly expressed in the CNS of mice infected with CVS-11. The presence of perforin and granzymes both in the Purkinje cells and CD3 T lymphocytes strongly suggested that apoptosis of the former cells was induced by the latter cells. PMID:22116324

  19. Genetic analysis of Enterobius vermicularis isolated from a chimpanzee with lethal hemorrhagic colitis and pathology of the associated lesions.

    PubMed

    Yaguchi, Yuji; Okabayashi, Sachi; Abe, Niichiro; Masatou, Haruhisa; Iida, Shinya; Teramoto, Isao; Matsubayashi, Makoto; Shibahara, Tomoyuki

    2014-11-01

    Human pinworms, Enterobius vermicularis, are normally recognized as minor pathogens. However, a fatal case of human pinworm infection has been reported in a nonhuman primate, a zoo reared chimpanzee. Here, we histopathologically examined the lesions in tissues from the deceased chimpanzee and genetically characterized the isolated worms to investigate the pathogenicity and determine the phylogeny. We identified ulcers deep in the submucosa where many parasites were found to have invaded the lamina propria mucosa or submucous tissue. An inflammatory reaction consisting mainly of neutrophils and lymphocytes but not eosinophils was observed around the parasites, and intense hemorrhage in the lamina propria was confirmed. The parasites were morphologically similar to E. vermicularis based on the shape of the copulatory spicules. Mitochondrial cytochrome c oxidase subunit 1 gene products were amplified from worm DNA by PCR and were genetically identified as E. vermicularis based on >98.7% similarity of partial sequences. Phylogenetic analysis revealed that the sequences clustered together with other chimpanzee E. vermicularis isolates in a group which has been referred to as type C and which differs from human isolates (type A). The samples were negative for bacterial pathogens and Entamoeba histolytica indicating that E. vermicularis could be pathogenic in chimpanzees. Phylogenetic clustering of the isolates indicated that the parasite may be host specific. PMID:25138069

  20. The Lethality Test System

    NASA Astrophysics Data System (ADS)

    Parsons, W. M.; Sims, J. R.; Parker, J. V.

    1986-11-01

    The Lethality Test System (LTS) under construction at Los Alamos is an electromagnetic launcher facility designed to perform impact experiments at velocities up to 15 km/sec. The launcher is a 25 mm round bore, plasma armature railgun 22 m in length. Preinjection is accomplished with a two-stage light gas gun capable of 7 km/sec. The railgun power supply utilizes traction motors, vacuum interrupters, and pulse transformers. An assembly of 28 traction motors, equipped with flywheels, stores approximately 80 MJ at 92 percent of full speed and energizes the primary windings of three pulse transformers at a current of 50 kA. At peak current an array of vacuum interrupters disconnects the transformer primary windings and forces the current to flow in the secondary windings. The secondary windings are connected to the railgun, and by staging the vacuum interrupter openings, a 1-1.3 MA ramped current waveform will be delivered to the railgun.

  1. Lethality test system

    SciTech Connect

    Parsons, W.M.; Sims, J.R.; Parker, J.V.

    1986-01-01

    The Lethality Test System (LTS), presently under construction at Los Alamos, is an electromagnetic launcher facility designed to perform impact experiments at velocities up to 15 km/s. The launcher is a 25 mm round bore, plasma armature railgun extending 22 m in length. Preinjection is accomplished with a two-stage gas gun capable of 7 km/s. The railgun power supply utilizes traction motors, vacuum interrupters, and pulse transformers. An assembly of 28 traction motors, equipped with flywheels, stores approximately 80 MJ at 92% of full speed and energizes the primary windings of three pulse transformers at a current of 50 kA. At peak current an array of vacuum interrupters disconnects the transformer primary windings and forces the current to flow in the secondary windings. The secondary windings are connected to the railgun, and by staging the vacuum interrupter openings, a 1 MA to 1.3 MA ramped current waveform will be delivered to the railgun.

  2. Co-lethality studied as an asset against viral drug escape: the HIV protease case

    PubMed Central

    2010-01-01

    Background Co-lethality, or synthetic lethality is the documented genetic situation where two, separately non-lethal mutations, become lethal when combined in one genome. Each mutation is called a "synthetic lethal" (SL) or a co-lethal. Like invariant positions, SL sets (SL linked couples) are choice targets for drug design against fast-escaping RNA viruses: mutational viral escape by loss of affinity to the drug may induce (synthetic) lethality. Results From an amino acid sequence alignment of the HIV protease, we detected the potential SL couples, potential SL sets, and invariant positions. From the 3D structure of the same protein we focused on the ones that were close to each other and accessible on the protein surface, to possibly bind putative drugs. We aligned 24,155 HIV protease amino acid sequences and identified 290 potential SL couples and 25 invariant positions. After applying the distance and accessibility filter, three candidate drug design targets of respectively 7 (under the flap), 4 (in the cantilever) and 5 (in the fulcrum) amino acid positions were found. Conclusions These three replication-critical targets, located outside of the active site, are key to our anti-escape strategy. Indeed, biological evidence shows that 2/3 of those target positions perform essential biological functions. Their mutational variations to escape antiviral medication could be lethal, thus limiting the apparition of drug-resistant strains. Reviewers This article was reviewed by Arcady Mushegian, Shamil Sunyaev and Claus Wilke. PMID:20565756

  3. Molecular analysis of genetic fidelity in Cannabis sativa L. plants grown from synthetic (encapsulated) seeds following in vitro storage.

    PubMed

    Lata, Hemant; Chandra, Suman; Techen, Natascha; Khan, Ikhlas A; ElSohly, Mahmoud A

    2011-12-01

    The increasing utilization of synthetic (encapsulated) seeds for germplasm conservation and propagation necessitates the assessment of genetic stability of conserved propagules following their plantlet conversion. We have assessed the genetic stability of synthetic seeds of Cannabis sativa L. during in vitro multiplication and storage for 6 months at different growth conditions using inter simple sequence repeat (ISSR) DNA fingerprinting. Molecular analysis of randomly selected plants from each batch was conducted using 14 ISSR markers. Of the 14 primers tested, nine produced 40 distinct and reproducible bands. All the ISSR profiles from in vitro stored plants were monomorphic and comparable to the mother plant which confirms the genetic stability among the clones. GC analysis of six major cannabinoids [Δ(9)-tetrahydrocannabinol, tetrahydrocannabivarin, cannabidiol, cannabichromene, cannabigerol and cannabinol] showed homogeneity in the re-grown clones and the mother plant with insignificant differences in cannabinoids content, thereby confirming the stability of plants derived from synthetic seeds following 6 months storage. PMID:21805186

  4. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?

    PubMed

    Brown, Dean G; Boström, Jonas

    2016-05-26

    An analysis of chemical reactions used in current medicinal chemistry (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The analysis revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki-Miyaura coupling, and SNAr reactions, most likely due to commercial availability of reagents, high chemoselectivity, and a pressure on delivery. We show that these practices result in overpopulation of certain types of molecular shapes to the exclusion of others using simple PMI plots. We hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design. PMID:26571338

  5. The 2008 Super Tuesday Tornado Outbreak: Synthetic Dual Doppler Analysis of Contrasting Tornadic Storm Types

    NASA Technical Reports Server (NTRS)

    Knupp, Kevin R.; Coleman, Timothy; Carey, Larry; Peterson, Walt; Elkins, Calvin

    2008-01-01

    During the Super Tuesday Tornado Outbreak on 5-6 February, a significant number of storms passed within about 40 km of WSR-88D radars. This distance, combined with the significant motion vector (from the southwest at 20-25 m per second) of relatively steady storms, is amenable to a synthetic dual Doppler analysis during the times when the storms passed the WSR-88D locations. Nine storms will be analyzed using the SDD technique. The following table provides their general characteristics and nearest approach to the 88D radars. For this data set, storm structure ranges from isolated supercell to QLCS. Each storm will be analyzed for a 40-60 min period during passage by the WSR-88D radar to determine general storm properties. Analysis of high-resolution single Doppler data around the time of passage (plus or minus 30 min), combined with 1-2 SDD analyses, will be used to examine the kinematic structure of low-level circulations (e.g., mesocyclone, downdraft) and the relation to the parent storm. This analysis may provide insights on the fundamental differences between cyclonic circulations in supercell storms and those within QCLS's.

  6. Synthetic Aperture Radar (sar) and Optical Imagery Data Fusion: Crop Yield Analysis in Southeast Asia

    NASA Astrophysics Data System (ADS)

    Parks, S. M.

    2012-08-01

    With the expanding energy crisis and rising food prices, crop yield analysis in Southeast Asia is an increasingly important topic in this region. Rice is the most important food crop in Southeast Asia and the ability to accurately predict crop yields during a growing season is useful for decision-makers, aid providers, and commercial trade organizations. The use of optical satellite image data by itself is difficult due to the almost constant cloud in many parts of Southeast Asia. However, Synthetic Aperture Radar (SAR), or SAR data, which can image the Earth's surface through cloud cover, is suitable for many agricultural purposes, such as the detection of rice fields, and the identification of different crop species. Crop yield analysis is difficult in this region due to many factors. Rice cropping systems are often characterized by the type of rice planted, the size of rice field, the sowing dates for different fields, different types of rice cropping systems from one area to another, as well as cultural practices such as sowing and transplanting. This paper will discuss the use of SAR data fused with optical imagery to improve the ability to perform crop yield analysis on rice crops in Southeast Asia.

  7. Passive Synthetic Aperture Hitchhiker Imaging of Ground Moving Targets - Part 2: Performance Analysis.

    PubMed

    Wacks, Steven; Yazici, Birsen

    2014-07-01

    In Part 1 of this work, we present a passive synthetic aperture imaging and velocity estimation method for ground moving targets using a network of passive receivers. The method involves inversion of a Radon transform type forward model via a novel filtered backprojection approach combined with entropy optimization. The method is applicable to noncooperative transmitters of opportunity where the transmitter locations and transmitted waveforms are unknown. Furthermore, it can image multiple targets moving at different velocities in arbitrary imaging geometries. In this paper, we present a detailed analysis of the performance of our method. First the resolution analysis in position and velocity spaces is presented. The analysis identifies several factors that contribute positively or negativity towards position and velocity resolution. Next, we present a novel theory to analyze and predict smearing artifacts in position images due to error in velocity estimation of moving targets. Specifically, we show that small errors in the velocity estimation result in small positioning errors. We present extensive numerical simulations to demonstrate the theoretical results. While our primary interest lies in radar, the theory, methods and algorithms introduced in our work are also applicable to passive acoustic, seismic, and microwave imaging. PMID:25020091

  8. Cell-to-Cell Communication Circuits: Quantitative Analysis of Synthetic Logic Gates

    PubMed Central

    Hoffman-Sommer, Marta; Supady, Adriana; Klipp, Edda

    2012-01-01

    One of the goals in the field of synthetic biology is the construction of cellular computation devices that could function in a manner similar to electronic circuits. To this end, attempts are made to create biological systems that function as logic gates. In this work we present a theoretical quantitative analysis of a synthetic cellular logic-gates system, which has been implemented in cells of the yeast Saccharomyces cerevisiae (Regot et al., 2011). It exploits endogenous MAP kinase signaling pathways. The novelty of the system lies in the compartmentalization of the circuit where all basic logic gates are implemented in independent single cells that can then be cultured together to perform complex logic functions. We have constructed kinetic models of the multicellular IDENTITY, NOT, OR, and IMPLIES logic gates, using both deterministic and stochastic frameworks. All necessary model parameters are taken from literature or estimated based on published kinetic data, in such a way that the resulting models correctly capture important dynamic features of the included mitogen-activated protein kinase pathways. We analyze the models in terms of parameter sensitivity and we discuss possible ways of optimizing the system, e.g., by tuning the culture density. We apply a stochastic modeling approach, which simulates the behavior of whole populations of cells and allows us to investigate the noise generated in the system; we find that the gene expression units are the major sources of noise. Finally, the model is used for the design of system modifications: we show how the current system could be transformed to operate on three discrete values. PMID:22934039

  9. Synthetic vascular hemodialysis access vs native arteriovenous fistula: A cost-utility analysis

    PubMed Central

    Rosas, Sylvia E; Feldman, Harold I

    2011-01-01

    Objective To determine the cost-effectiveness of two different vascular access strategies among incident dialysis patients. Summary Background Data Vascular access is a principal cause of morbidity and cost in hemodialysis patients. Recent guidelines and initiatives are intended to increase the proportion of patients with a fistula. However, there is growing awareness of the high prevalence of fistula failures and attendant complications. Methods A decision analysis using a Markov model was implemented to compare two different vascular access strategies among incident dialysis patients: a) placing an arteriovenous fistula (AVF1st) as the initial access followed by a synthetic vascular access if the AVF did not mature compared to b) placing a synthetic vascular access (SVA1st) as the initial access device. The cost-utility was evaluated across a range of the risk of complications from temporary catheters and SVA. Results Under base case assumptions, the AVF1st strategy yielded 2.19 QALYs compared to 2.06 QALYs from the SVA1st strategy. The incremental cost-effectiveness was $9389/QALY for AVF1st compared to SVA1st and was less than $50,000 per QALY as long as the probability of maturation is 36% or greater. AVF1st was the dominant strategy when the AVF maturation rate was 69% or greater. Conclusion The high risk of complications of temporary catheters and the overall low AVF maturation rate explain why a universal policy of AVF 1st for all incident dialysis patients may not optimize clinical outcomes. Strong consideration should be given to a more patient-centered approach taking into account the likelihood of AVF maturation. PMID:21918428

  10. Constraining shallow seismic event depth via synthetic modeling for Expert Technical Analysis at the IDC

    NASA Astrophysics Data System (ADS)

    Stachnik, J.; Rozhkov, M.; Baker, B.; Bobrov, D.; Friberg, P. A.

    2015-12-01

    Depth of event is an important criterion of seismic event screening at the International Data Center, CTBTO. However, a thorough determination of the event depth can be conducted mostly through special analysis because the IDC's Event Definition Criteria is based, in particular, on depth estimation uncertainties. This causes a large number of events in the Reviewed Event Bulletin to have depth constrained to the surface. When the true origin depth is greater than that reasonable for a nuclear test (3 km based on existing observations), this may result in a heavier workload to manually distinguish between shallow and deep events. Also, IDC depth criterion is not applicable to the events with the small t(pP-P) travel time difference, which is the case of the nuclear test. Since the shape of the first few seconds of signal of very shallow events is very sensitive to the presence of the depth phase, cross correlation between observed and theoretic seismogram can provide an estimate for the depth of the event, and so provide an expansion to the screening process. We exercised this approach mostly with events at teleseismic and partially regional distances. We found that such approach can be very efficient for the seismic event screening process, with certain caveats related mostly to the poorly defined crustal models at source and receiver which can shift the depth estimate. We used adjustable t* teleseismic attenuation model for synthetics since this characteristic is not determined for most of the rays we studied. We studied a wide set of historical records of nuclear explosions, including so called Peaceful Nuclear Explosions (PNE) with presumably known depths, and recent DPRK nuclear tests. The teleseismic synthetic approach is based on the stationary phase approximation with Robert Herrmann's hudson96 program, and the regional modelling was done with the generalized ray technique by Vlastislav Cerveny modified to the complex source topography.

  11. Method of reliable determination of minimal lethal antibiotic concentrations.

    PubMed Central

    Pearson, R D; Steigbigel, R T; Davis, H T; Chapman, S W

    1980-01-01

    The lack of a standardized, statistically reliable method for in vitro determinations of the minimal lethal or bactericidal concentrations of antibiotics has complicated analyses of isolates of Staphylococcus aureus which appear to be inhibited but not killed by the usual concentrations of cell wall-active antibiotics. We describe a method which identifies some of the covariants involved in determinations of minimal lethal concentrations. Lethality was defined as a 99.9% reduction in the initial inoculum of bacteria after 24 h of incubation. We limited the sample volume to 0.01 ml to minimize the inhibitory effect of antibiotic and corresponding rejection values, which detected lethality with a high degree of sensitivity and specificity. When the number of colonies on subculture was equal to or less than the rejection value, the antibiotic was considered lethal for the test organism. Rejection values encompassed initial inocula from 10(5) to 10(7) colony-forming units per ml for single and duplicate samples and allowed for 1 or 5% variability in pipette volumes and errors in initial inoculum determinations. This method was used to determine the minimal lethal concentrations of semi-synthetic penicillins for S. aureau isolates, one of which was tolerant to the killing action of penicillin. Images PMID:7447427

  12. Multi-Resolution Clustering Analysis and Visualization of Around One Million Synthetic Earthquake Events

    NASA Astrophysics Data System (ADS)

    Kaneko, J. Y.; Yuen, D. A.; Dzwinel, W.; Boryszko, K.; Ben-Zion, Y.; Sevre, E. O.

    2002-12-01

    The study of seismic patterns with synthetic data is important for analyzing the seismic hazard of faults because one can precisely control the spatial and temporal domains. Using modern clustering analysis from statistics and a recently introduced visualization software, AMIRA, we have examined the multi-resolution nature of a total assemblage involving 922,672 earthquake events in 4 numerically simulated models, which have different constitutive parameters, with 2 disparately different time intervals in a 3D spatial domain. The evolution of stress and slip on the fault plane was simulated with the 3D elastic dislocation theory for a configuration representing the central San Andreas Fault (Ben-Zion, J. Geophys. Res., 101, 5677-5706, 1996). The 4 different models represent various levels of fault zone disorder and have the following brittle properties and names: uniform properties (model U), a Parkfield type Asperity (A), fractal properties (F), and multi-size-heterogeneities (model M). We employed the MNN (mutual nearest neighbor) clustering method and developed a C-program that calculates simultaneously a number of parameters related to the location of the earthquakes and their magnitude values .Visualization was then used to look at the geometrical locations of the hypocenters and the evolution of seismic patterns. We wrote an AmiraScript that allows us to pass the parameters in an interactive format. With data sets consisting of 150 year time intervals, we have unveiled the distinctly multi-resolutional nature in the spatial-temporal pattern of small and large earthquake correlations shown previously by Eneva and Ben-Zion (J. Geophys. Res., 102, 24513-24528, 1997). In order to search for clearer possible stationary patterns and substructures within the clusters, we have also carried out the same analysis for corresponding data sets with time extending to several thousand years. The larger data sets were studied with finer and finer time intervals and multi

  13. Analysis of new synthetic drugs by ion mobility time-of-flight mass spectrometry.

    PubMed

    Sysoev, Alexey A; Poteshin, Sergey S; Chernyshev, Denis M; Karpov, Alexander V; Tuzkov, Yuriy B; Kyzmin, Vyacheslav V; Sysoev, Alexander A

    2014-01-01

    Characteristic ion mobility mass spectrometry data, reduced mobility, and limits of detection (signal-to-noise ratio = 3) were determined for six synthetic drugs and cocaine by ion mobility time-of-flight mass spectrometry (IM-TOF-MS) with electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI). The studied synthetic illicit drugs recently appeared on the recreational drug market as designer drugs and were methylone, 4-MEC (4'-methylethcathinone), 3,4-MDPV (3,4-methylenedioxypyrovalerone), JWH-210 [4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone], JWH-250 [2-(2-methoxyphenyl)-1-(1-pentyl-1H-indol-3-yl)ethanone], and JWH-203 [1-pentyl-3-(2'-chlorophenylacetyl) indole]. Absolute reduced mobilities in nitrogen were 1.35, 1.28, 1.41, 1.30, 1.18, 0.98, 1.09, and 1.07 cm2V(-1)s(-1), for methylone [M-H]+, methylone [M+H]+, 4-MEC [M-H]+, 4-MEC [M+H]+, 3,4-MDPV [M+H]+, JWH-210 [M+H]+, JWH-250 [M+H]+, and JWH-203 [M+H]+, respectively. Selected illicit drugs are easily identified by IM-TOF-MS during a 100s analysis. Relative Limits of detection ranged from 4 to 400 nM are demonstrated for these compounds. Such relative limits of detection correspond to 14 pg to 2 ng absolute limits of detection. Better detection limits are obtained in APCI mode for all the illicit drugs except cocaine. ESI mode was found to be preferable for the IM-TOF-MS detection of cocaine at trace levels. A single sample analysis is completed in an order of magnitude less time than that for conventional liquid chromatography/mass spectrometry approach. The application allows one to consider IM-TOF-MS as a good candidate for a method to determine quickly the recently surfaced designer drugs marketed on the internet as "bath salts," "spice," and "herbal blends". PMID:24895779

  14. [From synthetic biology to synthetic humankind].

    PubMed

    Nouvel, Pascal

    2015-01-01

    In this paper, we propose an historical survey of the expression "synthetic biology" in order to identify its main philosophical components. The result of the analysis is then used to investigate the meaning of the notion of "synthetic man". It is shown that both notions share a common philosophical background that can be summed up by the short but meaningful assertion: "biology is technology". The analysis allows us to distinguish two notions that are often confused in transhumanist literature: the notion of synthetic man and the notion of renewed man. The consequences of this crucial distinction are discussed. PMID:26238764

  15. Rare earth element concentrations in geological and synthetic samples using synchrotron X-ray fluorescence analysis

    USGS Publications Warehouse

    Chen, J.R.; Chao, E.C.T.; Back, J.M.; Minkin, J.A.; Rivers, M.L.; Sutton, S.R.; Cygan, G.L.; Grossman, J.N.; Reed, M.J.

    1993-01-01

    The concentrations of rare earth elements (REEs) in specific mineral grains from the Bayan Obo ore deposit and synthetic high-silica glass samples have been measured by synchrotron X-ray fluorescence (SXRF) analysis using excitation of the REE K lines between 33 and 63 keV. Because SXRF, a nondestructive analytical technique, has much lower minimum detection limits (MDLs) for REEs, it is an important device that extends the in situ analytical capability of electron probe microanalysis (EPMA). The distribution of trace amounts of REEs in common rock-forming minerals, as well as in REE minerals and minerals having minor quantities of REEs, can be analyzed with SXRF. Synchrotron radiation from a bending magnet and a wiggler source at the National Synchrotron Light Source, Brookhaven National Laboratory, was used to excite the REEs. MDLs of 6 ppm (La) to 26 ppm (Lu) for 3600 s in 60-??m-thick standard samples were obtained with a 25-??m diameter wiggler beam. The MDLs for the light REEs were a factor of 10-20 lower than the MDLs obtained with a bending magnet beam. The SXRF REE concentrations in mineral grains greater than 25 ??m compared favorably with measurements using EPMA. Because EPMA offered REE MDLs as low as several hundred ppm, the comparison was limited to the abundant light REEs (La, Ce, Pr, Nd). For trace values of medium and heavy REEs, the SXRF concentrations were in good agreement with measurements using instrumental neutron activation analysis (INAA), a bulk analysis technique. ?? 1993.

  16. A new mixed micellar electrokinetic chromatography method for analysis of natural and synthetic anabolic steroids.

    PubMed

    Zhang, Lan; Chen, Jinfeng; He, Yu; Chi, Yuwu; Chen, Guonan

    2009-01-15

    A simple, rapid and low-costing new mixed surfactant MEKC method has been developed for the analysis of five neutral anabolic steroids in this paper. It was found that the bile salt coupling with Triton X-100 was a suitable bi-micellar surfactant for the separation of these anabolic steroids with similar structure. The separation conditions were optimized in detail. The five natural and synthetic anabolic steroids, such as androstenedione (AD), 19-norandrostenedione (NAD), 1,4-androstadiene-3,17-dione (ADD), methandrostenolone (MA) and methyltestosterone (MT) were separated and detected in an alkaline buffer system (pH 9.0) containing 15 mM Britton-Robinson (BR) buffer, 50mM sodium cholate (SC) and 0.1% (v/v) Triton X-100 with detection wavelength at 241 nm and 18 kV of separation voltage. Under the optimal conditions, five coexistence neutral steroids were completely separated within 12 min with the detection limits ranged from 0.20 to 0.51 microg/mL. This method was successfully used for detection and confirmation of the anabolic steroid methandrostenolone in methandrostenolone tablets and in the real human urine, GC-MS method was applied to confirm the free methandrostenolone existence in the urine sample in order to validate the reliability of MEKC method. PMID:19064082

  17. Synthetic spectral analysis of a kinetic model for slow-magnetosonic waves in solar corona

    NASA Astrophysics Data System (ADS)

    Ruan, Wenzhi; He, Jiansen; Zhang, Lei; Vocks, Christian; Marsch, Eckart; Tu, Chuanyi; Peter, Hardi; Wang, Linghua

    2016-03-01

    We propose a kinetic model of slow-magnetosonic waves to explain various observational features associated with the propagating intensity disturbances (PIDs) occurring in the solar corona. The characteristics of slow mode waves, e.g, inphase oscillations of density, velocity, and thermal speed, are reproduced in this kinetic model. Moreover, the red-blue (R-B) asymmetry of the velocity distribution as self-consistently generated in the model is found to be contributed from the beam component, as a result of the competition between Landau resonance and Coulomb collisions. Furthermore, we synthesize the spectral lines and make the spectral analysis, based on the kinetic simulation data of the flux tube plasmas and the hypothesis of the surrounding background plasmas. It is found that the fluctuations of parameters of the synthetic spectral lines are basically consistent with the observations: (1) the line intensity, Doppler shift, and line width are fluctuating in phase; (2) the R-B asymmetry usually oscillate out of phase with the former three parameters; (3) the blueward asymmetry is more evident than the redward asymmetry in the R-B fluctuations. The oscillations of line parameters become weakened for the case with denser surrounding background plasmas. Similar to the observations, there is no doubled-frequency oscillation of the line width for the case with flux-tube plasmas flowing bulkly upward among the static background plasmas. Therefore, we suggest that the "wave + beam flow" kinetic model may be a viable interpretation for the PIDs observed in the solar corona.

  18. ATLAS Versus NextGen Model Atmospheres: A Combined Analysis of Synthetic Spectral Energy Distributions

    NASA Astrophysics Data System (ADS)

    Bertone, E.; Buzzoni, A.; Chávez, M.; Rodríguez-Merino, L. H.

    2004-08-01

    We carried out a critical appraisal of the two theoretical models, Kurucz' ATLAS9 and PHOENIX/NextGen, for stellar atmosphere synthesis. Our tests relied on the theoretical fit of spectral energy distributions (SEDs) for a sample of 334 target stars along the whole spectral-type sequence, from the classical optical catalogs of Gunn & Stryker and Jacoby et al. The best-fitting physical parameters (Teff, logg) of stars allowed an independent calibration of the temperature and bolometric scale versus empirical classification parameters (i.e., spectral type and MK luminosity class); in addition, the comparison of the synthetic templates from the ATLAS and NextGen grids allowed us to probe the capability of the models to match spectrophotometric properties of real stars and assess the impact of the different input physics. We can sketch the following main conclusions of our analysis: (1) Fitting accuracy of both theoretical libraries drastically degrades at low Teff at which both ATLAS and NextGen models still fail to properly account for the contribution of molecular features in the observed SED of K-M stars. (2) Compared with empirical calibrations, both ATLAS and NextGen fits tend, on average, to predict slightly warmer (by 4%-8%) Teff for both giant and dwarf stars of fixed spectral type, but ATLAS provides, in general, a sensibly better fit (a factor of 2 lower σ of flux residuals) than NextGen. (3) There is a striking tendency of NextGen to label target stars with an effective temperature and surface gravity higher than that of ATLAS. The effect is especially evident for MK I-III objects for which about one in four stars is clearly misclassified by NextGen in logg. This is a consequence of some ``degeneracy'' in the solution space, partly induced by the different input physics and geometry constraints in the computation of the integrated emerging flux (ATLAS model atmospheres assume standard plane-parallel layers, while NextGen adopts, for low-gravity stars, a

  19. A kinematic analysis of the spine during rugby scrummaging on natural and synthetic turfs

    PubMed Central

    Swaminathan, Ramesh; Williams, Jonathan M.; Jones, Michael D.; Theobald, Peter S.

    2016-01-01

    ABSTRACT Artificial surfaces are now an established alternative to grass (natural) surfaces in rugby union. Little is known, however, about their potential to reduce injury. This study characterises the spinal kinematics of rugby union hookers during scrummaging on third-generation synthetic (3G) and natural pitches. The spine was sectioned into five segments, with inertial sensors providing three-dimensional kinematic data sampled at 40 Hz/sensor. Twenty-two adult, male community club and university-level hookers were recruited. An equal number were analysed whilst scrummaging on natural or synthetic turf. Players scrummaging on synthetic turf demonstrated less angular velocity in the lower thoracic spine for right and left lateral bending and right rotation. The general reduction in the range of motion and velocities, extrapolated over a prolonged playing career, may mean that the synthetic turf could result in fewer degenerative injuries. It should be noted, however, that this conclusion considers only the scrummaging scenario. PMID:26375051

  20. A kinematic analysis of the spine during rugby scrummaging on natural and synthetic turfs.

    PubMed

    Swaminathan, Ramesh; Williams, Jonathan M; Jones, Michael D; Theobald, Peter S

    2016-01-01

    Artificial surfaces are now an established alternative to grass (natural) surfaces in rugby union. Little is known, however, about their potential to reduce injury. This study characterises the spinal kinematics of rugby union hookers during scrummaging on third-generation synthetic (3G) and natural pitches. The spine was sectioned into five segments, with inertial sensors providing three-dimensional kinematic data sampled at 40 Hz/sensor. Twenty-two adult, male community club and university-level hookers were recruited. An equal number were analysed whilst scrummaging on natural or synthetic turf. Players scrummaging on synthetic turf demonstrated less angular velocity in the lower thoracic spine for right and left lateral bending and right rotation. The general reduction in the range of motion and velocities, extrapolated over a prolonged playing career, may mean that the synthetic turf could result in fewer degenerative injuries. It should be noted, however, that this conclusion considers only the scrummaging scenario. PMID:26375051

  1. Coal conversion processes and analysis methodologies for synthetic fuels production. [technology assessment and economic analysis of reactor design for coal gasification

    NASA Technical Reports Server (NTRS)

    1979-01-01

    Information to identify viable coal gasification and utilization technologies is presented. Analysis capabilities required to support design and implementation of coal based synthetic fuels complexes are identified. The potential market in the Southeast United States for coal based synthetic fuels is investigated. A requirements analysis to identify the types of modeling and analysis capabilities required to conduct and monitor coal gasification project designs is discussed. Models and methodologies to satisfy these requirements are identified and evaluated, and recommendations are developed. Requirements for development of technology and data needed to improve gasification feasibility and economies are examined.

  2. Gonadosomatic mosaicism for lethal mutations in Drosophila lethal mutations disturbing larval development

    SciTech Connect

    Ivanov, A.I.; Sakharova, N.Yu.

    1988-11-01

    Phenogenetic analysis of autonomous lethal mutations obtained by the method of gonadosomatic mosaicism which manifested during larval stages, established that the nuclei of hypodermal cells, salivary glands suprapharyngeal ganglion, pharynx, esophagus, gizzard, and hindgut are the derivatives of the same nucleus (from the first two nuclei of cleavage) as the nuclei of the cells of the imaginal-somatic tissues.

  3. Nucleus anomaly test and chromosomal analysis of bone marrow cells of the Chinese hamster and dominant lethal test in male mice after treatment with fluorescent whitening agents.

    PubMed

    Müller, D; Fritz, H; Langauer, M; Strasser, F F

    1975-01-01

    Four fluorescent whitening agents (FWAs) were tested for mutagenic activity after oral administration in the following three different mammalian test systems: (1) Dominant lethal test in the male mouse; (2) Cytogenetic studies on metaphase chromosomes from the bone marrow of the Chinese hamster; (3) Nucleus anomaly test in somatic interphase cells (bone marrow) of the Chinese hamster. These investigations yielded no evidence of dominant lethal effects of any of the four compounds on the progeny of male mice. Furthermore, the data obtained from chromosome analyses and the nucleus anomaly test revealed no effects at all. Thus, the results obtained in all these tests gave no indication of mutagenic activity after the administration of these compounds in dosages up to approximately 1/3 or the LD50. PMID:1064545

  4. Synthetic Aperture Radar Interferometry Analysis of Ground Deformation within the Coso Geothermal Site, California

    NASA Astrophysics Data System (ADS)

    Brawner, Erik

    Earth's surface movement may cause as a potential hazard to infrastructure and people. Associated earthquake hazards pose a potential side effect of geothermal activity. Modern remote sensing techniques known as Interferometric Synthetic Aperture Radar (InSAR) can measure surface change with a high degree of precision to mm scale movements. Previous work has identified a deformation anomaly within the Coso Geothermal site in eastern California. Surface changes have not been analyzed since the 1990s, allowing a decade of geothermal production impact to occur since previously assessed. In this study, InSAR data was acquired and analyzed between the years 2005 and 2010. Acquired by the ENVISAT satellite from both ascending and descending modes. This provides an independent dataset from previous work. Incorporating data generated from a new sensor covering a more modern temporal study period. Analysis of this time period revealed a subsidence anomaly in correlation with the extents of the geothermal production area under current operation. Maximum subsidence rates in the region reached approximately 3.8 cm/yr. A similar rate assessed from previous work throughout the 1990s. The correlation of subsidence patterns suggests a linear source of deformation from measurements spanning multiple decades. Regions of subsidence branch out from the main anomaly to the North-Northeast and to the South where additional significant peaks of subsidence occurring. The extents of the deformation anomaly directly correlate with the dispersal of geothermal production well site locations. Depressurization within the geothermal system provides a leading cause to surface subsidence from excessive extraction of hydrothermal fluids. As a result of minimal reinjection of production fluids.

  5. Retrospective analysis of synthetic cannabinoids in serum samples--epidemiology and consumption patterns.

    PubMed

    Jaenicke, Nathalie J; Pogoda, Werner; Paulke, Alexander; Wunder, Cora; Toennes, Stefan W

    2014-09-01

    Herbal mixtures contain synthetic cannabinoids, which can cause severe intoxications. Due to the great variety and the changing spectrum of substances on the drug market, prevalence data are limited, and data on prevalence rates of synthetic cannabinoids in forensic cases are not available. The present study was performed to survey the prevalence of synthetic cannabinoids in cases of traffic and criminal offences in the German state Hesse in 2010. The applied analytical method covered all synthetic cannabinoids on the drug market at that time, and with 20% of the blood samples (422 out of 2201) a representative number was reanalyzed. In twelve samples synthetic cannabinoids were identified and a prevalence of 2.8% was estimated. Consumption patterns showed predominantly cases of multi-drug consumption (10 cases); the combination with cannabis or alcohol was frequent (four cases each). The observed deficits were moderate with the exception of aggravation of paranoia in one case. The symptoms were either compatible with the effects of cannabinoid agonists or attributable to alcohol or other drugs found in the blood samples. Our current analytical strategy is to perform such analyses only in cases where use is suspected or where symptoms are not explained by routine toxicological analyses. Hence, the positive rate is rather low highlighting the need to keep up with the developments on the drug market and to establish sensitive screening methods covering a broad range of substances that can be updated fast, e.g., relying on collections of mass spectrometric reference data. PMID:25050839

  6. Analysis of synthetic motor oils for additive elements by ICP-AES

    SciTech Connect

    Williams, M.C.; Salmon, S.G.

    1995-12-31

    Standard motor oils are made by blending paraffinic or naphthenic mineral oil base stocks with additive packages containing anti-wear agents, dispersants, corrosion inhibitors, and viscosity index improvers. The blender can monitor the correct addition of the additives by determining the additive elements in samples dissolved in a solvent by ICP-AES. Internal standardization is required to control sample transport interferences due to differences in viscosity between samples and standards. Synthetic motor oils, made with poly-alpha-olefins and trimethylol propane esters, instead of mineral oils, pose an additional challenge since these compounds affect the plasma as well as having sample transport interference considerations. The synthetic lubricant base stocks add significant oxygen to the sample matrix, which makes the samples behave differently than standards prepared in mineral oil. Determination of additive elements in synthetic motor oils will be discussed.

  7. Analysis of the structure of synthetic and natural melanins by solid-phase

    SciTech Connect

    Duff, G.A.; Roberts, J.E.; Foster, N.

    1988-09-06

    The structures of one synthetic and two natural melanins are examined by solid-state NMR using cross polarization, magic angle sample spinning, and high-power proton decoupling. The structural features of synthetic dopa malanin are compared to those of melanin from malignant melanoma cells grown in culture and sepia melanin from squid ink. Natural abundance /sup 13/C and /sup 15/N spectra show resonances consistent with known pyrrolic and indolic structures within the heterogeneous biopolymer; /sup 13/C spectra indicate the presence of aliphatic residues in all three materials. These solid-phase experiments illustrate the promise of solid-phase NMR for elucidating structural from insoluble biomaterials.

  8. Synthetic profile analysis of the observed (0,0) Swan band of Comet Halley

    SciTech Connect

    Krishna swamy, K.S. )

    1991-05-01

    The time-dependent rotational population distribution for the (0,0) band of the Swan system was carried out. These population distributions are used to calculate the synthetic spectra over the wavelength region 5165-5132 A for comparing with the excellent spectra of Lambert et al. (1990) for Comet Halley. The synthetic spectra for the rotational population distribution corresponding to a time interval of about 8000 sec gives a good fit to the observed spectra over the whole special region. This seems to indicate that the level population does not appear to have reached the steady state values. 16 refs.

  9. Hair analysis as a tool to evaluate the prevalence of synthetic cannabinoids in different populations of drug consumers.

    PubMed

    Salomone, A; Luciano, C; Di Corcia, D; Gerace, E; Vincenti, M

    2014-01-01

    Among the new psychoactive products, herbal mixtures containing synthetic cannabimimetics are likely the most abused worldwide. In this study, a specific ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the detection of 23 synthetic cannabinoids in hair samples was developed in order to (1) expand the number of screened compounds, coherent with new substances emerging in the European territory, (2) evaluate their consumption on a large period of examination, and (3) evaluate the diffusion of cannabimimetics among different populations of drug consumers. The method employs digestion of hair sample with NaOH followed by extraction with n-hexane/ethylacetate, and injection into the UHPLC-MS/MS system. After validation, the method was applied to the analysis of 344 hair samples previously tested in our laboratory for the most common drugs. Overall, 15 samples were found positive for at least one synthetic cannabinoid. Coherent with previously published results, the present data show that young males, former or still active Cannabis consumers, represent the population most often involved in synthetic cannabimimetics consumption. Several cases of poly-abuse were also determined. The drug most frequently detected was JWH-073 (11 samples) generally at low concentration (mean 7.69 ± 14.4 pg/mg, median 1.9 pg/mg, range 1.6-50.5 pg/mg), followed by JWH-122 (8 samples, mean concentration: 544 ± 968 pg/mg, median 28.4 pg/mg, range 7.4-2800 pg/mg). Other detected drugs included JWH-250, JWH-081, JWH-018, JWH-210, JWH-019, and AM-1220. For several positive samples, the synthetic cannabinoid concentration was lower than 50 pg/mg, underlining the need for established cut-off values for discrimination between chronic consumption and occasional use (or external contamination). PMID:24115381

  10. Definition of lethality thresholds for KE less-lethal projectiles

    NASA Astrophysics Data System (ADS)

    Cuadros, Jaime H.

    1997-01-01

    The interest in the definition and application of the lethality threshold for KE less-lethal projectiles has increased in the last few years, as the demand for proper use of these weapons has increased from the public at large and the law enforcement community. Experiments have been performed and reported utilizing commercially available projectiles in 12 ga., 37 mm against an anthropomorphic dummy and damage criteria developed by the automobile industry. The utility of the method is discussed and future trends are presented.

  11. Analysis of risk factors associated with vaginal erosion after synthetic sling procedures for stress urinary incontinence.

    PubMed

    Chen, Huey-Yi; Ho, Ming; Hung, Yao-Ching; Huang, Li-Chia

    2008-01-01

    The goal of this study was to analyze the risk factors associated with vaginal erosion after synthetic sling procedure for stress urinary incontinence. Follow-up evaluations were at 1 week, 1 to 3 months, 6 months, and annually after the operation. The evaluations included detailed history taking, vaginal examinations, and perineal ultrasonographic urethrocystography. The vaginal erosion rate (6/239) after the synthetic sling procedure was 2.5%. We assessed the relationship between clinical features and vaginal erosion. Of these, only diabetes mellitus (DM) was a significant risk factor for vaginal erosion. Women with DM were 8.3 times more at risk than women without DM for developing vaginal erosion after synthetic sling procedure (p < 0.05). The vaginal erosion-free rate during the 24-month follow-up decreased significantly in women with DM. The rate of vaginal erosion associated with type III multifilamentous polypropylene sling (intravaginal slingplasty) is 10.7% more than that with type I monofilament polypropylene sling (such as tension-free vaginal tape and inside out transobturator vaginal tape) (p = 0.054). Women with DM should be informed that vaginal erosion is a possible complication after synthetic sling procedure. PMID:17594046

  12. An Assessment of Social Welfare in Spain: Territorial Analysis Using a Synthetic Welfare Indicator

    ERIC Educational Resources Information Center

    Espina, Pilar Zarzosa; Arechavala, Noelia Somarriba

    2013-01-01

    The aim of this paper is measure social welfare in Spanish provinces. To achieve this, we use the distance method P[subscript 2] to compose a synthetic indicator of welfare for 2007, the last year for which data are available. The index comprises information on different social indicators from various life domains and enables a classification of…

  13. Analysis of synthetic and biological microparticles on several flow cytometric platforms

    EPA Science Inventory

    Microparticles (MPs) are membrane vesicles (0.1 to 1 urn) released from cells upon activation. The limit of detection ofmost standard flow cytometers is just below 1 urn. Recent advances enable detection of particles lower than 0.5 urn, Synthetic. beads are used to define size ra...

  14. Evaluation and haplotype analysis of elite synthetic hexaploid wheat lines for resistance to Hessian fly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Synthetic hexaploid wheat (SHW), derived from tetraploid wheat ' Aegilops tauschii hybrid, is an excellent source of resistance genes for various diseases and insects in wheat. The objectives of this study were to evaluate the elite SHW lines developed at the International Maize and Wheat Improvemen...

  15. Molecular genetic analysis of the Influenza A(H1N1)pdm09 virus from lethal and recovered cases in Russia from 2009 to 2014: Deletions in the nucleoprotein.

    PubMed

    Yatsyshina, Svetlana; Renteeva, Anna; Deviatkin, Andrei; Vorobyeva, Nadezhda; Minenko, Angrey; Valdokhina, Anna; Elkina, Mariya; Kuleshov, Konstantin; Shipulin, German

    2015-08-01

    Influenza A(H1N1)pdm09 virus caused about 2000 laboratory confirmed lethal cases in Russia during 2009-2010 and 1302, 135 and 29 cases in the 2010-2011, 2012-2013 and 2013-2014 seasons respectively. The on average short duration (7.8±5 days) of lethal cases of Influenza A(H1N1)pdm09 infections in Russia suggests primary viral rather than secondary bacterial pneumonia. Hemorrhagic syndrome was recorded in 36.6% of patients. An examination of 221 lung samples from lethal influenza cases for the presence of bacterial DNA that could cause pneumonia did not reveal bacterial superinfections in 86% of cases. Molecular-genetic analyses of Influenza A(H1N1)pdm09 viruses from lethal and recovered cases were performed. Amino acids G and N at position 222 of the influenza virus hemagglutinin, which increase the affinity for the lower respiratory tract receptors, were detected more often in the lungs of patients who died than in respiratory swabs collected from recovered patients (p<0.0001 and p=0.007). Viruses harboring various mutations (222D/G/N/S) was significantly associated with lung samples compared with respiratory swabs from recovered patients (p<0.0001). Amino acid 222E, which increases the affinity for upper respiratory tract receptors, was found more frequently in recovered patients than in patients with lethal disease (27% versus 3%, p=0.005). Phylogenetic analysis identified an isolated cluster of viruses in the 2009-2010 season that harbored amino acid 222E, which could explain the high transmissibility of the virus at the beginning of the pandemic. Bayesian skyline plot implied a decline in the effective population size of Influenza A(H1N1)pdm09 viruses in Russia from 2010-2011 to 2011-2012, followed by an increase in 2012-2013; this trend was accompanied by the increased genetic diversity of the hemagglutinin antigenic sites. Mutations of viral RNA leading to oseltamivir resistance were found in 2.8% of tested patients during only 2010-2011 season. Deletions

  16. Genome-wide association for grain morphology in synthetic hexaploid wheats using digital imaging analysis

    PubMed Central

    2014-01-01

    Background Grain size and shape greatly influence grain weight which ultimately enhances grain yield in wheat. Digital imaging (DI) based phenomic characterization can capture the three dimensional variation in grain size and shape than has hitherto been possible. In this study, we report the results from using digital imaging of grain size and shape to understand the relationship among different components of this trait, their contribution to enhance grain weight, and to identify genomic regions (QTLs) controlling grain morphology using genome wide association mapping with high density diversity array technology (DArT) and allele-specific markers. Results Significant positive correlations were observed between grain weight and grain size measurements such as grain length (r = 0.43), width, thickness (r = 0.64) and factor from density (FFD) (r = 0.69). A total of 231 synthetic hexaploid wheats (SHWs) were grouped into five different sub-clusters by Bayesian structure analysis using unlinked DArT markers. Linkage disequilibrium (LD) decay was observed among DArT loci > 10 cM distance and approximately 28% marker pairs were in significant LD. In total, 197 loci over 60 chromosomal regions and 79 loci over 31 chromosomal regions were associated with grain morphology by genome wide analysis using general linear model (GLM) and mixed linear model (MLM) approaches, respectively. They were mainly distributed on homoeologous group 2, 3, 6 and 7 chromosomes. Twenty eight marker-trait associations (MTAs) on the D genome chromosomes 2D, 3D and 6D may carry novel alleles with potential to enhance grain weight due to the use of untapped wild accessions of Aegilops tauschii. Statistical simulations showed that favorable alleles for thousand kernel weight (TKW), grain length, width and thickness have additive genetic effects. Allelic variations for known genes controlling grain size and weight, viz. TaCwi-2A, TaSus-2B, TaCKX6-3D and TaGw2-6A, were also associated

  17. Analysis of the Greenland Ice Sheet's surface hydrology using Synthetic Aperture Radar imagery

    NASA Astrophysics Data System (ADS)

    Miles, Katie; Benedek, Corinne; Tedesco, Marco; Willis, Ian

    2016-04-01

    The behaviour of surface water on the Greenland Ice Sheet (GrIS) has recently received much attention due to its ponding to form supraglacial lakes. These can drain and impact ice sheet dynamics by facilitating increased basal sliding, thus leading to a more rapid transfer of ice to the oceans and contributing to rising sea levels. Research into supraglacial lakes has primarily used the optical and infrared wavelength bands of MODIS due to their high temporal resolution. However, this comes with an associated low spatial resolution, potentially resulting in smaller lakes being overlooked, and an inability to image through clouds or in darkness. Conversely, Synthetic Aperture Radar (SAR), a satellite-borne active imaging method uses microwave wavelength bands which are unaffected by cloud or lack of illumination from the sun. SAR imagery often has a much higher spatial resolution than optical imagery without compromising temporal resolution, and radar systems have even detected lakes covered by ice/snow or buried at shallow depths [Koenig et al., 2015]. This gives SAR imagery the potential to significantly increase the size of the database of supraglacial lakes. The current Sentinel-1A mission comprises two polar-orbiting satellites performing C-band SAR imaging, and provides a novel method for investigating the surface hydrology of the GrIS. Here, we explore a year's worth of images since the launch of Sentinel-1A in April 2014. These images have a higher spatial (5 m x 20 m) and temporal (up to daily) resolution than any previously available imagery, so will revolutionise the amount of information that can be yielded about GrIS hydrology. We use these images in combination with other remotely sensed data, including Landsat-8 imagery, to elicit spatial and temporal variations in the water content of the GrIS's surface ice layers. Our primary focus is on the area upstream of Jakobshavn Isbræ, where preliminary analysis has indicated that liquid water may persist

  18. Synthetic fuels

    SciTech Connect

    Sammons, V.O.

    1980-01-01

    This guide is designed for those who wish to learn more about the science and technology of synthetic fuels by reviewing materials in the collections of the Library of Congress. This is not a comprehensive bibliography, it is designed to put the reader on target. Subject headings used by the Library of Congress under which books on synthetic fuels can be located are: oil-shale industry; oil-shales; shale oils; synthetic fuels; synthetic fuels industry; coal gasification; coal liquefaction; fossil fuels; hydrogen as fuel; oil sands; petroleum, synthesis gas; biomass energy; pyrolysis; and thermal oil recovery. Basic texts, handbooks, government publications, journals, etc. were included. (DP)

  19. Analysis of ligand binding to the synthetic dodecapeptide 185-196 of the acetylcholine receptor alpha subunit.

    PubMed

    Neumann, D; Barchan, D; Fridkin, M; Fuchs, S

    1986-12-01

    A synthetic dodecapeptide corresponding to residues 185-196 of the Torpedo acetylcholine receptor alpha subunit, which contains the adjacent cysteine residues at positions 192 and 193, was recently shown by us to contain the essential elements for alpha-bungarotoxin binding. In the present study, we have used Sepharose-linked peptides for quantitative analysis of the cholinergic binding properties of this and other synthetic peptides. Sepharose-linked peptides corresponding to residues 1-20, 126-143, 143-158, 169-181, 185-196, 193-210, and 394-409 of the alpha subunit of Torpedo acetylcholine receptor, as well as a peptide corresponding to residues 185-196 of the alpha subunit of human acetylcholine receptor, were tested for their toxin-binding capacity. Of these immobilized peptides, only peptide 185-196 of the Torpedo acetylcholine receptor bound toxin significantly, thus verifying that this synthetic peptide contains essential components of the receptor toxin-binding site. Analysis of toxin binding to the peptide yielded a dissociation constant of 3.5 X 10(-5) M. This binding was inhibited by various cholinergic ligands. The inhibition potency obtained was alpha-bungarotoxin greater than Naja naja siamensis toxin greater than d-tubocurarine greater than decamethonium greater than acetylcholine greater than carbamoylcholine. This pharmacological profile resembles that of the nicotinic acetylcholine receptor and therefore suggests that the synthetic dodecapeptide also includes the neurotransmitter binding site. Reduction and carboxymethylation of the cysteine residues on peptide 185-196 inhibit its capacity to bind toxin, demonstrating that an intact disulfide is required for toxin binding. A decrease in toxin binding was also obtained following chemical modification of the tryptophan residue at position 187, thus implying its possible involvement in toxin binding. The failure to detect binding of toxin to the corresponding human sequence 185-196, in which the

  20. Analysis of ligand binding to the synthetic dodecapeptide 185-196 of the acetylcholine receptor alpha subunit.

    PubMed Central

    Neumann, D; Barchan, D; Fridkin, M; Fuchs, S

    1986-01-01

    A synthetic dodecapeptide corresponding to residues 185-196 of the Torpedo acetylcholine receptor alpha subunit, which contains the adjacent cysteine residues at positions 192 and 193, was recently shown by us to contain the essential elements for alpha-bungarotoxin binding. In the present study, we have used Sepharose-linked peptides for quantitative analysis of the cholinergic binding properties of this and other synthetic peptides. Sepharose-linked peptides corresponding to residues 1-20, 126-143, 143-158, 169-181, 185-196, 193-210, and 394-409 of the alpha subunit of Torpedo acetylcholine receptor, as well as a peptide corresponding to residues 185-196 of the alpha subunit of human acetylcholine receptor, were tested for their toxin-binding capacity. Of these immobilized peptides, only peptide 185-196 of the Torpedo acetylcholine receptor bound toxin significantly, thus verifying that this synthetic peptide contains essential components of the receptor toxin-binding site. Analysis of toxin binding to the peptide yielded a dissociation constant of 3.5 X 10(-5) M. This binding was inhibited by various cholinergic ligands. The inhibition potency obtained was alpha-bungarotoxin greater than Naja naja siamensis toxin greater than d-tubocurarine greater than decamethonium greater than acetylcholine greater than carbamoylcholine. This pharmacological profile resembles that of the nicotinic acetylcholine receptor and therefore suggests that the synthetic dodecapeptide also includes the neurotransmitter binding site. Reduction and carboxymethylation of the cysteine residues on peptide 185-196 inhibit its capacity to bind toxin, demonstrating that an intact disulfide is required for toxin binding. A decrease in toxin binding was also obtained following chemical modification of the tryptophan residue at position 187, thus implying its possible involvement in toxin binding. The failure to detect binding of toxin to the corresponding human sequence 185-196, in which the

  1. 77 FR 6548 - Notice of Availability of Ballistic Survivability, Lethality and Vulnerability Analyses

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-08

    ... Laboratory's (ARL's), Survivability, Lethality Analysis Directorate (SLAD) is a leader in ballistic..., telephone (410) 278- 5028. For further technical information, please contact Denise Jordan, (410)...

  2. Atomic force microscopy analysis of synthetic membranes applied in release studies

    NASA Astrophysics Data System (ADS)

    Olejnik, Anna; Nowak, Izabela

    2015-11-01

    Synthetic membranes are commonly used in drug release studies and are applied mostly in quality control. They contain pores through which the drug can be diffused directly into the receptor fluid. Investigation of synthetic membranes permits determination of their structure and characterization of their properties. We suggest that the preliminary characterization of the membranes can be relevant to the interpretation of the release results. The aim of this study was to compare eight synthetic membranes by using atomic force microscopy in order to predict and understand their behavior in the release experiments. The results proved that polytetrafluoroethylene membrane was not suitable for the release study of tetrapeptide due to its hydrophobic nature, thickness and the specific structure with high trapezoid shaped blocks. The additional substructures in pores of mixed cellulose esters and nylon membranes detected by AFM influenced the diffusion rate of the active compound. These findings indicate that the selection of the membrane for the release studies should be performed cautiously by taking into consideration the membrane properties and by analyzing them prior the experiment.

  3. Generation of synthetic image sequences for the verification of matching and tracking algorithms for deformation analysis

    NASA Astrophysics Data System (ADS)

    Bethmann, F.; Jepping, C.; Luhmann, T.

    2013-04-01

    This paper reports on a method for the generation of synthetic image data for almost arbitrary static or dynamic 3D scenarios. Image data generation is based on pre-defined 3D objects, object textures, camera orientation data and their imaging properties. The procedure does not focus on the creation of photo-realistic images under consideration of complex imaging and reflection models as they are used by common computer graphics programs. In contrast, the method is designed with main emphasis on geometrically correct synthetic images without radiometric impact. The calculation process includes photogrammetric distortion models, hence cameras with arbitrary geometric imaging characteristics can be applied. Consequently, image sets can be created that are consistent to mathematical photogrammetric models to be used as sup-pixel accurate data for the assessment of high-precision photogrammetric processing methods. In the first instance the paper describes the process of image simulation under consideration of colour value interpolation, MTF/PSF and so on. Subsequently the geometric quality of the synthetic images is evaluated with ellipse operators. Finally, simulated image sets are used to investigate matching and tracking algorithms as they have been developed at IAPG for deformation measurement in car safety testing.

  4. Analysis of Microbe-Associated Molecular Pattern-Responsive Synthetic Promoters with the Parsley Protoplast System.

    PubMed

    Kanofsky, Konstantin; Lehmeyer, Mona; Schulze, Jutta; Hehl, Reinhard

    2016-01-01

    Plants recognize pathogens by microbe-associated molecular patterns (MAMPs) and subsequently induce an immune response. The regulation of gene expression during the immune response depends largely on cis-sequences conserved in promoters of MAMP-responsive genes. These cis-sequences can be analyzed by constructing synthetic promoters linked to a reporter gene and by testing these constructs in transient expression systems. Here, the use of the parsley (Petroselinum crispum) protoplast system for analyzing MAMP-responsive synthetic promoters is described. The synthetic promoter consists of four copies of a potential MAMP-responsive cis-sequence cloned upstream of a minimal promoter and the uidA reporter gene. The reporter plasmid contains a second reporter gene, which is constitutively expressed and hence eliminates the requirement of a second plasmid used as a transformation control. The reporter plasmid is transformed into parsley protoplasts that are elicited by the MAMP Pep25. The MAMP responsiveness is validated by comparing the reporter gene activity from MAMP-treated and untreated cells and by normalizing reporter gene activity using the constitutively expressed reporter gene. PMID:27557767

  5. [Lethal intoxication with baclofen].

    PubMed

    Dukova, O A; Pokrovsky, A A; Melent'ev, A V; Krasnov, E A; Suvorova, E V; Efremov, A A

    2015-01-01

    The objective of the present study was to select and develop simpler methods for the quantitative determination of baclofen in blood with the use of HPLC and tandem MS (MS-MS) techniques and its qualitative determination in cadaveric organs by the GC/MS technique. These mathods were shown to be suitable for the purpose of forensic medical analysis, clinical, toxicological, and therapeutic monitoring. The special emphasis is laid on the methods used to investigate the biological materials obtained from the subjects who died from baclofen intoxication. PMID:25874317

  6. Numerical analysis of thermally assisted spin-transfer torque magnetization reversal in synthetic ferrimagnetic free layers

    SciTech Connect

    Shen, J.; Shi, M.; Tanaka, T. Matsuyama, K.

    2015-05-07

    The spin transfer torque magnetization reversal of synthetic ferrimagnetic free layers under pulsed temperature rise was numerically studied by solving the Landau–Lifshitz–Gilbert equation, taking into account the stochastic random fields, the temperature dependence of magnetic parameters, and the spin torque terms. The anti-parallel magnetization configuration was retained at the elevated temperature, due to interlayer dipole coupling. A significant thermal assistance effect, resulting in a 40% reduction in the switching current, was demonstrated during a nanosecond pulsed temperature rise up to 77% of the Curie temperature.

  7. Direct spectrophotometric method for analysis of food supplements containing synthetic polyhydroquinones

    NASA Astrophysics Data System (ADS)

    Vasilevsky, A. M.; Konoplev, G. A.; Stepanova, O. S.; Toropov, D. K.; Zagorsky, A. L.

    2016-04-01

    A novel direct spectrophotometric method for quantitative determination of Oxiphore® drug substance (synthetic polyhydroquinone complex) in food supplements is developed. Absorption spectra of Oxiphore® water solutions in the ultraviolet region are presented. Samples preparation procedures and mathematical methods of spectra post-analytical procession are discussed. Basic characteristics of the automatic CCD-based UV spectrophotometer and special software implementing the developed method are described. The results of the trials of the developed method and software are analyzed: the error of determination for Oxiphore® concentration in water solutions of the isolated substance and singlecomponent food supplements did not exceed 15% (average error was 7…10%).

  8. Numerical analysis of thermally assisted spin-transfer torque magnetization reversal in synthetic ferrimagnetic free layers

    NASA Astrophysics Data System (ADS)

    Shen, J.; Shi, M.; Tanaka, T.; Matsuyama, K.

    2015-05-01

    The spin transfer torque magnetization reversal of synthetic ferrimagnetic free layers under pulsed temperature rise was numerically studied by solving the Landau-Lifshitz-Gilbert equation, taking into account the stochastic random fields, the temperature dependence of magnetic parameters, and the spin torque terms. The anti-parallel magnetization configuration was retained at the elevated temperature, due to interlayer dipole coupling. A significant thermal assistance effect, resulting in a 40% reduction in the switching current, was demonstrated during a nanosecond pulsed temperature rise up to 77% of the Curie temperature.

  9. Robustness Analysis of Regional Water Supply Portfolios using Synthetic Inflow Scenarios with Variable Drought Frequency

    NASA Astrophysics Data System (ADS)

    Herman, J. D.; Zeff, H. B.; Lamontagne, J. R.; Reed, P. M.; Characklis, G. W.

    2015-12-01

    Robustness analyses of water supply systems have moved toward exploratory simulation to discover scenarios in which existing or planned policies may fail to meet stakeholder objectives. Such assessments rely heavily on the choice of plausible future scenarios, which, in the case of drought management, requires sampling or generating a broad ensemble of reservoir inflows which do not necessarily reflect the historical record. Here we adapt a widely used synthetic streamflow generation method to adjust the frequency of low-flow periods, which can be related to impactful historical events from the perspective of decision makers. Specifically, the modified generation procedure allows the user to specify parameters n, p such that events with observed weekly non-exceedance frequency p appear in the synthetic scenario with approximate frequency np (i.e., the pth percentile flow occurs n times more frequently). Additionally, the generator preserves the historical autocorrelation of streamflow and its seasonality, as well as approximate multi-site correlation. Using model simulations from recent work in multi-objective urban drought portfolio planning in North Carolina, a region whose water supply faces both climate and population pressures, we illustrate the decision-relevant consequences caused by raising the frequency of low flows associated with the 2007-2008 drought. This method explores system performance under extreme events of increasing frequency prior to reconciling these findings with climate model projections, and thus can be used to support bottom-up robustness methods in water systems planning.

  10. Plasma synthetic jet actuator: electrical and optical analysis of the discharge

    NASA Astrophysics Data System (ADS)

    Belinger, A.; Naudé, N.; Cambronne, J. P.; Caruana, D.

    2014-08-01

    Active flow control is based on the development of robust actuators which are reliable, small and easy to integrate. A promising actuator referred to as plasma synthetic jet actuator produces a synthetic jet with high exhaust velocities and holds the promise of enabling high-speed flows. With this high velocity jet, it is possible to reduce fluid phenomena such as transition and turbulence, thus making it possible to increase an aircraft's performance whilst at the same time reducing its environmental impact. This high velocity jet is produced by a pulsed discharge in a microcavity. In this paper, we focus on the properties of the discharge in order to understand the functioning of the actuator. In the first part an electrical description of the discharge in presented. Afterwards, optical measurements (optical emission spectroscopy and ICCD photograph) enable the determination of temperature, volume and duration of the discharge. At the end of the paper we present an electrical model of the discharge, which can be obtained both from electrical measurements and from macroscopic properties of the discharge (temperature, volume). This electrical model can easily be included in electrical simulation software.

  11. Metabolism and toxicological analysis of synthetic cannabinoids in biological fluids and tissues.

    PubMed

    Presley, B C; Gurney, S M R; Scott, K S; Kacinko, S L; Logan, B K

    2016-07-01

    Synthetic cannabinoids, which began proliferating in the United States in 2009, have gone through numerous iterations of modification to their chemical structures. More recent generations of compounds have been associated with significant adverse outcomes following use, including cognitive and psychomotor impairment, seizures, psychosis, tissue injury and death. These effects increase the urgency for forensic and public health laboratories to develop methods for the detection and identification of novel substances, and apply these to the determination of their metabolism and disposition in biological samples. This comprehensive review describes the history of the appearance of the drugs in the United States, discusses the naming conventions emerging to designate new structures, and describes the most prominent new compounds linked to the adverse effects now associated with their use. We review in depth the metabolic pathways that have been elucidated for the major members of each of the prevalent synthetic cannabinoid drug subclasses, the enzyme systems responsible for their metabolism, and the use of in silico approaches to assist in predicting and identifying the metabolites of novel compounds and drug subclasses that will continue to appear. Finally, we review and critique analytical methods applied to the detection of the drugs and their metabolites, including immunoassay screening, and liquid chromatography mass spectrometry confirmatory techniques applied to urine, serum, whole blood, oral fluid, hair, and tissues. PMID:27257717

  12. Cotton crop spectral imaging analysis: a web-based hyperspectral synthetic imagery simulation system

    NASA Astrophysics Data System (ADS)

    Alarcon, Vladimir J.; Sassenrath, Gretchen F.

    2004-11-01

    The development of spectral libraries for specific vegetation species and soils is useful for identifying different physiological or physical-chemical characteristics. Usually, spectral libraries are provided as a data-base add-in of current commercial software used for analyzing hyperspectral imagery. The use of those databases requires installation of the software in the user"s machine for either visualizing or using the spectral libraries. There are also spectral libraries available on the web but the data is static and partitioned by spectrum of vegetation or soil because the size of the files of actual hyperspectral images precludes it"s publication on the web. In this paper, a web-based simulation environment for generating hyperspectral synthetic imagery of cotton plots is presented. The system was developed using Java and is based on a previous synthetic imagery program1. The mathematical and numerical formulation of the model is briefly sketched. The core computing components of the simulation environment were written in C for their computational efficiency. The emerging Java Native Interface (JNI) technique and standard Java techniques were used to design a user-friendly simulator. The simulation system provides interactive user control and real time visualization of the resulting hyperspectral image through standard web browsers. It shows potential for providing web-based hyperspectral libraries, in the form of images, for public use.

  13. Synthetic oils

    NASA Technical Reports Server (NTRS)

    Hatton, R. E.

    1973-01-01

    Synthetic lubricants are discussed by chemical class and their general strengths and weaknesses in terms of lubrication properties are analyzed. Comparative ratings are given for 14 chemical classes and are used as a guide for lubricant selection. The effects of chemical structure on the properties of the lubricant are described with special emphasis on thermal stability. The diversity of synthetic lubricants which is provided by the wide range of properties permits many applications, some of which are reported.

  14. Synthetic Genetic Arrays: Automation of Yeast Genetics.

    PubMed

    Kuzmin, Elena; Costanzo, Michael; Andrews, Brenda; Boone, Charles

    2016-01-01

    Genome-sequencing efforts have led to great strides in the annotation of protein-coding genes and other genomic elements. The current challenge is to understand the functional role of each gene and how genes work together to modulate cellular processes. Genetic interactions define phenotypic relationships between genes and reveal the functional organization of a cell. Synthetic genetic array (SGA) methodology automates yeast genetics and enables large-scale and systematic mapping of genetic interaction networks in the budding yeast,Saccharomyces cerevisiae SGA facilitates construction of an output array of double mutants from an input array of single mutants through a series of replica pinning steps. Subsequent analysis of genetic interactions from SGA-derived mutants relies on accurate quantification of colony size, which serves as a proxy for fitness. Since its development, SGA has given rise to a variety of other experimental approaches for functional profiling of the yeast genome and has been applied in a multitude of other contexts, such as genome-wide screens for synthetic dosage lethality and integration with high-content screening for systematic assessment of morphology defects. SGA-like strategies can also be implemented similarly in a number of other cell types and organisms, includingSchizosaccharomyces pombe,Escherichia coli, Caenorhabditis elegans, and human cancer cell lines. The genetic networks emerging from these studies not only generate functional wiring diagrams but may also play a key role in our understanding of the complex relationship between genotype and phenotype. PMID:27037078

  15. Development of synthetic velocity - depth damage curves using a Weighted Monte Carlo method and Logistic Regression analysis

    NASA Astrophysics Data System (ADS)

    Vozinaki, Anthi Eirini K.; Karatzas, George P.; Sibetheros, Ioannis A.; Varouchakis, Emmanouil A.

    2014-05-01

    Damage curves are the most significant component of the flood loss estimation models. Their development is quite complex. Two types of damage curves exist, historical and synthetic curves. Historical curves are developed from historical loss data from actual flood events. However, due to the scarcity of historical data, synthetic damage curves can be alternatively developed. Synthetic curves rely on the analysis of expected damage under certain hypothetical flooding conditions. A synthetic approach was developed and presented in this work for the development of damage curves, which are subsequently used as the basic input to a flood loss estimation model. A questionnaire-based survey took place among practicing and research agronomists, in order to generate rural loss data based on the responders' loss estimates, for several flood condition scenarios. In addition, a similar questionnaire-based survey took place among building experts, i.e. civil engineers and architects, in order to generate loss data for the urban sector. By answering the questionnaire, the experts were in essence expressing their opinion on how damage to various crop types or building types is related to a range of values of flood inundation parameters, such as floodwater depth and velocity. However, the loss data compiled from the completed questionnaires were not sufficient for the construction of workable damage curves; to overcome this problem, a Weighted Monte Carlo method was implemented, in order to generate extra synthetic datasets with statistical properties identical to those of the questionnaire-based data. The data generated by the Weighted Monte Carlo method were processed via Logistic Regression techniques in order to develop accurate logistic damage curves for the rural and the urban sectors. A Python-based code was developed, which combines the Weighted Monte Carlo method and the Logistic Regression analysis into a single code (WMCLR Python code). Each WMCLR code execution

  16. Analysis of Natural Graphite, Synthetic Graphite, and Thermosetting Resin Candidates for Use in Fuel Compact Matrix

    SciTech Connect

    Trammell, Michael P; Pappano, Peter J

    2011-09-01

    The AGR-1 and AGR-2 compacting process involved overcoating TRISO particles and compacting them in a steel die. The overcoating step is the process of applying matrix to the OPyC layer of TRISO particles in a rotating drum in order to build up an overcoat layer of desired thickness. The matrix used in overcoating is a mixture of natural graphite, synthetic graphite, and thermosetting resin in the ratio, by weight, of 64:16:20. A wet mixing process was used for AGR-1 and AGR-2, in that the graphites and resin were mixed in the presence of ethyl alcohol. The goal of the wet mixing process was to 'resinate' the graphite particles, or coat each individual graphite particle with a thin layer of resin. This matrix production process was similar to the German, Chinese, Japanese, and South African methods, which also use various amount of solvent during mixing. See Appendix 1 for information on these countries matrix production techniques. The resin used for AGR-1 and AGR-2 was provided by Hexion, specifically Hexion grade Durite SC1008. Durite SC1008 is a solvated (liquid) resole phenolic resin. A resole resin does not typically have a hardening agent added. The major constituent of SC1008 is phenol, with minor amounts of formaldehyde. Durite SC1008 is high viscosity, so additional ethyl alcohol was added during matrix production in order to reduce its viscosity and enhance graphite particle resination. The current compacting scale up plan departs from a wet mixing process. The matrix production method specified in the scale up plan is a co-grinding jet mill process where powdered phenolic resin and graphite are all fed into a jet mill at the same time. Because of the change in matrix production style, SC1008 cannot be used in the jet milling process because it is a liquid. The jet milling/mixing process requires that a suite of solid or powdered resins be investigated. The synthetic graphite used in AGR-1 and AGR-2 was provided by SGL Carbon, grade KRB2000. KRB2000 is a

  17. Boron analysis by electron microprobe using MoB4C layered synthetic crystals

    USGS Publications Warehouse

    McGee, J.J.; Slack, J.F.; Herrington, C.R.

    1991-01-01

    Preliminary electron microprobe studies of B distribution in minerals have been carried out using MoB4C-layered synthetic crystals to improve analytical sensitivity for B. Any microprobe measurements of the B contents of minerals using this crystal must include analyses for Cl to assess and correct for the interference of Cl X-rays on the BK?? peak. Microprobe analyses for B can be made routinely in tourmaline and other B-rich minerals, and minor B contents also can be determined in common rock-forming minerals. Incorporation of unusually high B contents in minerals other than borosilicates has been discovered in prograde and retrograde minerals in tourmalinites from the Broken Hill district, Australia, and may reflect high B activities produced during the metamorphism of tourmaline-rich rocks. -from Authors

  18. Analysis of urban area land cover using SEASAT Synthetic Aperture Radar data

    NASA Technical Reports Server (NTRS)

    Henderson, F. M. (Principal Investigator)

    1980-01-01

    Digitally processed SEASAT synthetic aperture raar (SAR) imagery of the Denver, Colorado urban area was examined to explore the potential of SAR data for mapping urban land cover and the compatability of SAR derived land cover classes with the United States Geological Survey classification system. The imagery is examined at three different scales to determine the effect of image enlargement on accuracy and level of detail extractable. At each scale the value of employing a simplistic preprocessing smoothing algorithm to improve image interpretation is addressed. A visual interpretation approach and an automated machine/visual approach are employed to evaluate the feasibility of producing a semiautomated land cover classification from SAR data. Confusion matrices of omission and commission errors are employed to define classification accuracies for each interpretation approach and image scale.

  19. Stereo and enantioselective separation and identification of synthetic pyrethroids, and photolytical isomerization analysis.

    PubMed

    Li, Z Y; Luo, X N; Li, Q L; Zhang, E Q; Zhao, J H; Zhang, W S

    2015-02-01

    Permethrin, cypermethrin and cyfluthrin are three important pyrethroids with similar structures and contain four, eight and eight stereoisomers, respectively. All the stereoisomers were completely resolved by a combination of achiral and chiral high-performance liquid chromatography with hexane/isopropanol as the mobile phase. The absolute configurations for the stereoisomers were also assigned on the basis of enantioselective resolution of permethrinic acid. For cypermethrin and cyfluthrin, although there is the only difference being one F atom substitution in cyfluthrin, the cis-I diastereomer exhibited a reversal of enantiomer order. Three specific stereoisomers were further isolated to investigate the photolysis and chiral stability of synthetic pyrethroids at the enantiomeric level. The results clearly revealed that significant isomerization occurred along with the photolysis process. The isomerization occurred at chiral 1-C position, 3-C position or both in the cyclopropyl ring, and the chiral 3-C exhibited a higher inversion tendency. PMID:25319199

  20. Using Videos Derived from Simulations to Support the Analysis of Spatial Awareness in Synthetic Vision Displays

    NASA Technical Reports Server (NTRS)

    Boton, Matthew L.; Bass, Ellen J.; Comstock, James R., Jr.

    2006-01-01

    The evaluation of human-centered systems can be performed using a variety of different methodologies. This paper describes a human-centered systems evaluation methodology where participants watch 5-second non-interactive videos of a system in operation before supplying judgments and subjective measures based on the information conveyed in the videos. This methodology was used to evaluate the ability of different textures and fields of view to convey spatial awareness in synthetic vision systems (SVS) displays. It produced significant results for both judgment based and subjective measures. This method is compared to other methods commonly used to evaluate SVS displays based on cost, the amount of experimental time required, experimental flexibility, and the type of data provided.

  1. Quantitative high-throughput analysis of synthetic genetic interactions in Caenorhabditis elegans by RNA interference

    PubMed Central

    Fortunato, Angelo

    2009-01-01

    Biological processes are highly dynamic but the current representation of molecular networks is static and largely qualitative. To investigate the dynamic property of genetic networks, a novel quantitative high-throughput method based on RNA interference and capable of calculating the relevance of each interaction, was developed. With this approach, it will be possible to identify not only the components of a network, but also to investigate quantitatively how network and biological processes react to perturbations. As a first application of this method, the genetic interactions of a weak loss-of-function mutation in the gene efl-1/E2F with all the genes of chromosome III were investigated during embryonic development of Caenorhabditis elegans. Fifteen synthetic genetic interactions of efl-1/E2F with the genes of chromosome III were detected, measured and ranked by statistical relevance. PMID:19059334

  2. Analysis of properties of synthetic mineral microparticles for retention and drainage system

    NASA Astrophysics Data System (ADS)

    Lee, Sa Yong

    Over the past 20 years there has been a revolution involving the use of nano- or macro-sized particles as a component of drainage and retention systems during the manufacture of paper. More recently a group of patented technologies called Synthetic Mineral Microparticles (SMM) has been invented and developed. This system has potential to further promote the drainage of water and retention of fine particles during papermaking. Prior research, as well as our own preliminary research showed that the SMM system has advantages in both of drainage and retention, compared with montmorillonite (bentonite), which is one of the most popular materials presently used in this kind of application. In spite of the demonstrated advantages of this SMM system, the properties and activity of SMM particles in the aqueous state have not been elucidated yet. To help understand the molecular mechanisms involved in SMM technology, streaming current and potentiometric titration were employed to characterize the charge behavior of SMM, depending on the synthetic conditions, which included variation of the Al/Si ratio, partial neutralization of Al species, salt addition and shear rate. Surface area of SMM and the distribution of SMM particle size were investigated with scanning electron microscopy in order to elucidate the relationship between the morphology and coagulation behavior of SMM, versus the pre-stated synthetic conditions, as well as to estimate the optimal conditions to produce SMM as a retention and drainage aid for use during papermaking. Through the streaming current titration experiments it was found that pH variation, caused by the change of Al/Si ratio and partial neutralization of aluminum's acidity, profoundly affects the charge properties of SMM. These effects can be attributed to the variation of Al-ion speciation and the influence ionizable groups on the Si-containing particle surfaces. The relationship between Al/Si ratio and isoelectric pH, measured by potentiometric

  3. A-Differential Synthetic Aperture Radar Interferometry analysis of a Deep Seated Gravitational Slope Deformation occurring at Bisaccia (Italy).

    PubMed

    Di Martire, Diego; Novellino, Alessandro; Ramondini, Massimo; Calcaterra, Domenico

    2016-04-15

    This paper presents the results of an investigation on a Deep Seated Gravitational Slope Deformation (DSGSD), previously only hypothesized by some authors, affecting Bisaccia, a small town located in Campania region, Italy. The study was conducted through the integration of conventional methods (geological-geomorphological field survey, air-photo interpretation) and an Advanced-Differential Interferometry Synthetic Aperture Radar (A-DInSAR) technique. The DSGSD involves a brittle lithotype (conglomerates of the Ariano Irpino Supersynthem) resting over a Structurally Complex Formation (Varycoloured Clays of Calaggio Formation). At Bisaccia, probably as a consequence of post-cyclic recompression phenomena triggered by reiterated seismic actions, the rigid plate made up of conglomeratic sediments resulted to be split in five portions, showing different rates of displacements, whose deformations are in the order of some centimeter/year, thus inducing severe damage to the urban settlement. A-DInSAR techniques confirmed to be a reliable tool in monitoring slow-moving landslides. In this case 96 ENVIronmental SATellite-Advanced Synthetic Aperture Radar (ENVISAT-ASAR) images, in ascending and descending orbits, have been processed using SUBSOFT software, developed by the Remote Sensing Laboratory (RSLab) group from the Universitat Politècnica de Catalunya (UPC). The DInSAR results, coupled with field survey, supported the analysis of the instability mechanism and confirmed the historical record of the movements already available for the town. PMID:26849321

  4. Detailed Analysis of (−)-Palmyrolide A and Some Synthetic Derivatives as Voltage-Gated Sodium Channel Antagonists

    PubMed Central

    2015-01-01

    A small library of synthetic (−)-palmyrolide A diastereomers, analogues, and acyclic precursors have been examined with respect to their interaction with voltage-gated sodium channels (VGSCs). Toward this goal, the ability of (−)-palmyrolide A and analogues to antagonize veratridine-stimulated Na+ influx in primary cultures of mouse cerebrocortical neurons was assessed. We found that synthetic (−)-palmyrolide A and its enantiomer functioned as VGSC antagonists to block veratridine-induced sodium influx. A detailed NMR and computational analysis of four diastereomers revealed that none had the same combination of shape and electrostatic potential as exhibited by natural (−)-palmyrolide A. These data indicate that the relative configuration about the tert-butyl and methyl substituents appears to be a prerequisite for biological function. Additional testing revealed that the enamide double bond was not necessary for blocking veratridine-induced sodium influx, whereas the acyclic analogues and other macrolide diastereomers tested were inactive as inhibitors of VGSCs, suggesting that the intact macrolide was required. PMID:25343669

  5. Synthetic Jets

    NASA Technical Reports Server (NTRS)

    Milanovic, Ivana M.

    2003-01-01

    Current investigation of synthetic jets and synthetic jets in cross-flow examined the effects of orifice geometry and dimensions, momentum-flux ratio, cluster of orifices, pitch and yaw angles as well as streamwise development of the flow field. This comprehensive study provided much needed experimental information related to the various control strategies. The results of the current investigation on isolated and clustered synthetic jets with and without cross-flow will be further analyzed and documented in detail. Presentations at national conferences and publication of peer- reviewed journal articles are also expected. Projected publications will present both the mean and turbulent properties of the flow field, comparisons made with the data available in an open literature, as well as recommendations for the future work.

  6. Analysis of the interaction of phytoestrogens and synthetic chemicals: An in vitro/in vivo comparison

    SciTech Connect

    Charles, Grantley D. . E-mail: charles_grantley@allergan.com; Gennings, Chris; Tornesi, Belen; Kan, H. Lynn; Zacharewski, Timothy R.; Bhaskar Gollapudi, B.; Carney, Edward W.

    2007-02-01

    In the evaluation of chemical mixture toxicity, it is desirable to develop an evaluation paradigm which incorporates some critical attributes of real world exposures, particularly low dose levels, larger numbers of chemicals, and chemicals from synthetic and natural sources. This study evaluated the impact of low level exposure to a mixture of six synthetic chemicals (SC) under conditions of co-exposure to various levels of plant-derived phytoestrogen (PE) compounds. Estrogenic activity was evaluated using an in vitro human estrogen receptor (ER) transcriptional activation assay and an in vivo immature rat uterotrophic assay. Initially, dose-response curves were characterized for each of the six SCs (methoxyclor, o,p-DDT, octylphenol, bisphenol A, {beta}-hexachlorocyclohexane, 2,3-bis(4-hydroxyphenyl)-propionitrile) in each of the assays. The six SCs were then combined at equipotent ratios and tested at 5-6 dose levels spanning from very low, sub-threshold levels, to a dose in which every chemical in the mixture was at its individual estrogenic response threshold. The SC mixtures also were tested in the absence or presence of 5-6 different levels of PEs, for a total of 36 (in vitro) or 25 (in vivo) treatment groups. Both in vitro and in vivo, low concentrations of the SC mixture failed to increase estrogenic responses relative to those induced by PEs alone. However, significant increases in response occurred when each chemical in the SC mixture was near or above its individual response threshold. In vitro, interactions between high-doses of SCs and PEs were greater than additive, whereas mixtures of SCs in the absence of PEs interacted in a less than additive fashion. In vivo, the SC and PE mixture responses were consistent with additivity. These data illustrate a novel approach for incorporating key attributes of real world exposures in chemical mixture toxicity assessments, and suggest that chemical mixture toxicity is likely to be of concern only when the

  7. Fingerprint analysis and synthetic adulterant search in Hedera helix formulations by capillary electrophoresis.

    PubMed

    Cianchino, V; Ortega, C; Acosta, G; Martínez, L D; Gomez, M R

    2007-04-01

    A high-performance capillary electrophoretic (CE) method has been developed for obtaining electropherograms of various extracts and the commercial formulation (fingerprints) of Hedera helix L used in Argentina as a cough's treatment. Also, a capillary zone electrophoresis (CZE) method was developed for the search, identification and determination of some possible adulterants. These likely adulterants are common synthetic drugs used in respiratory diseases (antitussive, decongestant and bronchodilator agents). Under optimum conditions, the analytes (ephedrine, codeine, diphenhydramine and constituents of H. helix formulations) were separated within less than 10 min in 20 mM sodium tetraborate buffer (pH 9.0). The present procedure was validated with respect to selectivity, linearity range, limits of detection (LOD) and quantification (LOQ), precision (repeatability and intermediate precision), solution stability and accuracy; the results obtained were satisfactory. Good linearity was obtained over two orders of magnitude and detection limits (S/N = 3) were better than 1.2 microg ml(-1) for all analytes. The CE methodology was successfully applied to the search and subsequent determination of ephedrine, codeine and diphenhydramine in H. helix extracts and its phytopharmaceutical products. PMID:17484280

  8. Analysis of data acquired by synthetic aperture radar over Dade County, Florida, and Acadia Parish, Louisiana

    NASA Technical Reports Server (NTRS)

    Wu, S. T.

    1983-01-01

    Results of digital processing of airborne X-band synthetic aperture radar (SAR) data acquired over Dade County, Florida, and Acadia Parish, Louisiana are presented. The goal was to investigate the utility of SAR data for land cover mapping and area estimation under the AgRISTARS Domestic Crops and Land Cover Project. In the case of the Acadia Paris study area, LANDSAT multispectral scanner (MSS) data were also used to form a combined SAR and MSS data set. The results of accuracy evaluation for the SAR, MSS, and SAR/MSS data using supervised classification show that the combined SAR/MSS data set results in an improved classification accuracy of the five land cover classes as compared with SAR-only and MSS-only data sets. In the case of the Dade County study area, the results indicate that both HH and VV polarization data are highly responsive to the row orientation of the row crop but not to the specific vegetation which forms the row structure. On the other hand, the HV polarization data are relatively insensitive to the orientation of row crop. Therefore, the HV polarization data may be used to discriminate the specific vegetation that forms the row structure.

  9. Observation of sea-ice dynamics using synthetic aperture radar images: Automated analysis

    NASA Technical Reports Server (NTRS)

    Vesecky, John F.; Samadani, Ramin; Smith, Martha P.; Daida, Jason M.; Bracewell, Ronald N.

    1988-01-01

    The European Space Agency's ERS-1 satellite, as well as others planned to follow, is expected to carry synthetic-aperture radars (SARs) over the polar regions beginning in 1989. A key component in utilization of these SAR data is an automated scheme for extracting the sea-ice velocity field from a time sequence of SAR images of the same geographical region. Two techniques for automated sea-ice tracking, image pyramid area correlation (hierarchical correlation) and feature tracking, are described. Each technique is applied to a pair of Seasat SAR sea-ice images. The results compare well with each other and with manually tracked estimates of the ice velocity. The advantages and disadvantages of these automated methods are pointed out. Using these ice velocity field estimates it is possible to construct one sea-ice image from the other member of the pair. Comparing the reconstructed image with the observed image, errors in the estimated velocity field can be recognized and a useful probable error display created automatically to accompany ice velocity estimates. It is suggested that this error display may be useful in segmenting the sea ice observed into regions that move as rigid plates of significant ice velocity shear and distortion.

  10. Development and Analysis of Synthetic Composite Materials Emulating Patient AAA Wall Material Properties

    NASA Astrophysics Data System (ADS)

    Margossian, Christa M.

    Abdominal Aortic Aneurysm (AAA) rupture accounts for 14,000 deaths a year in the United States. Since the number of ruptures has not decreased significantly in recent years despite improvements in imaging and surgical procedures, there is a need for an accurate, noninvasive technique capable of establishing rupture risk for specific patients and discriminating lesions at high risk. In this project, synthetic composite materials replicating patient-specific wall stiffness and strength were developed and their material properties evaluated. Composites utilizing various fibers were developed to give a range of stiffness from 1825.75 kPa up through 8187.64 kPa with one base material, Sylgard 170. A range of strength from 631.12 kPa to 1083 kPa with the same base material was also found. By evaluating various base materials and various reinforcing fibers, a catalogue of stiffnesses and strengths was started to allow for adaptation to specific patient properties. Three specific patient properties were well-matched with two composites fabricated: silk thread-reinforced Sylgard 170 and silk thread-reinforced Dragon Skin 20. The composites showed similar stiffnesses to the specific patients while reaching target stresses at particular strains. Not all patients were matched with composites as of yet, but recommendations for future matches are able to be determined. These composites will allow for the future evaluation of flow-induced wall stresses in models replicating patient material properties and geometries.

  11. Synthetic hardware performance analysis in virtualized cloud environment for healthcare organization.

    PubMed

    Tan, Chee-Heng; Teh, Ying-Wah

    2013-08-01

    The main obstacles in mass adoption of cloud computing for database operations in healthcare organization are the data security and privacy issues. In this paper, it is shown that IT services particularly in hardware performance evaluation in virtual machine can be accomplished effectively without IT personnel gaining access to actual data for diagnostic and remediation purposes. The proposed mechanisms utilized the hypothetical data from TPC-H benchmark, to achieve 2 objectives. First, the underlying hardware performance and consistency is monitored via a control system, which is constructed using TPC-H queries. Second, the mechanism to construct stress-testing scenario is envisaged in the host, using a single or combination of TPC-H queries, so that the resource threshold point can be verified, if the virtual machine is still capable of serving critical transactions at this constraining juncture. This threshold point uses server run queue size as input parameter, and it serves 2 purposes: It provides the boundary threshold to the control system, so that periodic learning of the synthetic data sets for performance evaluation does not reach the host's constraint level. Secondly, when the host undergoes hardware change, stress-testing scenarios are simulated in the host by loading up to this resource threshold level, for subsequent response time verification from real and critical transactions. PMID:23709190

  12. Analysis Of Atmoshperic Effects On X-Band Synthetic Aperture Radar Observations And Precipitations Estimation

    NASA Astrophysics Data System (ADS)

    Mori, S.; Pulvirenti, L.; Marzano, F. S.; Pierdicca, N.

    2013-12-01

    This paper proposes a new methodology for the detection and quantitative estimation of intense atmospheric precipitations on images acquired by Synthetic Aperture Radars (SARs) operating at X-Band wavelengths. The proposed methodology consists of two successive steps. The first one allows detecting and distinguishing areas subjected to intense precipitation events, permanent water surfaces, flood areas and snow coverage. The second step derives an estimation of the precipitation rate using the event attenuation estimated at the previous step. This methodology is applied on two COSMO-SkyMed (CSK) satellite case studies. The first one is relative to a severe precipitation weather event, occurred in northwestern Italy (close to Liguria region) on November 3-8, 2011. The second one is relative to Hurricane “Irene” event, occurred in Eastern United States (close to Delaware) on late August 2011. In both cases X-SAR echoes and estimated rain rate is compared with corresponding products derived by available ground Weather Radars (WRs). The correlation of the precipitating cloud fields between CSK X-SAR and WR images is significant in all case studies.

  13. Tasers--less than lethal!

    PubMed

    Sharma, Abiram; Theivacumar, Nada S; Souka, Hesham M

    2009-05-01

    We report a case of potentially lethal injury associated with the use of Taser. A 42-year-old man was stopped by police for potential detention. He held a large carving knife over his epigasrium threatening to stab himself. With a view to achieving immobilisation, a Taser gun was used. On activation of the Taser, the subject suffered a 7-cm wide and 10-cm deep stab injury to the upper abdomen. In this case, activation of the Taser resulted in the contraction of skeletal muscles, flexors more intensely than extensors, resulting in the stab injury. PMID:19416583

  14. Tasers – Less than Lethal!

    PubMed Central

    Sharma, Abiram; Theivacumar, Nada S; Souka, Hesham M

    2009-01-01

    We report a case of potentially lethal injury associated with the use of Taser. A 42-year-old man was stopped by police for potential detention. He held a large carving knife over his epigasrium threatening to stab himself.With a view to achieving immobilisation, a Taser gun was used. On activation of the Taser, the subject suffered a 7-cm wide and 10-cm deep stab injury to the upper abdomen. In this case, activation of the Taser resulted in the contraction of skeletal muscles, flexors more intensely than extensors, resulting in the stab injury. PMID:19416583

  15. Synthetic Astrobiology

    NASA Technical Reports Server (NTRS)

    Rothschild, Lynn J.

    2016-01-01

    Synthetic biology - the design and construction of new biological parts and systems and the redesign of existing ones for useful purposes - has the potential to transform fields from pharmaceuticals to fuels. Our lab has focused on the potential of synthetic biology to revolutionize all three major parts of astrobiology: Where do we come from? Where are we going? and Are we alone? For the first and third, synthetic biology is allowing us to answer whether the evolutionary narrative that has played out on planet earth is likely to have been unique or universal. For example, in our lab we are re-evolving the biosynthetic pathways of amino acids in order to understand potential capabilities of an early organism with a limited repertoire of amino acids and developing techniques for the recovery of metals from spent electronics on other planetary bodies. And what about the limits for life? Can we create organisms that expand the envelope for life? In the future synthetic biology will play an increasing role in human activities both on earth, in fields as diverse as human health and the industrial production of novel bio-composites. Beyond earth, we will rely increasingly on biologically-provided life support, as we have throughout our evolutionary history. In order to do this, the field will build on two of the great contributions of astrobiology: studies of the origin of life and life in extreme environments.

  16. Synthetic Astrobiology

    NASA Technical Reports Server (NTRS)

    Rothschild, Lynn J.

    2015-01-01

    Synthetic biology - the design and construction of new biological parts and systems and the redesign of existing ones for useful purposes - has the potential to transform fields from pharmaceuticals to fuels. Our lab has focused on the potential of synthetic biology to revolutionize all three major parts of astrobiology: Where do we come from? Where are we going? and Are we alone? For the first and third, synthetic biology is allowing us to answer whether the evolutionary narrative that has played out on planet earth is likely to have been unique or universal. For example, in our lab we are re-evolving the biosynthetic pathways of amino acids in order to understand potential capabilities of an early organism with a limited repertoire of amino acids and developing techniques for the recovery of metals from spent electronics on other planetary bodies. In the future synthetic biology will play an increasing role in human activities both on earth, in fields as diverse as human health and the industrial production of novel bio-composites. Beyond earth, we will rely increasingly on biologically-provided life support, as we have throughout our evolutionary history. In order to do this, the field will build on two of the great contributions of astrobiology: studies of the origin of life and life in extreme environments.

  17. The benefits of using time-frequency analysis with synthetic aperture focusing technique

    SciTech Connect

    Albright, Austin E-mail: claytonda@ornl.gov; Clayton, Dwight E-mail: claytonda@ornl.gov

    2015-03-31

    Improvements in detection and resolution are always desired and needed. There are various instruments available for the inspection of concrete structures that can be used with confidence for detecting different defects. However, more often than not that confidence is heavily dependent on the experience of the operator rather than the clear, objective discernibility of the output of the instrument. The challenge of objective discernment is amplified when the concrete structures contain multiple layers of reinforcement, are of significant thickness, or both, such as concrete structures in nuclear power plants. We seek to improve and extend the usefulness of results produced using the synthetic aperture focusing technique (SAFT) on data collected from thick, complex concrete structures. A secondary goal is to improve existing SAFT results, with regards to repeatedly and objectively identifying defects and/or internal structure of concrete structures. Towards these goals, we are applying the time-frequency technique of wavelet packet decomposition and reconstruction using a mother wavelet that possesses the exact reconstruction property. However, instead of analyzing the coefficients of each decomposition node, we select and reconstruct specific nodes based on the frequency band it contains to produce a frequency band specific time-series representation. SAFT is then applied to these frequency specific reconstructions allowing SAFT to be used to visualize the reflectivity of a frequency band and that band's interaction with the contents of the concrete structure. We apply our technique to data sets collected using a commercial, ultrasonic linear array (MIRA) from two 1.5m × 2m × 25cm concrete test specimens. One specimen contains multiple layers of rebar. The other contains honeycomb, crack, and rebar bonding defect analogs. This approach opens up a multitude of possibilities for improved detection, readability, and overall improved objectivity. We will focus on

  18. The Benefits of Using Time-Frequency Analysis with Synthetic Aperture Focusing Technique

    SciTech Connect

    Albright, Austin P; Clayton, Dwight A

    2015-01-01

    Improvements in detection and resolution are always desired and needed. There are various instruments available for the inspection of concrete structures that can be used with confidence for detecting different defects. However, more often than not that confidence is heavily dependent on the experience of the operator rather than the clear, objective discernibility of the output of the instrument. The challenge of objective discernment is amplified when the concrete structures contain multiple layers of reinforcement, are of significant thickness, or both, such as concrete structures in nuclear power plants. We seek to improve and extend the usefulness of results produced using the synthetic aperture focusing technique (SAFT) on data collected from thick, complex concrete structures. A secondary goal is to improve existing SAFT results, with regards to repeatedly and objectively identifying defects and/or internal structure of concrete structures. Towards these goals, we are applying the time-frequency technique of wavelet packet decomposition and reconstruction using a mother wavelet that possesses the exact reconstruction property. However, instead of analyzing the coefficients of each decomposition node, we select and reconstruct specific nodes based on the frequency band it contains to produce a frequency band specific time-series representation. SAFT is then applied to these frequency specific reconstructions allowing SAFT to be used to visualize the reflectivity of a frequency band and that band s interaction with the contents of the concrete structure. We apply our technique to data sets collected using a commercial, ultrasonic linear array (MIRA) from two 1.5m x 2m x 25cm concrete test specimens. One specimen contains multiple layers of rebar. The other contains honeycomb, crack, and rebar bonding defect analogs. This approach opens up a multitude of possibilities for improved detection, readability, and overall improved objectivity. We will focus on

  19. Phase-locked flow field analysis in a synthetic human larynx model

    NASA Astrophysics Data System (ADS)

    Lodermeyer, Alexander; Becker, Stefan; Döllinger, Michael; Kniesburges, Stefan

    2015-04-01

    The fluid flow within a human larynx plays an essential role in the fluid-structure-acoustic interaction during voice production. This study addresses the flow field downstream of aerodynamically driven, synthetic vocal folds. In order to quantitatively investigate the supraglottal formation of the flow field within one oscillation cycle of the vocal folds, a phase-locked PIV technique is introduced. The pseudo-time-resolved measurement results were averaged for each phase angle. When including a supraglottal channel, the jet was deflected from the centerline of the supraglottal channel and changed the direction of deflection in different cycles. The result is a bistable flow field. Therefore, a sorting method based on the mean cyclic supraglottal pressure difference was introduced. For both states of the flow field, a recirculation area was detected, interacting with the arising glottal jet in every oscillation cycle. This interaction could be identified as the major cause for supraglottal jet deflection, and the sense of rotation of the recirculation area defined the direction of deflection. The asymmetric structure of the flow field was caused by the geometric boundary condition, i.e., due to the present supraglottal channel. An additional key factor was found to be the contact between the two vocal folds in each oscillation cycle which interrupted the jet flow periodically. Removing the supraglottal channel resulted in a symmetric jet location. When avoiding vocal fold contact, the bistable behavior vanished and the jet was steadily deflected to one lateral side. In the present study, it cannot be confirmed that the Coanda effect is responsible for the deflection.

  20. The benefits of using time-frequency analysis with synthetic aperture focusing technique

    NASA Astrophysics Data System (ADS)

    Albright, Austin; Clayton, Dwight

    2015-03-01

    Improvements in detection and resolution are always desired and needed. There are various instruments available for the inspection of concrete structures that can be used with confidence for detecting different defects. However, more often than not that confidence is heavily dependent on the experience of the operator rather than the clear, objective discernibility of the output of the instrument. The challenge of objective discernment is amplified when the concrete structures contain multiple layers of reinforcement, are of significant thickness, or both, such as concrete structures in nuclear power plants. We seek to improve and extend the usefulness of results produced using the synthetic aperture focusing technique (SAFT) on data collected from thick, complex concrete structures. A secondary goal is to improve existing SAFT results, with regards to repeatedly and objectively identifying defects and/or internal structure of concrete structures. Towards these goals, we are applying the time-frequency technique of wavelet packet decomposition and reconstruction using a mother wavelet that possesses the exact reconstruction property. However, instead of analyzing the coefficients of each decomposition node, we select and reconstruct specific nodes based on the frequency band it contains to produce a frequency band specific time-series representation. SAFT is then applied to these frequency specific reconstructions allowing SAFT to be used to visualize the reflectivity of a frequency band and that band's interaction with the contents of the concrete structure. We apply our technique to data sets collected using a commercial, ultrasonic linear array (MIRA) from two 1.5m × 2m × 25cm concrete test specimens. One specimen contains multiple layers of rebar. The other contains honeycomb, crack, and rebar bonding defect analogs. This approach opens up a multitude of possibilities for improved detection, readability, and overall improved objectivity. We will focus on

  1. Synthetic aperture radar interferometry coherence analysis over Katmai volcano group, Alaska

    USGS Publications Warehouse

    Lu, Zhiming; Freymueller, J.T.

    1998-01-01

    The feasibility of measuring volcanic deformation or monitoring deformation of active volcanoes using space-borne synthetic aperture radar (SAR) interferometry depends on the ability to maintain phase coherence over appropriate time intervals. Using ERS 1 C band (?? = 5.66 cm) SAR imagery, we studied the seasonal and temporal changes of the interferometric SAR coherence for fresh lava, weathered lava, tephra with weak water reworking, tephra with strong water reworking, and fluvial deposits representing the range of typical volcanic surface materials in the Katmai volcano group, Alaska. For interferograms based on two passes with 35 days separation taken during the same summer season, we found that coherence increases after early June, reaches a peak between the middle of July and the middle of September, and finally decreases until the middle of November when coherence is completely lost for all five sites. Fresh lava has the highest coherence, followed by either weathered lava or fluvial deposits. These surfaces maintain relatively high levels of coherence for periods up to the length of the summer season. Coherence degrades more rapidly with time for surfaces covered with tephra. For images taken in different summers, only the lavas maintained coherence well enough to provide useful interferometric images, but we found only a small reduction in coherence after the first year for surfaces with lava. Measurement of volcanic deformation is possible using summer images spaced a few years apart, as long as the surface is dominated by lavas. Our studies suggest that in order to make volcanic monitoring feasible along the Aleutian arc or other regions with similar climatic conditions, observation intervals of the satellite with C band SAR should be at least every month from July through September, every week during the late spring/early summer or late fall, and every 2-3 days during the winter. Copyright 1998 by the American Geophysical Union.

  2. Synthetic oligomer analysis using atmospheric pressure photoionization mass spectrometry at different photon energies.

    PubMed

    Desmazières, Bernard; Legros, Véronique; Giuliani, Alexandre; Buchmann, William

    2014-01-15

    Atmospheric pressure photoionization (APPI) followed by mass spectrometric detection was used to ionize a variety of polymers: polyethylene glycol, polymethyl methacrylate, polystyrene, and polysiloxane. In most cases, whatever the polymer or the solvent used (dichloromethane, tetrahydrofuran, hexane, acetone or toluene), only negative ion mode produced intact ions such as chlorinated adducts, with no or few fragmentations, in contrast to the positive ion mode that frequently led to important in-source fragmentations. In addition, it was shown that optimal detection of polymer distributions require a fine tuning of other source parameters such as temperature and ion transfer voltage. Series of mass spectra were recorded in the negative mode, in various solvents (dichloromethane, tetrahydrofuran, hexane, toluene, and acetone), by varying the photon energy from 8eV up to 10.6eV using synchrotron radiation. To these solvents, addition of a classical APPI dopant (toluene or acetone) was not necessary. Courtesy of the synchrotron radiation, it was demonstrated that the photon energy required for an efficient ionization of the polymer was correlated to the ionization energy of the solvent. As commercial APPI sources typically use krypton lamps with energy fixed at 10eV and 10.6eV, the study of the ionization of polymers over a wavelength range allowed to confirm and refine the previously proposed ionization mechanisms. Moreover, the APPI source can efficiently be used as an interface between size exclusion chromatography or reverse phase liquid chromatography and MS for the study of synthetic oligomers. However, the photoionization at fixed wavelength of polymer standards with different molecular weights showed that it was difficult to obtain intact ionized oligomers with molecular weights above a few thousands. PMID:24370106

  3. Numerical Analysis of Synthetic Jet Flow Control on a Vertical Tail

    NASA Astrophysics Data System (ADS)

    Martin, Jeff

    Airflow over a stabilizer-rudder assembly is simulated on an unstructured grid using a stream-line upwind Petrov-Galerkin (SUPG) weighted residual finite element formulation of the incompressible Navier-Stokes equations. These studies seek to determine the effectiveness of synthetic jet flow control in increasing side force over the vertical tail. The two models under investigation are the Beta model, with 12 jets aligned along the span of the stabilizer, and a Beta model scaled up by a factor of 1.969, with 24 jets aligned along the span of the stabilizer. These two models have Reynolds numbers of 3.6x10 5 and 7.1x105, respectively, where both are based on the mean aerodynamic chord. The flow solver, Phasta, is used to run these simulations. URANS simulations on the Beta model with a 5° sideslip angle and 20° rudder deflection angle show that unsteady blowing with a blowing ratio of 1.0 increases the total side force coefficient by 14% with respect to the baseline. The Cp data obtained as a function of percent chord showed improvement in Cp from unsteady blowing in the outboard region, but negligible change in the inboard region. This data is in agreement with experimental values. Speed isosurface data was obtained for the Beta model with a 0° sideslip angle and 30° rudder deflection angle, with steady blowing. It was found that these isosurfaces create ridges and valleys along the span, suggesting interference between the jets. The same result was found for the scaled-up Beta model with a 0° sideslip angle and 30° rudder deflection angle, with steady blowing.

  4. The Rorschach Suicide Constellation: assessing various degrees of lethality.

    PubMed

    Fowler, J C; Piers, C; Hilsenroth, M J; Holdwick, D J; Padawer, J R

    2001-04-01

    In this article we examine the relation between the Rorschach Comprehensive System's Suicide Constellation (S-CON; Exner, 1993; Exner & Wiley, 1977) and lethality of suicide attempts during the course of patients' hospitalization at the Austen Riggs Center (Stockbridge, MA). Patient records were rated as nonsuicidal (n = 37), parasuicidal (n = 37), or near-lethal (n = 30) based on the presence and lethality of self-destructive acts. Diagnostic efficiency statistics utilizing a cutoff score of 7 or more positive indicators successfully predicted which patients would engage in near-lethal suicidal activity relative to parasuicidal patients (overall correct classification rate [OCC] = .79), nonsuicidal inpatients (OCC = .79), and college students (OCC = .89). Although these predictions were influenced by relatively high base rates in the hospital population (14.5%), base rate estimates were calculated for other hypothetical populations revealing different prediction estimates that should be considered when judging the relative efficacy of the S-CON. Logistic regression analysis revealed that an S-CON score of 7 or more was the sole predictor of near-lethal suicide attempts among 9 psychiatric and demographic variables. PMID:11393464

  5. Critical body residues, Michaelis-Menten analysis of bioaccumulation, lethality and behaviour as endpoints of waterborne Ni toxicity in two teleosts.

    PubMed

    Leonard, Erin M; Marentette, Julie R; Balshine, Sigal; Wood, Chris M

    2014-03-01

    Traditionally, water quality guidelines/criteria are based on lethality tests where results are expressed as a function of waterborne concentrations (e.g. LC50). However, there is growing interest in the use of uptake and binding relationships, such as biotic ligand models (BLM), and in bioaccumulation parameters, such as critical body residue values (e.g. CBR50), to predict metal toxicity in aquatic organisms. Nevertheless, all these approaches only protect species against physiological death (e.g. mortality, failed recruitment), and do not consider ecological death which can occur at much lower concentrations when the animal cannot perform normal behaviours essential for survival. Therefore, we investigated acute (96 h) Ni toxicity in two freshwater fish species, the round goby (Neogobius melanostomus) and rainbow trout (Oncorhynchus mykiss) and compared LC, BLM, and CBR parameters for various organs, as well as behavioural responses (spontaneous activity). In general, round goby were more sensitive. Ni bioaccumulation displayed Michaelis-Menten kinetics in most tissues, and round goby gills had lower Kd (higher binding affinity) but similar Bmax (binding site density) values relative to rainbow trout gills. Round goby also accumulated more Ni than did trout in most tissues at a given exposure concentration. Organ-specific 96 h acute CBR values tended to be higher in round goby but 96 h acute CBR50 and CBR10 values in the gills were very similar in the two species. In contrast, LC50 and LC10 values were significantly higher in rainbow trout. With respect to BLM parameters, gill log KNiBL values for bioaccumulation were higher by 0.4-0.8 log units than the log KNiBL values for toxicity in both species, and both values were higher in goby (more sensitive). Round goby were also more sensitive with respect to the behavioural response, exhibiting a significant decline of 63-75 % in movements per minute at Ni concentrations at and above only 8 % of the LC50 value

  6. Electroshock weapons can be lethal!

    NASA Astrophysics Data System (ADS)

    Lundquist, Marjorie

    2008-03-01

    Electroshock weapons (EWs)-stun guns, tasers, riot shields-are electroconductive devices designed to safely incapacitate healthy men neuromuscularly, so they are called nonlethal or less-lethal. EW firms seeking large nonmilitary markets targeted law enforcement and corrections personnel, who began using EWs in prisons/jails and on public patrol in 1980 in the USA. This shifted the EW-shocked population from healthy soldiers to a heterogeneous mix of both sexes, ages 6-92, in a wide variety of health conditions! An EW operates by disrupting normal physiological processes, producing transient effects in healthy people. But if a person's health is sufficiently compromised, the margin of safety can be lost, resulting in death or permanent health problems. 325 people have died after EW shock since 1980. Did the EW cause these deaths? Evidence indicates that EWs do play a causal role in most such deaths. EWs can be lethal for people in diabetic shock^1 (hypoglycemia), which may be why Robert Dziekanski-a Polish immigrant to Canada-died so quickly after he was tasered at Vancouver Airport: not having eaten for over 10 hours, he likely was severely hypoglycemic. The EW death rate in North America is 30 times higher than need be, because EW users have not been properly trained to use EWs on a heterogeneous population safely! ^1J. Clinical Engineering 30(3):111(2005).

  7. The Old Nova V603 Aquila: A Far Ultraviolet Synthetic Spectral Analysis using its New Hubble FGS Parallax

    NASA Astrophysics Data System (ADS)

    Sion, Edward M.; Bisol, A. C.; Godon, P.

    2014-01-01

    We present the results of a synthetic spectral analysis of the far ultraviolet archival HST and FUSE observations of the fast old nova V630 Aql (P_orb= 3.317 h). Our analysis utilizes the new Hubble FGS parallax distance of 249 pc +9/-8 pc (Harrison et al.2013, ApJ, 767, 7) for this nearly face-on old nova ( i = 13 degrees), a white dwarf mass of 1.2 ± 0.2 solar masses (Arenas et al.2000, MNRAS, 311, 135) and a low reddening of E(B-V) = 0.07 (Gallagher & Holm 1974, ApJ, 189, L123). Our analysis includes full, optically accretion disks since V603 Aql is neither a polar nor an intermediate polar (Mukai & Orio 2005, ApJ, 622, 602). We present the results of our FUV spectral analysis and compare them with parameters derived from X-ray studies. This work is supported by NASA grant NNX13AF12G to Villanova University

  8. Two-stream Instabilities within the Front of Supercritical Quasi-perpendicular Shocks: a Synthetic Analysis

    NASA Astrophysics Data System (ADS)

    Muschietti, L.; Lembege, B.

    2015-12-01

    toward upstream for the oblique whistlers, as expected. We present a synthetic view of wave emissions of two-stream origin and connect our results with the low-frequency whistlers of Hellinger and Mangeney [JGR 102, 1997], the MTSI-1 and 2 of Matsukyio and Scholer [JGR 111, 2006], and the Bernstein waves of Muschietti and Lembege [JGR 118, 2013].

  9. Generating a synthetic genome by whole genome assembly: φX174 bacteriophage from synthetic oligonucleotides

    PubMed Central

    Smith, Hamilton O.; Hutchison, Clyde A.; Pfannkoch, Cynthia; Venter, J. Craig

    2003-01-01

    We have improved upon the methodology and dramatically shortened the time required for accurate assembly of 5- to 6-kb segments of DNA from synthetic oligonucleotides. As a test of this methodology, we have established conditions for the rapid (14-day) assembly of the complete infectious genome of bacteriophage φX174 (5,386 bp) from a single pool of chemically synthesized oligonucleotides. The procedure involves three key steps: (i) gel purification of pooled oligonucleotides to reduce contamination with molecules of incorrect chain length, (ii) ligation of the oligonucleotides under stringent annealing conditions (55°C) to select against annealing of molecules with incorrect sequences, and (iii) assembly of ligation products into full-length genomes by polymerase cycling assembly, a nonexponential reaction in which each terminal oligonucleotide can be extended only once to produce a full-length molecule. We observed a discrete band of full-length assemblies upon gel analysis of the polymerase cycling assembly product, without any PCR amplification. PCR amplification was then used to obtain larger amounts of pure full-length genomes for circularization and infectivity measurements. The synthetic DNA had a lower infectivity than natural DNA, indicating approximately one lethal error per 500 bp. However, fully infectious φX174 virions were recovered after electroporation into Escherichia coli. Sequence analysis of several infectious isolates verified the accuracy of these synthetic genomes. One such isolate had exactly the intended sequence. We propose to assemble larger genomes by joining separately assembled 5- to 6-kb segments; ≈60 such segments would be required for a minimal cellular genome. PMID:14657399

  10. Parametric analysis of synthetic aperture radar data for the study of forest stand characteristics

    NASA Technical Reports Server (NTRS)

    Wu, Shih-Tseng

    1988-01-01

    A parametric analysis of a Gulf Coast forest stand was performed using multipolarization, multipath airborne SAR data, and forest plot properties. Allometric equations were used to compute the biomass and basal area for the test plots. A multiple regression analysis with stepwise selection of independent variables was performed. It is found that forest stand characteristics such as biomass, basal area, and average tree height are correlated with SAR data.

  11. The Danger Assessment: Validation of a Lethality Risk Assessment Instrument for Intimate Partner Femicide

    ERIC Educational Resources Information Center

    Campbell, Jacquelyn C.; Webster, Daniel W.; Glass, Nancy

    2009-01-01

    The Danger Assessment (DA) is an instrument designed to assess the likelihood of lethality or near lethality occurring in a case of intimate partner violence. This article describes the development, psychometric validation, and suggestions for use of the DA. An 11-city study of intimate partner femicide used multivariate analysis to test the…

  12. We want what’s best for our baby: Prenatal Parenting of Babies with Lethal Conditions

    PubMed Central

    Côté-Arsenault, Denise; Krowchuk, Heidi; Hall, Wendasha Jenkins; Denney-Koelsch, Erin

    2015-01-01

    This article reports on qualitative research into the experience of couples who chose to continue their pregnancies after receiving a lethal fetal diagnosis, and to embrace the parenting of their baby in the shortened time they have. This analysis of interview data is part of a larger research project describing parents’ experiences of continuing pregnancy with a known lethal fetal diagnosis (LFD). PMID:26594107

  13. Examining the Impact of Psychiatric Diagnosis and Comorbidity on the Medical Lethality of Adolescent "Suicide Attempts"

    ERIC Educational Resources Information Center

    Mc Manama O'Brien, Kimberly H.; Berzin, Stephanie C.

    2012-01-01

    Specific psychiatric diagnoses and comorbidity patterns were examined to determine if they were related to the medical lethality of "suicide attempts" among adolescents presenting to an urban general hospital (N = 375). Bivariate analysis showed that attempters with substance abuse disorders had higher levels of lethality than attempters without…

  14. Synthetic chromosomes.

    PubMed

    Schindler, Daniel; Waldminghaus, Torsten

    2015-11-01

    What a living organism looks like and how it works and what are its components-all this is encoded on DNA, the genetic blueprint. Consequently, the way to change an organism is to change its genetic information. Since the first pieces of recombinant DNA have been used to transform cells in the 1970s, this approach has been enormously extended. Bigger and bigger parts of the genetic information have been exchanged or added over the years. Now we are at a point where the construction of entire chromosomes becomes a reachable goal and first examples appear. This development leads to fundamental new questions, for example, about what is possible and desirable to build or what construction rules one needs to follow when building synthetic chromosomes. Here we review the recent progress in the field, discuss current challenges and speculate on the appearance of future synthetic chromosomes. PMID:26111960

  15. Antibodies that neutralize human beta interferon biologic activity recognize a linear epitope: analysis by synthetic peptide mapping.

    PubMed Central

    Redlich, P N; Hoeprich, P D; Colby, C B; Grossberg, S E

    1991-01-01

    The location of biologically relevant epitopes on recombinant human beta interferon in which Ser-17 replaces Cys-17 (rh[Ser17]IFN-beta) was evaluated by testing the immunoreactivity of antibodies against 159 sequential, overlapping octamer peptides. Three monoclonal antibodies (mAbs) that neutralize rh[Ser17]IFN-beta biologic activity, designated A1, A5, and A7, bound to peptides spanning only residues 39-48, whereas nonneutralizing mAb bound less specifically at multiple sites near the amino terminus. The immunoreactivity of peptides spanning residues 40-47 that contained a series of single amino acid substitutions suggested that residues 41-43 (Pro-Glu-Glu) and 46 (Gln) are important for the binding of neutralizing mAbs. The reactivity of mAbs to larger synthetic peptides containing rh[Ser17]IFN-beta sequences from residue 32 through residue 56 was evaluated. All mAbs except A7 reacted with synthetic peptides representing rh[Ser17]IFN-beta residues 32-47, 40-56, and 32-56, but only mAbs A1 and A5 bound to the core peptide composed of residues 40-47. Peptide 32-56 effectively blocked the binding of mAbs A1 and A5 to rh[Ser17]IFN-beta and markedly inhibited their neutralizing activity. Biologic activity of the peptides was undetectable. Rabbit antisera raised against peptides 32-47 and 40-56 recognized rh[Ser17]IFN-beta but did not neutralize its antiviral activity. Thus, structure-function analysis by peptide mapping has permitted the identification of a linear epitope recognized by neutralizing antibody on a biologically active cytokine. We conclude that the region spanning residues 32-56 is of major importance in the expression of the biologic activity of human IFN-beta. Images PMID:1708891

  16. Modeling and experimental analysis of phased array synthetic jet cross-flow interactions

    NASA Astrophysics Data System (ADS)

    Hasnain, Zohaib

    Synthetic Jet Actuators (SJAs) are fluidic devices capable of adding momentum to static or non-static bodies of fluid without adding mass. They are therefore categorized as zero-net-mass-flux (ZNMF) momentum source. In its simplest compact form a SJA consists of an oscillatory surface connected to a cavity with a single exit orifice through which the fluid enters and exits. SJA technology has been utilized in applications ranging from boundary layer control over aerodynamic surfaces to fluidic mixing in dispersion applications. The ZNMF nature of the technology means it is not subject to constraints experienced by traditional momentum sources that require the addition of mass in order to impart momentum. The momentum that can be added by a single SJA is limited by the energy transfer capabilities of the oscillating surface. In modern SJAs this surface usually is a piezoceramic/metal composite subjected to a high voltage AC signal. For applications such as flow control over aerodynamic surfaces, modern SJAs are used in an array configuration and are capable of altering the flow momentum by values ranging from 0.01-10%. While it is possible to build larger actuators to increase this value the benefits associated with the compact size would be lost. It is therefore desirable to tune other parameters associated with SJA arrays to increase this value. The specific motivation for this study comes from the desire to control the momentum addition capacity of a specific SJA array, without having to alter any geometric parameters. In a broader sense this study focuses on understanding the physics of SJA interaction in array configuration through experiments which are then used to guide in the design of modeling technique that predicts SJA array behavior in cross-flows. The first half of the project focused on understanding SJA behavior through modeling. Numerical techniques were initially used to model SJA and SJA arrays in cross-flows. Reduced numerical models were then

  17. Cyclopeptide toxins of lethal amanitas: Compositions, distribution and phylogenetic implication.

    PubMed

    Tang, Shanshan; Zhou, Qian; He, Zhengmi; Luo, Tao; Zhang, Ping; Cai, Qing; Yang, Zhuliang; Chen, Jia; Chen, Zuohong

    2016-09-15

    Lethal amanitas (Amanita sect. Phalloideae) are responsible for 90% of all fatal mushroom poisonings. Since 2000, more than ten new lethal Amanita species have been discovered and some of them had caused severe mushroom poisonings in China. However, the contents and distribution of cyclopeptides in these lethal mushrooms remain poorly known. In this study, the diversity of major cyclopeptide toxins in seven Amanita species from Eastern Asia and three species from Europe and North America were systematically analyzed, and a new approach to inferring phylogenetic relationships using cyclopeptide profile was evaluated for the first time. The results showed that there were diversities of the cyclopeptides among lethal Amanita species, and cyclopeptides from Amanita rimosa and Amanita fuligineoides were reported for the first time. The amounts of amatoxins in East Asian Amanita species were significantly higher than those in European and North American species. The analysis of distribution of amatoxins and phallotoxins in various Amanita species demonstrated that the content of phallotoxins was higher than that of amatoxins in Amanita phalloides and Amanita virosa. In contrast, the content of phallotoxins was significantly lower than that of amatoxins in all East Asian lethal Amanita species tested. However, the distribution of amatoxins and phallotoxins in different tissues showed the same tendency. Eight cyclopeptides and three unknown compounds were identified using cyclopeptide standards and high-resolution MS. Based on the cyclopeptide profiles, phylogenetic relationships of lethal amanitas were inferred through a dendrogram generated by UPGMA method. The results showed high similarity to the phylogeny established previously based on the multi-locus DNA sequences. PMID:27476461

  18. Assessing short- and long-time displacements in the Venice coastland by synthetic aperture radar interferometric point target analysis

    NASA Astrophysics Data System (ADS)

    Teatini, Pietro; Strozzi, Tazio; Tosi, Luigi; Wegmüller, Urs; Werner, Charles; Carbognin, Laura

    2007-03-01

    The Venice Lagoon in Italy is a unique environment vulnerable to loss in surface elevation relative to the mean sea level. We present detailed synthetic aperture radar (SAR) interferometric analyses on persistent point targets for the historical center of Venice, the tourist area of Sottomarina, and the Zennare farmland close to the southern lagoon edge. The selected areas are characterized by different degrees of development and our analyses show the remarkable capability of SAR Interferometric Point Target Analysis (IPTA) to map land displacement rates in densely urbanized zones and to detect movement information on isolated structures with a mm/year accuracy. A detailed analysis of the time series from 1992 to 2000 provided by IPTA shows that the vertical component of the measured displacements are the superposition of a short timescale, generally seasonal, movement on the order of 1 cm that is likely related to the fluctuation of environmental variables (temperature, piezometric head in the aquifer system underlying the lagoon, sea/lagoon water level) and a long-term ground deformation associated with building construction, the geomorphology of the area, and the human development of natural resources. If Venice is confirmed to be generally stable, significant long-term subsidence on the order of 4 mm/year is detected at the Sottomarina coastland. The highest displacement rates, of up to 8-10 mm/year, are recorded in the farmland bounding the lagoon margin where the movements are found to be highly site-specific.

  19. Molecular analysis of the biomass of a fluidized bed reactor treating synthetic vinasse at anaerobic and micro-aerobic conditions.

    PubMed

    Rodríguez, Elisa; Lopes, Alexandre; Fdz-Polanco, María; Stams, Alfons J M; García-Encina, Pedro A

    2012-03-01

    The microbial communities (Bacteria and Archaea) established in an anaerobic fluidized bed reactor used to treat synthetic vinasse (betaine, glucose, acetate, propionate, and butyrate) were characterized by denaturing gradient gel electrophoresis (DGGE) and phylogenetic analysis. This study was focused on the competitive and syntrophic interactions between the different microbial groups at varying influent substrate to sulfate ratios of 8, 4, and 2 and anaerobic or micro-aerobic conditions. Acetogens detected along the anaerobic phases at substrate to sulfate ratios of 8 and 4 seemed to be mainly involved in the fermentation of glucose and betaine, but they were substituted by other sugar or betaine degraders after oxygen application. Typical fatty acid degraders that grow in syntrophy with methanogens were not detected during the entire reactor run. Likely, sugar and betaine degraders outnumbered them in the DGGE analysis. The detected sulfate-reducing bacteria (SRB) belonged to the hydrogen-utilizing Desulfovibrio. The introduction of oxygen led to the formation of elemental sulfur (S(0)) and probably other sulfur compounds by sulfide-oxidizing bacteria (γ-Proteobacteria). It is likely that the sulfur intermediates produced from sulfide oxidation were used by SRB and other microorganisms as electron acceptors, as was supported by the detection of the sulfur respiring Wolinella succinogenes. Within the Archaea population, members of Methanomethylovorans and Methanosaeta were detected throughout the entire reactor operation. Hydrogenotrophic methanogens mainly belonging to the genus Methanobacterium were detected at the highest substrate to sulfate ratio but rapidly disappeared by increasing the sulfate concentration. PMID:21861082

  20. Morphology of synthetic chrysoberyl and alexandrite crystals: Analysis of experimental data and theoretical modeling

    NASA Astrophysics Data System (ADS)

    Gromalova, N. A.; Eremin, N. N.; Dorokhova, G. I.; Urusov, V. S.

    2012-07-01

    A morphological analysis of chrysoberyl and alexandrite crystals obtained by flux crystallization has been performed. Seven morphological types of crystals are selected. The surface energies of the faces of chrysoberyl and alexandrite crystals and their isostructural analogs, BeCr2O4 and BeFe2O4, have been calculated by atomistic computer modeling using the Metadise program. A "combined" approach is proposed which takes into account both the structural geometry and the surface energy of the faces and thus provides better agreement between the theoretical and experimentally observed faceting of chrysoberyl and alexandrite crystals.

  1. Man-Made Synthetic Receptors for Capture and Analysis of Ochratoxin A.

    PubMed

    Baggiani, Claudio; Giovannoli, Cristina; Anfossi, Laura

    2015-10-01

    Contemporary analytical methods have the sensitivity required for Ochratoxin A detection and quantification, but direct application of these methods on real samples can be rarely performed because of matrix complexity. Thus, efficient sample pre-treatment methods are needed. Recent years have seen the increasing use of artificial recognition systems as a viable alternative to natural receptors, because these materials seem to be particularly suitable for applications where selectivity for Ochratoxin A is essential. In this review, molecularly imprinted polymers, aptamers and tailor-made peptides for Ochratoxin A capture and analysis with particular attention to solid phase extraction applications will be discussed. PMID:26473924

  2. Man-Made Synthetic Receptors for Capture and Analysis of Ochratoxin A

    PubMed Central

    Baggiani, Claudio; Giovannoli, Cristina; Anfossi, Laura

    2015-01-01

    Contemporary analytical methods have the sensitivity required for Ochratoxin A detection and quantification, but direct application of these methods on real samples can be rarely performed because of matrix complexity. Thus, efficient sample pre-treatment methods are needed. Recent years have seen the increasing use of artificial recognition systems as a viable alternative to natural receptors, because these materials seem to be particularly suitable for applications where selectivity for Ochratoxin A is essential. In this review, molecularly imprinted polymers, aptamers and tailor-made peptides for Ochratoxin A capture and analysis with particular attention to solid phase extraction applications will be discussed. PMID:26473924

  3. A synthetic approach to abiogenesis.

    PubMed

    Attwater, James; Holliger, Philipp

    2014-05-01

    Synthetic biology seeks to probe fundamental aspects of biological form and function by construction (resynthesis) rather than deconstruction (analysis). Here we discuss how such an approach could be applied to assemble synthetic quasibiological systems able to replicate and evolve, illuminating universal properties of life and the search for its origins. PMID:24781322

  4. Using Synthetic Mouse Spike-In Transcripts to Evaluate RNA-Seq Analysis Tools

    PubMed Central

    Leshkowitz, Dena; Feldmesser, Ester; Friedlander, Gilgi; Jona, Ghil; Ainbinder, Elena; Parmet, Yisrael; Horn-Saban, Shirley

    2016-01-01

    One of the key applications of next-generation sequencing (NGS) technologies is RNA-Seq for transcriptome genome-wide analysis. Although multiple studies have evaluated and benchmarked RNA-Seq tools dedicated to gene level analysis, few studies have assessed their effectiveness on the transcript-isoform level. Alternative splicing is a naturally occurring phenomenon in eukaryotes, significantly increasing the biodiversity of proteins that can be encoded by the genome. The aim of this study was to assess and compare the ability of the bioinformatics approaches and tools to assemble, quantify and detect differentially expressed transcripts using RNA-Seq data, in a controlled experiment. To this end, in vitro synthesized mouse spike-in control transcripts were added to the total RNA of differentiating mouse embryonic bodies, and their expression patterns were measured. This novel approach was used to assess the accuracy of the tools, as established by comparing the observed results versus the results expected of the mouse controlled spiked-in transcripts. We found that detection of differential expression at the gene level is adequate, yet on the transcript-isoform level, all tools tested lacked accuracy and precision. PMID:27100792

  5. Analysis of ER-associated glycoprotein degradation using synthetic glycopeptide probes

    SciTech Connect

    Hagihara, Shinya; Goda, Kazuhito; Matsuo, Ichiro; Ito, Yukishige . E-mail: yukito@riken.jp

    2007-08-24

    Quality control of proteins is an essential process for maintaining normal cell activity. It ensures that only correctly folded proteins are produced and terminally misfolded proteins are eliminated by degradation. ER-associated degradation (ERAD) of misfolded proteins is an important aspect of protein quality control system. Recent studies have revealed that glycoprotein glycans play significant roles in this process. It includes polyubiquitination, deglycosylation, and proteasomal degradation. In the present study, a systematic analysis of these steps was carried out using chemically synthesized glycopeptides. We revealed that N-linked glycopeptides are degraded by 20S proteasome, but with drastically reduced rate compared to non-glycosylated peptide. This result strongly suggests that deglycosylating activity of peptide:N-glycanase (PNGase) is important for the facile degradation of glycoproteins. Our study showed, for the first time, that PNGase cleaves truncated glycans as short as chitobiose from peptide. However, this cleavage required the presence of hydrophobic region nearby N-glycosylation site. Furthermore, analysis of interactions with F-box protein Fbs1 was conducted with fluorescent correlation spectroscopy (FCS). It was shown that the presence of Fbs1 perturb the activity of PNGase toward high-mannose-type glycopeptides.

  6. Alcohol Consumption and Nearly Lethal Suicide Attempts.

    ERIC Educational Resources Information Center

    Powell, Kenneth E.; Kresnow, Marcie-jo; Mercy, James A.; Potter, Lloyd B.; Swann, Alan C.; Frankowski, Ralph F.; Lee, Roberta K.; Bayer, Timothy L.

    2002-01-01

    Presents a case-control study of the association between nearly lethal suicide attempts and facets of alcohol consumption; namely, drinking frequency, drinking quantity, binge drinking, alcoholism, drinking within 3 hours of suicide attempt, and age began drinking. In bivariate analyses, all measures were associated with nearly lethal suicide…

  7. Lethality of Suicide Attempt Rating Scale.

    ERIC Educational Resources Information Center

    Smith, K.; And Others

    1984-01-01

    Presents an 11-point scale for measuring the degree of lethality of suicide attempts. The scale has nine example "anchors" and uses the relative lethality of an extensive table of drugs. The scale can be used reliably by nonmedical personnel with no prior training. (Author/BL)

  8. Synthetic Cathinones ("Bath Salts")

    MedlinePlus

    ... still unknown about how synthetic cathinones affect the human brain. Researchers do know that synthetic cathinones are chemically ... of the chemicals in synthetic cathinones affect the human brain. Synthetic cathinones can cause: nosebleeds paranoia increased sociability ...

  9. Parametric analysis of synthetic aperture radar data for characterization of deciduous forest stands

    NASA Technical Reports Server (NTRS)

    Wu, Shih-Tseng

    1987-01-01

    The SAR sensor parameters that affect the estimation of deciduous forest stand characteristics were examined using data sets for the Gulf Coastal Plain region, acquired by the NASA/JPL multipolarization airborne SAR. In the regression analysis, the mean digital-number values of the three polarization data are used as the independent variables to estimate the average tree height (HT), basal area (BA), and total-tree biomass (TBM). The following results were obtained: (1) in the case of simple regression and using 28 plots, vertical-vertical (VV) polarization yielded the largest correlation coefficients (r) in estimating HT, BA, and TBM; (2) in the case of multiple regression, the horizontal-horizontal (HH) and VV polarization combination yielded the largest r value in estimating HT, while the VH and HH polarization combination yielded the largest r values in estimating BA and TBM. With the addition of a third polarization, the increase in r values is insignificant.

  10. Analysis of synthetic diamond single crystals by X-ray topography and double-crystal diffractometry

    SciTech Connect

    Prokhorov, I. A.; Ralchenko, V. G.; Bolshakov, A. P.; Polskiy, A. V.; Vlasov, A. V.; Subbotin, I. A.; Podurets, K. M.; Pashaev, E. M.; Sozontov, E. A.

    2013-12-15

    Structural features of diamond single crystals synthesized under high pressure and homoepitaxial films grown by chemical vapor deposition (CVD) have been analyzed by double-crystal X-ray diffractometry and topography. The conditions of a diffraction analysis of diamond crystals using Ge monochromators have been optimized. The main structural defects (dislocations, stacking faults, growth striations, second-phase inclusions, etc.) formed during crystal growth have been revealed. The nitrogen concentration in high-pressure/high-temperature (HPHT) diamond substrates is estimated based on X-ray diffraction data. The formation of dislocation bundles at the film-substrate interface in the epitaxial structures has been revealed by plane-wave topography; these dislocations are likely due to the relaxation of elastic macroscopic stresses caused by the lattice mismatch between the substrate and film. The critical thicknesses of plastic relaxation onset in CVD diamond films are calculated. The experimental techniques for studying the real diamond structure in optimizing crystal-growth technology are proven to be highly efficient.

  11. Polarimetric analysis of radar backscatter from ground-based scatterometers and wheat biomass monitoring with advanced synthetic aperture radar images

    NASA Astrophysics Data System (ADS)

    He, Lei; Tong, Ling; Li, Yuxia; Chen, Yan; Tan, Longfei; Guo, Caizheng

    2016-04-01

    This article presents an analysis of the scattering measurements for an entire wheat growth cycle by ground-based scatterometers at a frequency of 5.3 GHz. Since wheat ears are related to wheat growth and yield, the radar backscatter of wheat was analyzed at two different periods, i.e., with and without wheat ears. Simultaneously, parameters such as wheat and soil characteristics as well as volume scattering and soil scattering were analyzed for the two periods during the entire growth cycle. Wheat ears have been demonstrated to have a great influence on radar backscatter; therefore, a modified version of water-cloud model used for retrieving biomass should consider the effect of wheat ears. This work presents two retrieval models based on the water-cloud model and adopts the advanced integral equation model to simulate the soil backscatter before the heading stage and the backscatter from the layer under wheat ears after the heading stage. The research results showed that the biomass retrieved from the advanced synthetic aperture radar (ASAR) images to agree well with the data measured in situ after setting the modified water-cloud model for the growth stages with ears. Furthermore, it was concluded that wheat ears should form an essential component of theoretical modeling as they influence the final yield.

  12. Multi-omics data driven analysis establishes reference codon biases for synthetic gene design in microbial and mammalian cells.

    PubMed

    Ang, Kok Siong; Kyriakopoulos, Sarantos; Li, Wei; Lee, Dong-Yup

    2016-06-01

    In this study, we analyzed multi-omics data and subsets thereof to establish reference codon usage biases for codon optimization in synthetic gene design. Specifically, publicly available genomic, transcriptomic, proteomic and translatomic data for microbial and mammalian expression hosts, Escherichia coli, Saccharomyces cerevisiae, Pichia pastoris and Chinese hamster ovary (CHO) cells, were compiled to derive their individual codon and codon pair frequencies. Then, host dependent and -omics specific codon biases were generated and compared by principal component analysis and hierarchical clustering. Interestingly, our results indicated the similar codon bias patterns of the highly expressed transcripts, highly abundant proteins, and efficiently translated mRNA in microbial cells, despite the general lack of correlation between mRNA and protein expression levels. However, for CHO cells, the codon bias patterns among various -omics subsets are not distinguishable, forming one cluster. Thus, we further investigated the effect of different input codon biases on codon optimized sequences using the codon context (CC) and individual codon usage (ICU) design parameters, via in silico case study on the expression of human IFNγ sequence in CHO cells. The results supported that CC is more robust design parameter than ICU for improved heterologous gene design. PMID:26850284

  13. Targeted analysis with benchtop quadrupole-orbitrap hybrid mass spectrometer: application to determination of synthetic hormones in animal urine.

    PubMed

    Kumar, Praveen; Rúbies, Antoni; Centrich, Francesc; Granados, Mercè; Cortés-Francisco, Nuria; Caixach, Josep; Companyó, Ramon

    2013-05-30

    Sensitive and unequivocal determination of analytes/contaminants in complex matrices is a challenge in the field of food safety control. In this study, various acquisition modes (Full MS/AIF, Full MS+tMS/MS, Full MS/dd MS/MS and tSIM/ddMS/MS) and parameters of a quadrupole-orbitrap hybrid mass spectrometer (Q Exactive) were studied in detail. One of the main conclusions has been that, reducing the scan range for Full MS (using the quadrupole) and targeted modes give higher signal-to-noise (S/N) ratios and thereby better detection limits for analytes in matrix. The use of Q Exactive in a complex case, for the confirmatory analysis of hormones in animal urine is presented. A targeted SIM data dependent MS/MS (tSIM/ddMS/MS) acquisition method for determination of eight synthetic hormones (trenbolone, 17α ethinylestradiol, zeranol, stanozolol, dienestrol, diethylstilbestrol, hexestrol, taleranol) and a naturally occurring hormone (zearalenone) in animal urine were optimized to have sensitive precursors from targeted SIM mode and trigger MS/MS scans over the entire chromatograph peak. The method was validated according to EC/657/2002. CCα (decision limit) for the analytes ranged between 0.11 μg L(-1) and 0.69 μg L(-1) and CCβ (detection capability) ranged between 0.29 μg L(-1) and 0.90 μg L(-1). PMID:23680552

  14. Performance comparison of independent component analysis algorithms for fetal cardiac signal reconstruction: a study on synthetic fMCG data

    NASA Astrophysics Data System (ADS)

    Mantini, D.; Hild, K. E., II; Alleva, G.; Comani, S.

    2006-02-01

    Independent component analysis (ICA) algorithms have been successfully used for signal extraction tasks in the field of biomedical signal processing. We studied the performances of six algorithms (FastICA, CubICA, JADE, Infomax, TDSEP and MRMI-SIG) for fetal magnetocardiography (fMCG). Synthetic datasets were used to check the quality of the separated components against the original traces. Real fMCG recordings were simulated with linear combinations of typical fMCG source signals: maternal and fetal cardiac activity, ambient noise, maternal respiration, sensor spikes and thermal noise. Clusters of different dimensions (19, 36 and 55 sensors) were prepared to represent different MCG systems. Two types of signal-to-interference ratios (SIR) were measured. The first involves averaging over all estimated components and the second is based solely on the fetal trace. The computation time to reach a minimum of 20 dB SIR was measured for all six algorithms. No significant dependency on gestational age or cluster dimension was observed. Infomax performed poorly when a sub-Gaussian source was included; TDSEP and MRMI-SIG were sensitive to additive noise, whereas FastICA, CubICA and JADE showed the best performances. Of all six methods considered, FastICA had the best overall performance in terms of both separation quality and computation times.

  15. Terahertz Wide-Angle Imaging and Analysis on Plane-wave Criteria Based on Inverse Synthetic Aperture Techniques

    NASA Astrophysics Data System (ADS)

    Gao, Jing Kun; Qin, Yu Liang; Deng, Bin; Wang, Hong Qiang; Li, Jin; Li, Xiang

    2016-04-01

    This paper presents two parts of work around terahertz imaging applications. The first part aims at solving the problems occurred with the increasing of the rotation angle. To compensate for the nonlinearity of terahertz radar systems, a calibration signal acquired from a bright target is always used. Generally, this compensation inserts an extra linear phase term in the intermediate frequency (IF) echo signal which is not expected in large-rotation angle imaging applications. We carried out a detailed theoretical analysis on this problem, and a minimum entropy criterion was employed to estimate and compensate for the linear-phase errors. In the second part, the effects of spherical wave on terahertz inverse synthetic aperture imaging are analyzed. Analytic criteria of plane-wave approximation were derived in the cases of different rotation angles. Experimental results of corner reflectors and an aircraft model based on a 330-GHz linear frequency-modulated continuous wave (LFMCW) radar system validated the necessity and effectiveness of the proposed compensation. By comparing the experimental images obtained under plane-wave assumption and spherical-wave correction, it also showed to be highly consistent with the analytic criteria we derived.

  16. Lethal outcome in xanthogranulomatous endometritis.

    PubMed

    Noack, Frank; Briese, Juliane; Stellmacher, Florian; Hornung, Daniela; Horny, Hans-Peter

    2006-05-01

    Xanthogranulomatous inflammation is rare, mainly involving the kidneys, while primary xanthogranulomatous endometritis (XE) is a very unusual finding, histologically characterized by partial or complete replacement of the mucosa by granulation tissue with an abundance of foamy histiocytes, siderophages and multinucleated giant cells. We present the case of a 69-year-old woman with a short history of abdominal pain and a palpable mass in the pouch of Douglas. Dilatation of the cervix drained a pyometra. Histological examination of the curettage rendered the diagnosis of XE. Microbiological studies revealed enterococcus spp. and Peptostreptococcus magnus. Despite antibiotic treatment the patient died of heart failure due to systemic inflammation. Autopsy confirmed the diagnosis of XE with transmural extension into the peritoneal cavity. Such a lethal course of XE is extraordinary. Proposed causes of XE include obstruction, infection and hemorrhage. Demonstration of enterococcus spp. and P. magnus supports the probable significance of bacteria in the development of XE. Because this condition may mimic malignant disease macroscopically and histologically, knowledge of XE is of major importance for both pathologists and gynecologists. PMID:16725016

  17. Lethal photosensitization of Helicobacter species

    NASA Astrophysics Data System (ADS)

    Millson, Charles E.; Wilson, Michael; MacRobert, Alexander J.; Thurrell, Wendy; Mlkvy, Peter; Davies, Claire; Bown, Stephen G.

    1995-01-01

    Helicobacter pylori (H. pylori) is associated with a large number of gastroduodenal disorders. Clearance of the bacteria has been shown to benefit patients with duodenal ulcers, gastric ulcers, and certain rare types of gastric tumors. Broad-spectrum antibiotics are the mainstay of current treatment strategies but side-effects, poor compliance, and drug resistance limit their usefulness. We sensitized H. pylori with toluidine blue, haematoporphyrin derivative, aluminum disulphonated phthalocyanine, methylene blue or protoporphyrin IX prior to exposure to low-power laser light from either a gallium aluminum arsenide laser or a helium neon gas laser. All 5 sensitizers caused reductions of greater than 1000-fold in the number of viable bacteria. Light alone had no effect and only HpD caused a significant decrease in bacterial numbers without laser light. Next, we sensitized H. mustelae on explanted ferret gastric mucosa (ex vivo) with the same sensitizers and exposed them to light from a copper vapor pumped dye laser tuned appropriately. MB caused significant reductions in bacterial counts. Successful lethal photosensitization of Helicobacter pylori both in vitro and ex vivo raises the possibility of a local method for eradicating the bacteria, especially as the bacteria are only found in those parts of the upper gastrointestinal tract that are accessible to the endoscope.

  18. Habitat mapping of the Brazilian Pantanal using synthetic aperture radar imagery and object based image analysis

    NASA Astrophysics Data System (ADS)

    Evans, Teresa Lynne

    for both fine and medium resolution classifications related to issues of 1) scale of habitats, for instance, capoes, cordilheiras, and lakes, in relation to spatial resolution of the imagery, and 2) issues relating to variable flooding patterns in the subregion, and 3) arbitrary class membership rules. The 50 m spatial resolution classification of the entire Pantanal wetland resulted in an overall accuracy of 80%, and defined ten land cover classes. Given the analysis of the comparison of fine and relatively medium spatial resolution classifications of the Lower Nhecolândia subregion, I conclude that significant improvements in accuracy can be achieved with the finer spatial resolution dataset, particularly in subregions with high spatial heterogeneity in land cover. The produced habitat spatial distribution maps will provide vital information for determining refuge zones for terrestrial species, connectivity of aquatic habitats during the dry season, and crucial baseline data to aid in monitoring changes in the region, as well as to help define conservation strategies for habitat in this critically important wetland.

  19. In situ X-ray pair distribution function analysis of accelerated carbonation of a synthetic calcium-silicate-hydrate gel

    SciTech Connect

    Morandeau, Antoine E.; White, Claire E.

    2015-04-21

    Calcium–silicate–hydrate (C–S–H) gel is the main binder component in hydrated ordinary Portland cement (OPC) paste, and is known to play a crucial role in the carbonation of cementitious materials, especially for more sustainable alternatives containing supplementary cementitious materials. However, the exact atomic structural changes that occur during carbonation of C–S–H gel remain unknown. Here, we investigate the local atomic structural changes that occur during carbonation of a synthetic calcium–silicate–hydrate gel exposed to pure CO₂ vapour, using in situ X-ray total scattering measurements and subsequent pair distribution function (PDF) analysis. By analysing both the reciprocal and real-space scattering data as the C–S–H carbonation reaction progresses, all phases present during the reaction (crystalline and non-crystalline) have been identified and quantified, with the results revealing the emergence of several polymorphs of crystalline calcium carbonate (vaterite and calcite) in addition to the decalcified C–S–H gel. Furthermore, the results point toward residual calcium being present in the amorphous decalcified gel, potentially in the form of an amorphous calcium carbonate phase. As a result of the quantification process, the reaction kinetics for the evolution of the individual phases have been obtained, revealing new information on the rate of growth/dissolution for each phase associated with C–S–H gel carbonation. Moreover, the investigation reveals that the use of real space diffraction data in the form of PDFs enables more accurate determination of the phases that develop during complex reaction processes such as C–S–H gel carbonation in comparison to the conventional reciprocal space Rietveld analysis approach.

  20. Transcriptome Analysis of Porphyrin-Accumulated and X-Ray-Irradiated Cell Cultures under Limited Proliferation and Non-Lethal Conditions

    PubMed Central

    Takahashi, Junko; Misawa, Masaki; Iwahashi, Hitoshi

    2015-01-01

    5-Aminolevulinic acid (ALA) is a precursor of the photosensitizer used in photodynamic therapy. It accumulates in tumor cells and subsequently metabolizes to protoporphyrin IX (PpIX), which generates singlet oxygen after light irradiation. PpIX enhances the generation of reactive oxygen species following physicochemical interactions with X-rays. ALA-based treatment using fractionated doses of irradiation suppressed tumor growth in a mouse melanoma model. To study the transcriptomic effects of PpIX, microarray analyses were conducted using HeLa cells with limited proliferation capacity. Based on the p-values (p < 0.01), we selected genes showing altered expression in each treatment group with reference to the non-treatment (NT) group. We detected 290, 196 and 28 upregulated genes, as well as 203, 146 and 36 downregulated genes after a 6 h-long PpIX treatment (1 μg/mL) prior to 3 Gy X-ray irradiation (PpIX-XT), 3 Gy X-ray irradiation alone (XT) and PpIX treatment alone (PpIXT), respectively. Functional analysis revealed that a majority of the regulated genes in the XT and PpIX-XT groups were related to cell-cycle arrest. The XT and PpIX-XT groups differed in the quantity, but not in the quality of their gene expression. The combined effect of PpIX and X-ray irradiation sensitized HeLa cells to X-ray treatment.

  1. Analysis of total copper, cadmium and lead in refuse-derived fuels (RDF): study on analytical errors using synthetic samples.

    PubMed

    Skutan, Stefan; Aschenbrenner, Philipp

    2012-12-01

    Components with extraordinarily high analyte contents, for example copper metal from wires or plastics stabilized with heavy metal compounds, are presumed to be a crucial source of errors in refuse-derived fuel (RDF) analysis. In order to study the error generation of those 'analyte carrier components', synthetic samples spiked with defined amounts of carrier materials were mixed, milled in a high speed rotor mill to particle sizes <1 mm, <0.5 mm and <0.2 mm, respectively, and analyzed repeatedly. Copper (Cu) metal and brass were used as Cu carriers, three kinds of polyvinylchloride (PVC) materials as lead (Pb) and cadmium (Cd) carriers, and paper and polyethylene as bulk components. In most cases, samples <0.2 mm delivered good recovery rates (rec), and low or moderate relative standard deviations (rsd), i.e. metallic Cu 87-91% rec, 14-35% rsd, Cd from flexible PVC yellow 90-92% rec, 8-10% rsd and Pb from rigid PVC 92-96% rec, 3-4% rsd. Cu from brass was overestimated (138-150% rec, 13-42% rsd), Cd from flexible PVC grey underestimated (72-75% rec, 4-7% rsd) in <0.2 mm samples. Samples <0.5 mm and <1 mm spiked with Cu or brass produced errors of up to 220% rsd (<0.5 mm) and 370% rsd (<1 mm). In the case of Pb from rigid PVC, poor recoveries (54-75%) were observed in spite of moderate variations (rsd 11-29%). In conclusion, time-consuming milling to <0.2 mm can reduce variation to acceptable levels, even given the presence of analyte carrier materials. Yet, the sources of systematic errors observed (likely segregation effects) remain uncertain. PMID:23027034

  2. Simultaneous Analysis of Cannabinoid and Synthetic Cannabinoids in Dietary Supplements Using UPLC with UV and UPLC-MS-MS.

    PubMed

    Heo, Seok; Yoo, Geum Joo; Choi, Ji Yeon; Park, Hyoung Joon; Do, Jung-Ah; Cho, Sooyeul; Baek, Sun Young; Park, Sung-Kwan

    2016-06-01

    The primary purpose of this study was to develop and validate a method based on UPLC with UV and UPLC-MS-MS for the simultaneous analysis of different cannabinoids and synthetic cannabinoids in food as well as in herbal and dietary supplements. The limits of detection and quantitation of the method ranged from 0.1 to 0.3 and 0.3 to 0.9 μg/mL by UPLC with UV, respectively. The coefficient of determination was >0.999; the intra- and interday precision of the method were 0.1-3.7 and 0.9-4.1%, respectively. The intra- and interday accuracy were 94.8-103.1 and 98.3-100.9%, respectively. The mean recoveries of nine cannabinoids obtained from tablet samples ranged from 81.1 to 105.4%. The mean extraction recoveries of nine target cannabinoids obtained from various types of samples (tablets, capsules, powders, liquids, cookies and candies) ranged from 82.26 to 112.40%. The relative standard deviation (RSD) of the stability of the prepared sample solutions was <1.80%. Identification and quantification of the nine cannabinoids were accomplished by ion spray UPLC-MS-MS using multiple reaction monitoring. The UPLC-MS-MS method was validated for linearity (R(2) > 0.99); the precision was 0.1-4.0% (intraday) and 0.1-2.8% (interday), and the accuracy was 98.0-103.5% (intraday) and 97.1-103.2% (interday). The mean extraction recoveries of six types of samples were 82.2-114.5% and the RSD of stability was <6.54%, complying with the established international guidelines. The results indicated that the method can be used for rapid and accurate screening of cannabinoids present in food. PMID:27185817

  3. Mass spectrometric analysis for high molecular weight synthetic polymers using ultrasonic degradation and the mechanism of degradation.

    PubMed

    Kawasaki, Hideya; Takeda, Yoshiki; Arakawa, Ryuichi

    2007-06-01

    We have investigated ultrasonic degradations of poly(ethylene oxide) (PEG) and poly(methyl methacrylate) (PMMA) in aqueous media by means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). The ultrasonic degradation of polymers was monitored as a function of ultrasonication duration to examine the structural details of ultrasonic degradation polymers. PEG solution ultrasonication produced five types of oligomers (M approximately 1000 Da) with different end groups, irrespective of the initial average molecular masses (M=2, 6, 20, and 2000 kDa). Several degradation pathways with free radical reactions have been suggested to explain these degradation products: the ultrasonic degradation of PEG is initiated by breaking of the C-O bond in the PEG chain, generating polymeric radicals with two terminal groups, i.e., X*( approximately CH2CH2*) and Y*( approximately CH2CH2O*), followed by termination with extraction or release of a hydrogen atom. However, PMMA (M=1630 Da) ultrasonication generated only one type of degradation oligomer, which has a hydrogen group at both ends, the same as that of the original oligomer. It has been suggested that the presence of the radical terminal groups X*( approximately CH2*) and Y*( approximately (CH3)CCOO(CH3)C*) is due to selective C-C bond breaking in the chain during the ultrasonic degradation of PMMA. The MALDI-TOFMS combined with the ultrasonic degradation technique (UD/MALDI-TOFMS) developed in this study could be extended to the analysis of synthetic polymer structures with high molecular weights. PMID:17461552

  4. Imaging the Lithosphere-Asthenosphere Boundary Using Iterative Method of Receiver Function Analysis: A Synthetic Seismogram Approach

    NASA Astrophysics Data System (ADS)

    Maiti, T.; Eaton, D. W. S.; Liu, Q.; Sales de Andrade, E.

    2014-12-01

    Our study is based on the receiver-function (RF) analysis of a hypothetical regional geological model that extends from oceanic to thick cratonic lithosphere. RF techniques are used to study the interior of Earth. Teleseismic P waves are followed by a series of scattered waves, which occur due to P-to-S converted phases. The sequence of these scattered waves on a time series can be represented by receiver function (RF) for the station and may vary with the incidence angle and azimuth of the incoming P-wave. Here we use iterative deconvolution method to study receiver functions, which provides RF estimates with low noise levels. This method is based on least-squares minimization of the difference between the observed horizontal seismogram and a predicted signal generated by the convolution of an iterative spike train with the vertical-component of seismogram. The study is based on a hypothetical model (800x800x400km) on a mesh with 10 km grid spacing that is smoothly embedded within a standard global Earth model. Physical properties of the regional model match with prescribed surface heat-flow and geoid boundary conditions computed using an approach based on thermodynamics, mineral physics, and solid-Earth geophysics. The model also incorporates seismic anisotropy in the mantle beneath the hypothetical continent. A three dimensional model is computed that approximates the mantle flow around the hypothetical continental lithospheric keel. The anisotropy is computed from the flow model and is incorporated to the model. Synthetic seismograms are computed using SPECFEM3D_GLOBE, which provides full wave-equation modelling of seismic wave propagation incorporating material properties such as anisotropy, attenuation and fluid-solid interfaces. To ensure a realistic (non-ideal) azimuthal distribution, the event locations are based on a subset of a ten-year global catalog from 2001 to 2010 within the magnitude range from 6.0 to 7.0.

  5. Engineered female-specific lethality for control of pest Lepidoptera.

    PubMed

    Jin, Li; Walker, Adam S; Fu, Guoliang; Harvey-Samuel, Timothy; Dafa'alla, Tarig; Miles, Andrea; Marubbi, Thea; Granville, Deborah; Humphrey-Jones, Nerys; O'Connell, Sinead; Morrison, Neil I; Alphey, Luke

    2013-03-15

    The sterile insect technique (SIT) is a pest control strategy involving the mass release of radiation-sterilized insects, which reduce the target population through nonviable matings. In Lepidoptera, SIT could be more broadly applicable if the deleterious effects of sterilization by irradiation could be avoided. Moreover, male-only release can improve the efficacy of SIT. Adequate methods of male-only production in Lepidoptera are currently lacking, in contrast to some Diptera. We describe a synthetic genetic system that allows male-only moth production for SIT and also replaces radiation sterilization with inherited female-specific lethality. We sequenced and characterized the doublesex (dsx) gene from the pink bollworm (Pectinophora gossypiella). Sex-alternate splicing from dsx was used to develop a conditional lethal genetic sexing system in two pest moths: the diamondback moth (Plutella xylostella) and pink bollworm. This system shows promise for enhancing existing pink bollworm SIT, as well as broadening SIT-type control to diamondback moth and other Lepidoptera. PMID:23802263

  6. Proteomic strategy for probing complementary lethality of kinase inhibitors against pancreatic cancer.

    PubMed

    Lee, Jin-Gyun; McKinney, Kimberly Q; Mougeot, Jean-Luc; Bonkovsky, Herbert L; Hwang, Sun-Il

    2013-12-01

    In the present study, proteomic analysis was performed to discover combinational molecular targets for therapy and chemoresistance by comparing differential protein expression from Panc-1 cells treated with FDA-approved drugs such as sunitinib, imatinib mesylate, dasatinib, and PD184352. A total of 4041 proteins were identified in the combined data from all of the treatment groups by nano-electrospray ultra-performance LC and MS/MS analysis. Most of the proteins with significant changes are involved in apoptosis, cytoskeletal remodeling, and epithelial-to-mesenchymal transition. These processes are associated with increased chemoresistance and progression of pancreatic cancer. Among the differentially expressed proteins, heme oxygenase-1 (HO-1) was found in the sunitinib and imatinib mesylate treatment groups, which possibly acts as a specific target for synthetic lethality in combinational treatment. HO-1 was found to play a key role in sensitizing the chemoresistant Panc-1 cell line to drug therapy. Viability was significantly decreased in Panc-1 cells cotreated with sunitinib and imatinib mesylate at low doses, compared to those treated with sunitinib or imatinib mesylate alone. The results suggest that induction of chemosensitization by manipulating specific molecular targets can potentiate synergistic chemotherapeutic effects at lower, better tolerated doses, and in turn reduce the toxicity of multidrug treatment of pancreatic cancer. PMID:24167056

  7. Lethal methemoglobinemia and automobile exhaust inhalation.

    PubMed

    Vevelstad, Merete; Morild, Inge

    2009-05-30

    Inhalation of automobile exhaust gas often leads to death by CO intoxication. In some cases the measured carbon monoxide hemoglobin saturation level (COHb) is considerably below what is considered to be lethal. The death in such cases has been attributed to a combination of a high CO2 and a low O2 tension. In a recent case the deceased was found dead in a car equipped with a catalytic converter, with a hose leading exhaust from the engine to the interior of the car. Analysis revealed a moderately elevated COHb and a high methemoglobin saturation level (MetHb) in peripheral blood. No ethanol, narcotics or drugs were detected. Reports mentioning MetHb or methemoglobinemia in post-mortem cases are surprisingly scarce, and very few have related exhaust gas deaths to methemoglobinemia. High-degree methemoglobinemia causes serious tissue hypoxia leading to unconsciousness, arrhythmia and death. The existing literature in this field and the knowledge that exhaust fumes contain nitrogen oxide gases (NOx) that by inhalation and absorption can result in severe methemoglobinemia, led us to postulate that this death could possibly be attributed to a combination of methemoglobinemia and a moderately high COHb concentration. PMID:19261402

  8. CLOSED-LOOP STRIPPING ANALYSIS (CLSA) OF SYNTHETIC MUSK COMPOUNDS FROM FISH TISSUES WITH MEASUREMENT BY OC/MS/SIM

    EPA Science Inventory

    Synthetic musk compounds are used as inexpensive fragrance materials for the production
    of perfumes and as additives to soap, detergent, and shampoo. They have been found in surface water, fish tissues, and human breast milk. The ubiquity of this class of compounds in the env...

  9. Digital Image Correlation and Finite Element Simulations Applied to the Analysis of the Mechanisms of Plastic Deformation of Synthetic Halite

    NASA Astrophysics Data System (ADS)

    Raphanel, J.; Bourcier, M.; Dimanov, A.; Héripré, E.; Bornert, M.

    2012-04-01

    Synthetic halite elaborated with different microstructures ( i.e. grain sizes and grain size distribution) has been deformed by uniaxial compression in a scanning electron microscope, with measure of the grain orientations, surface observation of slip lines, digital image correlation (DIC) to provide full-field estimates of displacements and surface strains (Bourcier et al. 2012). These kinematic data have indicated that the plastic deformation of halite is mostly intragranular for samples with large grains, with a few grain boundaries experiencing glide. In many cases, the slip planes can be identified, with contrasted situations: cross slip, partition of grains into several parts showing different slip lines... DIC shows that intragranular strains are organized by bands which orientation may often be explained in terms of slip plane traces and which become denser as the strain magnitudes increase. In order to complete the analysis, the knowledge of the local stresses is needed. Since they cannot be measured directly, one turns to numerical simulations based on a Crystal Plasticity Finite Element Code (CPFE). The core of such codes is the description of the single crystal behavior. Salt and ionic crystals have been extensively studied in the past (Carter and Heard, 1970) and recently revisited (Picard et al., 2012). It has been established that the glide directions are <110> directions and that the glide planes are {110}, {100} and {111} with strongly temperature dependent initial critical shear stresses (CSS) and hardening behaviors. At room temperature, the {110}<110> systems have the lowest CSS but do not suffice to accommodate a general plastic strain, so there is an initial stress differential build up between a grain well-oriented for easy plastic glide and another "hard" grain until other systems are activated or another deformation mechanism arises. The structure on which these computations are performed is another key element : one has to reconstruct a 3D

  10. Assessment of ultra high performance supercritical fluid chromatography as a separation technique for the analysis of seized drugs: Applicability to synthetic cannabinoids.

    PubMed

    Breitenbach, Stephanie; Rowe, Walter F; McCord, Bruce; Lurie, Ira S

    2016-04-01

    The recent development of modern methods for ultra high performance supercritical fluid chromatography (UHPSFC) has great potential for impacting the analysis of seized drugs. In the separation of synthetic cannabinoids the technique has the potential to produce superior resolution of positional isomers and diastereomers. To demonstrate this potential we have examined the capability of UHPSFC for the analysis of two different groups of synthetic cannabinoids. The first group was a mixture of 22 controlled synthetic cannabinoids, and the second group included JWH018 and nine of its non-controlled positional isomers The clear superiority of UHPSFC over other separation techniques was demonstrated, in that it was capable of near baseline separation of all 10 positional isomers using a chiral column. In total we examined four achiral columns, including Acquity UPC(2) Torus 2-PIC, Acquity UPC(2) Torus Diol, Acquity UPC(2) Torus DEA and Acquity UPC(2) Torus 1-AA (1.7μm 3.0×100mm), and three chiral columns, including Acquity UPC(2) Trefoil AMY1, Acquity UPC(2) Trefoil CEL1 and Acquity UPC(2) Trefoil CEL2 (2.5μm 3.0×150mm), using mobile phase compositions that combined carbon dioxide with methanol, acetonitrile, ethanol or isopropanol modifier gradients. Detection was performed using simultaneous PDA UV detection and quadrupole mass spectrometry. The orthogonality of UHPSFC, GC and UHPLC for the analysis of these compounds was demonstrated using principal component analysis. Overall we feel that this new technique should prove useful in the analysis and detection of seized drug samples, and will be a useful addition to the compendium of methods for drug analysis. PMID:26947165

  11. Construction of polyketide overproducing Escherichia coli strains via synthetic antisense RNAs based on in silico fluxome analysis and comparative transcriptome analysis.

    PubMed

    Meng, Hai-Lin; Xiong, Zhi-Qiang; Song, Shu-Jie; Wang, Jianfeng; Wang, Yong

    2016-03-01

    Rapid assessment and optimization of the incompatible metabolic modules remain a challenge. Here, we developed a systematic approach to characterize the module interactions and improve the problematic modules during the 6-deoxyerythronolide B (6dEB) biosynthesis in E. coli. Tremendous differences in the overall trends of flux changes of various metabolic modules were firstly uncovered based on in silico fluxome analysis and comparative transcriptome analysis. Potential targets for improving 6dEB biosynthesis were identified through analyzing these discrepancies. All 25 predicted targets at modules of PP pathway and nucleotide metabolism were firstly tested for improving the 6dEB production in E. coli via synthetic antisense RNAs. Down-regulation of 18 targets genes leads to more than 20% increase in 6dEB yield. Combinatorial repression of targets with greater than 60% increase in 6dEB titer, e.g., anti-guaB/anti-zwf led to a 296.2% increase in 6dEB production (210.4 mg/L in flask) compared to the control (53.1 mg/L). This is the highest yield yet reported for polyketide heterologous biosynthesis in E. coli. This study demonstrates a strategy to enhance the yield of heterologous products in the chassis cell and indicates the effectiveness of antisense RNA for use in metabolic engineering. PMID:26709503

  12. Analysis of polarimetric synthetic aperture radar and passive visible light polarimetric imaging data fusion for remote sensing applications

    NASA Astrophysics Data System (ADS)

    Maitra, Sanjit

    The recent launch of spaceborne (TerraSAR-X, RADARSAT-2, ALOS-PALSAR, RISAT) and airborne (SIRC, AIRSAR, UAVSAR, PISAR) polarimetric radar sensors, with capability of imaging through day and night in almost all weather conditions, has made polarimetric synthetic aperture radar (PolSAR) image interpretation and analysis an active area of research. PolSAR image classification is sensitive to object orientation and scattering properties. In recent years, significant work has been done in many areas including agriculture, forestry, oceanography, geology, terrain analysis. Visible light passive polarimetric imaging has also emerged as a powerful tool in remote sensing for enhanced information extraction. The intensity image provides information on materials in the scene while polarization measurements capture surface features, roughness, and shading, often uncorrelated with the intensity image. Advantages of visible light polarimetric imaging include high dynamic range of polarimetric signatures and being comparatively straightforward to build and calibrate. This research is about characterization and analysis of the basic scattering mechanisms for information fusion between PolSAR and passive visible light polarimetric imaging. Relationships between these two modes of imaging are established using laboratory measurements and image simulations using the Digital Image and Remote Sensing Image Generation (DIRSIG) tool. A novel low cost laboratory based S-band (2.4GHz) PolSAR instrument is developed that is capable of capturing 4 channel fully polarimetric SAR image data. Simple radar targets are formed and system calibration is performed in terms of radar cross-section. Experimental measurements are done using combination of the PolSAR instrument with visible light polarimetric imager for scenes capturing basic scattering mechanisms for phenomenology studies. The three major scattering mechanisms studied in this research include single, double and multiple bounce. Single

  13. Surface pressure profiles, vortex structure and initialization for hurricane prediction. Part I: analysis of observed and synthetic structures

    NASA Astrophysics Data System (ADS)

    Ma, Yimin; Kafatos, Menas; Davidson, Noel E.

    2012-07-01

    Without detailed reconnaissance, consistent representation of hurricane-like vortices in initial conditions for operational prediction and research simulations still remains elusive. It is thus often necessary, particularly for high-resolution intensity forecasting, to use synthetic tropical cyclone circulations to initialize forecast models. Variants on three commonly used surface pressure profiles are evaluated for possible use. Enhancements to the original profiles are proposed that allows definition of both the inner-core and outer circulation. The latter improvement creates a vortex more consistent with the estimated outer structure which sometimes appears to be crucial to the evolving intensity of the storm. It also allows smoother merging of the synthetic vortex with the environment. Comparisons of the profiles against (a) structure estimates, (b) each other, (c) structures obtained via conservation of angular momentum, and (d) observed vorticity structures, suggest that a new enhanced Fujita profile best represents real TC structures. Student- t tests indicate that improved fitting to the observations is statistically significant.

  14. Preparation of polydopamine-coated magnetic nanoparticles for dispersive solid-phase extraction of water-soluble synthetic colorants in beverage samples with HPLC analysis.

    PubMed

    Chai, Weibo; Wang, Huijuan; Zhang, Ying; Ding, Guosheng

    2016-03-01

    A facile and sensitive dispersive solid-phase extraction (D-SPE) method for the extraction and enrichment of four representative synthetic colorants prior to high performance liquid chromatography analysis was introduced. As highly efficient adsorbents, polydopamine-coated Fe3O4 nanoparticles (Fe3O4@PDA NPs) were prepared by a simple and green procedure. Several factors affecting the extraction efficiency, mainly including the polymerization time of dopamine, pH of the sample solution, the amount of adsorbent, extraction time and the desorption conditions, were systematically studied. Under the optimized conditions, the enrichment factors for the four colorants were both higher than 176. The limits of detection (LODs) for the established d-SPE-HPLC method were found to be 0.20-0.25μgL(-1), which were lower than most chromatographic methods previously reported for synthetic colorant analysis. When used for quantitative analysis, wide linearity ranges (1-500μgL(-1) for amaranth and Ponceau 4R, and 0.80-500μgL(-1) for sunset yellow and allure red) were achieved with good correlation (R(2)≥0.9995). The developed method was also successfully applied to the analysis of colorants in beverage samples with satisfactory results, demonstrating its reliability and feasibility in real sample analysis. PMID:26717809

  15. New form of platyspondylic lethal chondrodysplasia.

    PubMed

    Akaba, K; Nishimura, G; Hashimoto, M; Wakabayashi, T; Kanasugi, H; Hayasaka, K

    1996-12-30

    We report on a sporadic case of hitherto unknown lethal skeletal dysplasia. The cardinal clinical manifestations consisted of frontal bossing, cloudy corneae, low nasal ridge, and micrognathia, hypoplastic thorax, and rhizomelic micromelia. Laryngoscopy and neck CT disclosed laryngeal stenosis, and brain CT demonstrated hypoplasia of the corpus callosum. Skeletal survey demonstrated hypoplasia of facial bones and short skull base, extremely severe platyspondyly, hypoplastic ilia, and delayed epiphyseal ossification and rhizomelic shortness of tubular bones. The long bones appeared overtubulated with exaggerated metaphyseal flaring. The humeri were particularly short and bowed. Bowing of the radii and ulnae with subluxation of radial heads presented as a Madelung-like deformity. Unlike the long bones, the short tubular bones were not short and normally modeled. The skeletal changes were superficially similar to those in a group of lethal platyspondylic chondrodysplasias, but were inconsistent with any known subtypes of this group or other lethal skeletal dysplasias. PMID:8989469

  16. Lethality of First Contact Dysentery Epidemics on Pacific Islands.

    PubMed

    Shanks, G Dennis

    2016-08-01

    Infectious diseases depopulated many isolated Pacific islands when they were first exposed to global pathogen circulation from the 18th century. Although the mortality was great, the lack of medical observers makes determination of what happened during these historical epidemics largely speculative. Bacillary dysentery caused by Shigella is the most likely infection causing some of the most lethal island epidemics. The fragmentary historical record is reviewed to gain insight into the possible causes of the extreme lethality that was observed during first-contact epidemics in the Pacific. Immune aspects of the early dysentery epidemics and postmeasles infection resulting in subacute inflammatory enteric disease suggest that epidemiologic isolation was the major lethality risk factor on Pacific islands in the 19th century. Other possible risk factors include human leukocyte antigen homogeneity from a founder effect and pathogen-induced derangement of immune tolerance to gut flora. If this analysis is correct, then Pacific islands are currently at no greater risk of emerging disease epidemics than other developing countries despite their dark history. PMID:27185765

  17. Lethal Injection for Execution: Chemical Asphyxiation?

    PubMed Central

    Zimmers, Teresa A; Sheldon, Jonathan; Lubarsky, David A; López-Muñoz, Francisco; Waterman, Linda; Weisman, Richard; Koniaris, Leonidas G

    2007-01-01

    Background Lethal injection for execution was conceived as a comparatively humane alternative to electrocution or cyanide gas. The current protocols are based on one improvised by a medical examiner and an anesthesiologist in Oklahoma and are practiced on an ad hoc basis at the discretion of prison personnel. Each drug used, the ultrashort-acting barbiturate thiopental, the neuromuscular blocker pancuronium bromide, and the electrolyte potassium chloride, was expected to be lethal alone, while the combination was intended to produce anesthesia then death due to respiratory and cardiac arrest. We sought to determine whether the current drug regimen results in death in the manner intended. Methods and Findings We analyzed data from two US states that release information on executions, North Carolina and California, as well as the published clinical, laboratory, and veterinary animal experience. Execution outcomes from North Carolina and California together with interspecies dosage scaling of thiopental effects suggest that in the current practice of lethal injection, thiopental might not be fatal and might be insufficient to induce surgical anesthesia for the duration of the execution. Furthermore, evidence from North Carolina, California, and Virginia indicates that potassium chloride in lethal injection does not reliably induce cardiac arrest. Conclusions We were able to analyze only a limited number of executions. However, our findings suggest that current lethal injection protocols may not reliably effect death through the mechanisms intended, indicating a failure of design and implementation. If thiopental and potassium chloride fail to cause anesthesia and cardiac arrest, potentially aware inmates could die through pancuronium-induced asphyxiation. Thus the conventional view of lethal injection leading to an invariably peaceful and painless death is questionable. PMID:17455994

  18. RNA-Seq-based transcriptome analysis of Korean rose bitterling (Rhodeus uyekii) exposed to synthetic estrogen 17-α-ethinylestradiol (EE2).

    PubMed

    Kong, Hee Jeong; Lee, Il Kyu; Kim, Julan; Kim, Woo-Jin; Kim, Hyung Soo; Cho, Wang Sik; Kim, Dong-Wook; Park, Jung Youn; An, Cheul Min

    2015-12-01

    The potential impact of natural and synthetic estrogens on aquatic ecosystems has become a subject of great interest in recent years. One synthetic estrogen, 17-alpha-ethinylestradiol (EE2), is present in municipal sewage discharges and causes gonad alterations in various fish species. To understand the possible damage caused by EE2, male Rhodeus uyekii were exposed to 100 ng/L EE2 for 7 days. RNA-Seq was performed to assess the effects of EE2 on gene expression in hepatic and skin tissues. The analysis revealed that EE2 induced the expression of various genes, including sex hormone genes, anti-Mullerian hormone, vitellogenin, and estrogen receptor alpha; cancer genes, breast cancer anti-estrogen resistance protein 3, caveolin 2, and Smad2; and apoptotic genes, p53, Bcl-2, TNF-α, and WDR36. These results suggest that the synthetic estrogen EE2 disturbs the endocrine system and regulates both carcinogenic and apoptotic gene expressions in R. uyekii. PMID:26112897

  19. Live deaths online: internet suicide and lethality.

    PubMed

    Klein, Carolina A

    2012-01-01

    The Internet provides an infinite platform for the portrayal of lethal events. Beyond mere display, however, it dispenses information, allows for participation and sharing of content, and constitutes a virtual interactive forum. The Internet may ultimately shape society's approach to perceiving and dealing with death. Thus, psychiatrists may wish to be aware of these matters so that they may be considered in assessments and clinical care. In this article, the author attempts to identify key online locations where lethality is portrayed and how it may affect the individual patient and practitioner and the population at large. PMID:23233475

  20. Suitability of Synthetic Driving Profiles from Traffic Micro-Simulation for Real-World Energy Analysis: Preprint

    SciTech Connect

    Hou, Yunfei; Wood, Eric; Burton, Evan; Gonder, Jeffrey

    2015-10-14

    A shift towards increased levels of driving automation is generally expected to result in improved safety and traffic congestion outcomes. However, little empirical data exists to estimate the impact that automated driving could have on energy consumption and greenhouse gas emissions. In the absence of empirical data on differences between drive cycles from present day vehicles (primarily operated by humans) and future vehicles (partially or fully operated by computers) one approach is to model both situations over identical traffic conditions. Such an exercise requires traffic micro-simulation to not only accurately model vehicle operation under high levels of automation, but also (and potentially more challenging) vehicle operation under present day human drivers. This work seeks to quantify the ability of a commercial traffic micro-simulation program to accurately model real-world drive cycles in vehicles operated primarily by humans in terms of driving speed, acceleration, and simulated fuel economy. Synthetic profiles from models of freeway and arterial facilities near Atlanta, Georgia, are compared to empirical data collected from real-world drivers on the same facilities. Empirical and synthetic drive cycles are then simulated in a powertrain efficiency model to enable comparison on the basis of fuel economy. Synthetic profiles from traffic micro-simulation were found to exhibit low levels of transient behavior relative to the empirical data. Even with these differences, the synthetic and empirical data in this study agree well in terms of driving speed and simulated fuel economy. The differences in transient behavior between simulated and empirical data suggest that larger stochastic contributions in traffic micro-simulation (relative to those present in the traffic micro-simulation tool used in this study) are required to fully capture the arbitrary elements of human driving. Interestingly, the lack of stochastic contributions from models of human drivers

  1. Toward Engineering Synthetic Microbial Metabolism

    PubMed Central

    McArthur, George H.; Fong, Stephen S.

    2010-01-01

    The generation of well-characterized parts and the formulation of biological design principles in synthetic biology are laying the foundation for more complex and advanced microbial metabolic engineering. Improvements in de novo DNA synthesis and codon-optimization alone are already contributing to the manufacturing of pathway enzymes with improved or novel function. Further development of analytical and computer-aided design tools should accelerate the forward engineering of precisely regulated synthetic pathways by providing a standard framework for the predictable design of biological systems from well-characterized parts. In this review we discuss the current state of synthetic biology within a four-stage framework (design, modeling, synthesis, analysis) and highlight areas requiring further advancement to facilitate true engineering of synthetic microbial metabolism. PMID:20037734

  2. Critical analysis of the maximum non inhibitory concentration (MNIC) method in quantifying sub-lethal injury in Saccharomyces cerevisiae cells exposed to either thermal or pulsed electric field treatments.

    PubMed

    Kethireddy, V; Oey, I; Jowett, Tim; Bremer, P

    2016-09-16

    Sub-lethal injury within a microbial population, due to processing treatments or environmental stress, is often assessed as the difference in the number of cells recovered on non-selective media compared to numbers recovered on a "selective media" containing a predetermined maximum non-inhibitory concentration (MNIC) of a selective agent. However, as knowledge of cell metabolic response to injury, population diversity and dynamics increased, the rationale behind the conventional approach of quantifying sub-lethal injury must be scrutinized further. This study reassessed the methodology used to quantify sub-lethal injury for Saccharomyces cerevisiae cells (≈ 4.75 Log CFU/mL) exposed to either a mild thermal (45°C for 0, 10 and 20min) or a mild pulsed electric field treatment (field strengths of 8.0-9.0kV/cm and energy levels of 8, 14 and 21kJ/kg). Treated cells were plated onto either Yeast Malt agar (YM) or YM containing NaCl, as a selective agent at 5-15% in 1% increments. The impact of sub-lethal stress due to initial processing, the stress due to selective agents in the plating media, and the subsequent variation of inhibition following the treatments was assessed based on the CFU count (cell numbers). ANOVA and a generalised least squares model indicated significant effects of media, treatments, and their interaction effects (P<0.05) on cell numbers. It was shown that the concentration of the selective agent used dictated the extent of sub-lethal injury recorded owing to the interaction effects of the selective component (NaCl) in the recovery media. Our findings highlight a potential common misunderstanding on how culture conditions impact on sub-lethal injury. Interestingly for S. cerevisiae cells the number of cells recovered at different NaCl concentrations in the media appears to provide valuable information about the mode of injury, the comparative efficacy of different processing regimes and the inherent degree of resistance within a population. This

  3. Lethal Effects of Helianthemum lippii (L.) on Acanthamoeba castellanii Cysts in Vitro

    PubMed Central

    Badria, F.A.; Hetta, M.H.; Sarhan, Rania M.; Ezz El-Din, M.H.

    2014-01-01

    Acanthamoeba spp. commonly cause Acanthamoeba keratitis which is typically associated with the wear of contact lenses. Therefore, finding an economic, efficient, and safe therapy of natural origin is of outmost importance. This study examined the in vitro lethal potential of ethyl acetate and methanol extracts of Helianthemum lippii (L.) (sun roses) against Acanthamoeba castellanii cysts isolated from patients with amoebic keratitis. Both extracts proved to be potent as regard to their lethal effects on A. castellanii cysts with comparable results to chlorhexidine. The ethyl acetate was more promising with cumulative lethality. It showed a highly significant lethal percentage along the duration of treatment. The analysis of the more potent ethyl acetate extract revealed the presence of 2.96 mg/100 g of total phenolics, 0.289 mg/100 ml of total flavonoids and 37 mg/100 mg of total tannins which highlighted their phytomedicinal role. PMID:25031463

  4. Synthetically persistent, self assembled [V(IV)2V(V)4] polyoxovanadates: facile synthesis, structure and magnetic analysis.

    PubMed

    Marino, Nadia; Lloret, Francisco; Julve, Miguel; Doyle, Robert P

    2011-12-01

    Slow diffusion in a H-tube at room temperature of a methanolic solution of [VO(acac)(2)] (Hacac = acetylacetone) and 1,10-phenanthroline (phen) or 2,2'-bipyridine (bipy) into an aqueous solution of sodium pyrophosphate (Na(4)P(2)O(7)) resulted in the serendipitous formation of X-ray quality crystals of mixed-valent, hexameric oxovanadates of general formula [V(6)O(12)(OCH(3))(4)(L)(4)]·solv [L = 1,10-phenanthroline (phen) for 1· 2CH(3)OH · 4H(2)O (1a), and 2,2'-bipyridine (bipy) for 2· 4H(2)O (2a)]. These were characterized by single-crystal X-ray diffraction, IR, elemental and thermogravimetric analysis (TGA). A facile, rationalized synthetic route for the isolation of 1a and 2a could be established following structural determination, involving NaOH in place of Na(4)P(2)O(7) as pH modulator. The use of distilled water (pH 7) as methanolic co-solvent also resulted in crystallization of the two complexes, proving the presence of a base in the reaction scheme is not vital, with slightly pH-depended yields noted for 2a only. A survey of the literature revealed the occurrence of several other procedures, from classical methods to hydrothermal routes, leading to different solvates of 1, the crystal structure of 2 being unreported in any form to date. The precise nature of the molecular assembly in these type of hybrid organic-inorganic poly-vanadates is contradictory in published reports. On the basis of newly acquired high resolution crystal data and supported by magnetic investigation of the samples, we propose herein a formulation as [(V(IV)O)(2)(V(V)O(2))(4)(μ(3)-O)(2)(μ-OCH(3))(4)(L)(4)], with two oxovanadyl(IV) and four dioxovanadyl(V) units per molecule. A net ferromagnetic coupling between the two isolated V(IV) metal centers was measured with literature-consistent J values of +16.1(1) and +19.7(1) cm(-1) for 1a and 2a, respectively [H = -JS(A)·S(B) + S(A)·D·S(B) + βH (g(A)S(A) + g(B)S(B))], suggesting that crystal packing forces do not significantly

  5. A new approach to the determination of the synthetic or natural origin of red pigments through spectroscopic analysis

    NASA Astrophysics Data System (ADS)

    Franquelo, Maria Luisa; Perez-Rodriguez, Jose Luis

    2016-09-01

    This work suggests a way of differentiation between the natural or synthetic origin of inorganic materials that were historically used in the Cultural Heritage field. An exhaustive review of different reported procedures of synthesis of pigments was conducted, as well as a review of the accompanying minerals in case of natural pigments. The natural or synthetic origin of the pigments studied in this work was performed through the characterization of the accompanying minerals, in the case of the natural pigments, or the trace elements that are present as part of synthesis by-products or washing/purifying reagents and/or reactants that have only been partly removed in the final steps of these processes. This work characterized red pigments due to their wide variety, complexity and possibility of use in different mixtures. The following pigments were studied: cinnabar-vermilion, red lead and iron pigments. Also mixtures of these pigments between them and with red lake were also studied. Natural cinnabar was accompanied by silicon oxide (opal, chalcedony or quartz), calcite, clay minerals and, sometimes, pyrite. K together with S indicated a synthetic pigment (vermilion) obtained through the wet method. Nevertheless, K has not been found in layers containing only vermilion in our samples. The presence of Sn in some cases indicated vermilion that came from the dry process. K from the synthesis always appeared in the red lead pigment. The red natural ochre was confirmed by presence of clay minerals and iron. It should be said that Ca and S, and sometimes Al and K, were usually found in Mars red pigment. The presence of Al and Ca allowed the identification of carmine lake.

  6. A new approach to the determination of the synthetic or natural origin of red pigments through spectroscopic analysis.

    PubMed

    Franquelo, Maria Luisa; Perez-Rodriguez, Jose Luis

    2016-09-01

    This work suggests a way of differentiation between the natural or synthetic origin of inorganic materials that were historically used in the Cultural Heritage field. An exhaustive review of different reported procedures of synthesis of pigments was conducted, as well as a review of the accompanying minerals in case of natural pigments. The natural or synthetic origin of the pigments studied in this work was performed through the characterization of the accompanying minerals, in the case of the natural pigments, or the trace elements that are present as part of synthesis by-products or washing/purifying reagents and/or reactants that have only been partly removed in the final steps of these processes. This work characterized red pigments due to their wide variety, complexity and possibility of use in different mixtures. The following pigments were studied: cinnabar-vermilion, red lead and iron pigments. Also mixtures of these pigments between them and with red lake were also studied. Natural cinnabar was accompanied by silicon oxide (opal, chalcedony or quartz), calcite, clay minerals and, sometimes, pyrite. K together with S indicated a synthetic pigment (vermilion) obtained through the wet method. Nevertheless, K has not been found in layers containing only vermilion in our samples. The presence of Sn in some cases indicated vermilion that came from the dry process. K from the synthesis always appeared in the red lead pigment. The red natural ochre was confirmed by presence of clay minerals and iron. It should be said that Ca and S, and sometimes Al and K, were usually found in Mars red pigment. The presence of Al and Ca allowed the identification of carmine lake. PMID:27219074

  7. Lethal Malaria: Marchiafava and Bignami Were Right

    PubMed Central

    White, Nicholas J.; Turner, Gareth D. H.; Day, Nicholas P. J.; Dondorp, Arjen M.

    2013-01-01

    One hundred and twenty years ago, the Italian malariologists Marchiafava and Bignami proposed that the fundamental pathological process underlying lethal falciparum malaria was microvascular obstruction. Since then, several alternative hypotheses have been proposed. These formed the basis for adjunctive interventions, which have either been ineffective or harmful. Recent evidence strongly suggests that Marchiafava and Bignami were right. PMID:23585685

  8. The evolution of lethal intergroup violence

    PubMed Central

    Kelly, Raymond C.

    2005-01-01

    Recent findings and analyses in evolutionary biology, archaeology, and ethnology provide a favorable conjuncture for examining the evolution of lethal intergroup violence among hominids during the 2.9-million-year Paleolithic time span. Here, I seek to identify and investigate the main turning points in this evolutionary trajectory and to delineate the periodization that follows from this inquiry. PMID:16129826

  9. Deadly Lessons: Understanding Lethal School Violence.

    ERIC Educational Resources Information Center

    Moore, Mark H., Ed.; Petrie, Carol V., Ed.; Braga, Anthony A., Ed.; McLaughlin, Brenda L., Ed.

    This collection of papers is the outcome of the National Academies' effort to glean information from six different case studies of student-perpetrated school shootings. Part 1, "Case Studies of Lethal School Violence," includes: "The Copycat Factor: Mental Illness, Guns, and the Shooting Incident at Heritage High School, Rockdale County, Georgia"…

  10. Digital Beamforming Synthetic Aperture Radar (DBSAR): Performance Analysis During the Eco-3D 2011 and Summer 2012 Flight Campaigns

    NASA Technical Reports Server (NTRS)

    Rincon, Rafael F.; Fatoyinbo, Temilola; Carter, Lynn; Ranson, K. Jon; Vega, Manuel; Osmanoglu, Batuhan; Lee, SeungKuk; Sun, Guoqing

    2014-01-01

    The Digital Beamforming Synthetic Aperture radar (DBSAR) is a state-of-the-art airborne radar developed at NASA/Goddard for the implementation, and testing of digital beamforming techniques applicable to Earth and planetary sciences. The DBSAR measurements have been employed to study: The estimation of vegetation biomass and structure - critical parameters in the study of the carbon cycle; The measurement of geological features - to explore its applicability to planetary science by measuring planetary analogue targets. The instrument flew two test campaigns over the East coast of the United States in 2011, and 2012. During the campaigns the instrument operated in full polarimetric mode collecting data from vegetation and topography features.

  11. Micromagnetic analysis of current-induced domain wall motion in a bilayer nanowire with synthetic antiferromagnetic coupling

    NASA Astrophysics Data System (ADS)

    Komine, Takashi; Aono, Tomosuke

    2016-05-01

    We demonstrate current-induced domain wall motion in bilayer nanowire with synthetic antiferromagnetic (SAF) coupling by modeling two body problems for motion equations of domain wall. The influence of interlayer exchange coupling and magnetostatic interactions on current-induced domain wall motion in SAF nanowires was also investigated. By assuming the rigid wall model for translational motion, the interlayer exchange coupling and the magnetostatic interaction between walls and domains in SAF nanowires enhances domain wall speed without any spin-orbit-torque. The enhancement of domain wall speed was discussed by energy distribution as a function of wall angle configuration in bilayer nanowires.

  12. On the shape and albedo variegation of asteroids - Results from Fourier analysis of synthetic and observed asteroid lightcurves

    NASA Technical Reports Server (NTRS)

    Barucci, M. Antonietta; Capria, M. Teresa; Harris, Alan W.; Fulchignoni, Marcello

    1989-01-01

    Fourier analyses have been conducted of those asteroids in the Lagerkvist et al. (1987) lightcurves with substantially complete phase coverage and point density, and for which a unique period has been identified. Fourier coefficients are thereby obtained for 188 lightcurves of 91 asteroids, as well as for 868 synthetic lightcurves from a set of models different in shape and albedo markings; by comparing model and asteroid lightcurve coefficients, the possible shape and albedo variations for 18 asteroids are derived. An attempt is made to define the general distribution of shapes of all asteroid samples analyzed.

  13. Cholesterol Metabolism and Prostate Cancer Lethality.

    PubMed

    Stopsack, Konrad H; Gerke, Travis A; Sinnott, Jennifer A; Penney, Kathryn L; Tyekucheva, Svitlana; Sesso, Howard D; Andersson, Swen-Olof; Andrén, Ove; Cerhan, James R; Giovannucci, Edward L; Mucci, Lorelei A; Rider, Jennifer R

    2016-08-15

    Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to nonlethal disease without evidence of metastases after at least 8 years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared with men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease. Cancer Res; 76(16); 4785-90. ©2016 AACR. PMID:27325648

  14. Analog synthetic biology

    PubMed Central

    Sarpeshkar, R.

    2014-01-01

    We analyse the pros and cons of analog versus digital computation in living cells. Our analysis is based on fundamental laws of noise in gene and protein expression, which set limits on the energy, time, space, molecular count and part-count resources needed to compute at a given level of precision. We conclude that analog computation is significantly more efficient in its use of resources than deterministic digital computation even at relatively high levels of precision in the cell. Based on this analysis, we conclude that synthetic biology must use analog, collective analog, probabilistic and hybrid analog–digital computational approaches; otherwise, even relatively simple synthetic computations in cells such as addition will exceed energy and molecular-count budgets. We present schematics for efficiently representing analog DNA–protein computation in cells. Analog electronic flow in subthreshold transistors and analog molecular flux in chemical reactions obey Boltzmann exponential laws of thermodynamics and are described by astoundingly similar logarithmic electrochemical potentials. Therefore, cytomorphic circuits can help to map circuit designs between electronic and biochemical domains. We review recent work that uses positive-feedback linearization circuits to architect wide-dynamic-range logarithmic analog computation in Escherichia coli using three transcription factors, nearly two orders of magnitude more efficient in parts than prior digital implementations. PMID:24567476

  15. Analog synthetic biology.

    PubMed

    Sarpeshkar, R

    2014-03-28

    We analyse the pros and cons of analog versus digital computation in living cells. Our analysis is based on fundamental laws of noise in gene and protein expression, which set limits on the energy, time, space, molecular count and part-count resources needed to compute at a given level of precision. We conclude that analog computation is significantly more efficient in its use of resources than deterministic digital computation even at relatively high levels of precision in the cell. Based on this analysis, we conclude that synthetic biology must use analog, collective analog, probabilistic and hybrid analog-digital computational approaches; otherwise, even relatively simple synthetic computations in cells such as addition will exceed energy and molecular-count budgets. We present schematics for efficiently representing analog DNA-protein computation in cells. Analog electronic flow in subthreshold transistors and analog molecular flux in chemical reactions obey Boltzmann exponential laws of thermodynamics and are described by astoundingly similar logarithmic electrochemical potentials. Therefore, cytomorphic circuits can help to map circuit designs between electronic and biochemical domains. We review recent work that uses positive-feedback linearization circuits to architect wide-dynamic-range logarithmic analog computation in Escherichia coli using three transcription factors, nearly two orders of magnitude more efficient in parts than prior digital implementations. PMID:24567476

  16. Carbon monoxide and lethal arrhythmias

    SciTech Connect

    Farber, J.P.; Schwartz, P.J.; Vanoli, E.; Stramba-Badiale, M.; De Ferrari, G.M. )

    1990-12-01

    The effect of acute exposure to carbon monoxide on ventricular arrhythmias was studied in a previously described chronically maintained animal model of sudden cardiac death. In 60 percent of dogs with a healed anterior myocardial infarction, the combination of mild exercise and acute myocardial ischemia induces ventricular fibrillation. The events in this model are highly reproducible, thus allowing study by internal control analysis. Dogs that develop ventricular fibrillation during the test of exercise and acute myocardial ischemia are considered at high risk for sudden death and are defined as 'susceptible'; dogs that survive the test without a fatal arrhythmia are considered at low risk for sudden death and are defined as 'resistant.' In the current study, the effects of carboxyhemoglobin levels ranging from 5 to 15 percent were tested in resistant and susceptible dogs. A trend toward higher heart rates was observed at all levels of carboxyhemoglobin, although significant differences were observed only with 15 percent carboxyhemoglobin. This trend was observed at rest and during exercise in both resistant and susceptible dogs. In resistant animals, in which acute myocardial ischemia is typically associated with bradycardia even under the control condition, this reflex response occurred earlier and was augmented after exposure to carbon monoxide. This effect may depend on the increased hypoxic challenge caused by carbon monoxide, and thus on an augmentation of the neural reflex activation or a sensitization of the sinus node to acetylcholine induced by hypoxia. In both resistant and susceptible dogs, carbon monoxide exposure induced a worsening of ventricular arrhythmias in a minority of cases. This worsening was not reproducible in subsequent trials. These data indicate that acute exposure to carbon monoxide is seldom arrhythmogenic in dogs that have survived myocardial infarction. (Abstract Truncated)

  17. Raising awareness of new psychoactive substances: chemical analysis and in vitro toxicity screening of 'legal high' packages containing synthetic cathinones.

    PubMed

    Araújo, Ana Margarida; Valente, Maria João; Carvalho, Márcia; Dias da Silva, Diana; Gaspar, Helena; Carvalho, Félix; de Lourdes Bastos, Maria; Guedes de Pinho, Paula

    2015-05-01

    The world's status quo on recreational drugs has dramatically changed in recent years due to the rapid emergence of new psychoactive substances (NPS), represented by new narcotic or psychotropic drugs, in pure form or in preparation, which are not controlled by international conventions, but that may pose a public health threat comparable with that posed by substances listed in these conventions. These NPS, also known as 'legal highs' or 'smart drugs', are typically sold via Internet or 'smartshops' as legal alternatives to controlled substances, being announced as 'bath salts' and 'plant feeders' and is often sought after for consumption especially among young people. Although NPS have the biased reputation of being safe, the vast majority has hitherto not been tested and several fatal cases have been reported, namely for synthetic cathinones, with pathological patterns comparable with amphetamines. Additionally, the unprecedented speed of appearance and distribution of the NPS worldwide brings technical difficulties in the development of analytical procedures and risk assessment in real time. In this study, 27 products commercialized as 'plant feeders' were chemically characterized by gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. It was also evaluated, for the first time, the in vitro hepatotoxic effects of individual synthetic cathinones, namely methylone, pentedrone, 4-methylethcathinone (4-MEC) and 3,4-methylenedioxypyrovalerone (MDPV). Two commercial mixtures ('Bloom' and 'Blow') containing mainly cathinone derivatives were also tested, and 3,4-methylenedioxymethamphetamine (MDMA) was used as the reference drug. The study allowed the identification of 19 compounds, showing that synthetic cathinones are the main active compounds present in these products. Qualitative and quantitative variability was found in products sold with the same trade name in matching or different 'smartshops'. In the toxicity studies performed in

  18. Synthetic light-curve analysis of the very short period binaries TY Bootis, AD Cancri, and V523 Cassiopeiae

    SciTech Connect

    Samec, R.G.; Van Hamme, W.; Bookmyer, B.B. Clemson Univ., SC South Carolina Univ., Conway Florida International Univ., Miami )

    1989-12-01

    New photometric observations of TY Boo, AD Cnc, and V523 Cas are subjected to synthetic light-curve analyses using the Wilson-Devinney code. Solutions for each of the systems, and the several competing theories of contact binary structure are discussed in light of the results. Both AD Cnc and V523 Cas are modeled with subluminous regions, and the resulting starspot parameters are reported. A simultaneous solution of the B, V light curves and the radial-velocity curves of V523 Cas is presented. Spectroscopic and photometric mass ratios were found to be discordant for both TY Boo and V523 Cas. However, recent spectroscopic work by Groissman seems to remove the discordancy for TY Boo. Absolute parameters are derived for V523 Cas. 43 refs.

  19. [Comparative analysis of natural and synthetic antimutagens as regulators of gene expression in human cells under exposure to ionizing radiation].

    PubMed

    Mikhailov, V F; Shishkina, A A; Vasilyeva, I M; Shulenina, L V; Raeva, N F; Rogozhin, E A; Startsev, M I; Zasukhina, G D; Gromov, S P; Alfimov, M V

    2015-02-01

    This paper studies the effect of plant peptides of thionine Ns-W2 extracted from seeds of fennel flower (Nigella sativa) and β-purothionine from wheat germs (Triticum kiharae), as well as a synthetic antimutagen (crown-compound), on the expression of several genes involved in the.control of cellular homeostasis, processes of carcinogenesis, and radiation response in human rhabdomyosarcoma cells (RD cells), T-lymphoblastoid cell line Jurkat, and blood cells. All of these agents acted as antimutagens-anticarcinogens, reducing the expression of genes involved in carcinogenesis (genes of families MMP, TIMP, and IAP and G-protein genes) in a tumor cell. A pronounced reduction in the mRNA level of these genes was caused by thionine Ns-W2, and the least effect was demonstrated by β-purothionine. Antimutagens had very little effect on the mRNA levels of the several studied genes in normal blood cells. PMID:25966580

  20. Synthetic light-curve analysis of the very short period binaries TY Bootis, AD Cancri, and V523 Cassiopeiae

    NASA Astrophysics Data System (ADS)

    Samec, Ronald G.; van Hamme, Walter; Bookmyer, Beverly B.

    1989-12-01

    New photometric observations of TY Boo, AD Cnc, and V523 Cas are subjected to synthetic light-curve analyses using the Wilson-Devinney code. Solutions for each of the systems, and the several competing theories of contact binary structure are discussed in light of the results. Both AD Cnc and V523 Cas are modeled with subluminous regions, and the resulting starspot parameters are reported. A simultaneous solution of the B, V light curves and the radial-velocity curves of V523 Cas is presented. Spectroscopic and photometric mass ratios were found to be discordant for both TY Boo and V523 Cas. However, recent spectroscopic work by Groissman seems to remove the discordancy for TY Boo. Absolute parameters are derived for V523 Cas.

  1. Biomechanical analysis of different types of pedicle screw augmentation: a cadaveric and synthetic bone sample study of instrumented vertebral specimens.

    PubMed

    Chao, Kuo-Hua; Lai, Yu-Shu; Chen, Wen-Chuan; Chang, Chia-Ming; McClean, Colin J; Fan, Chang-Yuan; Chang, Chia-Hao; Lin, Leou-Chyr; Cheng, Cheng-Kung

    2013-10-01

    This study aims to determine the pull-out strength, stiffness and failure pull-out energy of cement-augmented, cannulated-fenestrated pedicle screws in an osteoporotic cadaveric thoracolumbar model, and to determine, using synthetic bone samples, the extraction torques of screws pre-filled with cement and those with cement injected through perforations. Radiographs and bone mineral density measurements from 32 fresh thoracolumbar vertebrae were used to define specimen quality. Axial pull-out strength of screws was determined through mechanical testing. Mechanical pull-out strength, stiffness and energy-to-failure ratio were recorded for cement-augmented and non-cement-augmented screws. Synthetic bone simulating a human spinal bone with severe osteoporosis was used to measure the maximum extraction torque. The pull-out strength and stiffness-to-failure ratio of cement pre-filled and cement-injected screws were significantly higher than the non-cement-augmented control group. However, the cement pre-filled and cement-injected groups did not differ significantly across these values (p=0.07). The cement pre-filled group had the highest failure pull-out energy, approximately 2.8 times greater than that of the cement-injected (p<0.001), and approximately 11.5 times greater than that of the control groups (p<0.001). In the axial pull-out test, the cement-injected group had a greater maximum extraction torque than the cement pre-filled group, but was statistically insignificant (p=0.17). The initial fixation strength of cannulated screws pre-filled with cement is similar to that of cannulated screws injected with cement through perforations. This comparable strength, along with the heightened pull-out energy and reduced extraction torque, indicates that pedicle screws pre-filled with cement are superior for bone fixation over pedicle screws injected with cement. PMID:23669371

  2. Prevalence of lethal osteochondrodysplasias in Denmark.

    PubMed

    Andersen, P E

    1989-04-01

    The point prevalence at birth of lethal osteochondrodysplasias in a subregion of Denmark was estimated by a study of all children born January 1970 through December 1983. Two cases of thanatophoric dysplasia, one case of thanatophoric dysplasia with cloverleaf skull, two cases of micromelic bone dysplasia with cloverleaf skull, two cases of achondrogenesis type III, and three cases of achondrogenesis type IV were found. Two cases were unclassifiable due to lack of radiographs. In total, the point prevalence at birth was 15.4 per 100,000. Thus lethal osteochondrodysplasias seem to be more common than is generally assumed. The clinical and radiographic findings in micromelic bone dysplasia with cloverleaf skull are discussed in relation to thanatophoric dysplasia and achondrogenesis type IV. PMID:2789000

  3. Henipaviruses-unanswered questions of lethal zoonoses.

    PubMed

    Field, Hume; Kung, Nina

    2011-12-01

    The highly lethal Hendra and Nipah viruses have been described for little more than a decade, yet within that time have been aetiologically associated with major livestock and human health impacts, albeit on a limited scale. Do these emerging pathogens pose a broader threat, or are they inconsequential 'viral chatter'. Given their lethality, and the evident multi-generational human-to-human transmission associated with Nipah virus in Bangladesh, it seems prudent to apply the precautionary principle. While much is known of their clinical, pathogenic and epidemiologic features in livestock species and humans, a number of fundamental questions regarding the relationship between the viruses, their natural fruit-bat host and the environment remain unanswered. In this paper, we pose and probe these questions in context, and offer perspectives based primarily on our experience with Hendra virus in Australia, augmented with Nipah virus parallels. PMID:22440924

  4. Brine shrimp lethality assay of Bacopa monnieri.

    PubMed

    D'Souza, Prashanth; Deepak, Mundkinajeddu; Rani, Padmaja; Kadamboor, Sandhya; Mathew, Anjana; Chandrashekar, Arun P; Agarwal, Amit

    2002-03-01

    Successive petroleum ether, chloroform, ethanol and water extracts, a saponin rich fraction (SRF) and bacoside A isolated from Bacopa monnieri were tested for brine shrimp lethality. Successive ethanol extracts and SRF showed potent activity. Bacoside A showed the maximum activity with a LC(50) of 38.3 microg/mL. The results confirmed the previous reports of an anticancer effect of Bacopa monnieri and suggest bacoside A as the active constituent. PMID:11933129

  5. Specific ultrasonographic features of perinatal lethal hypophosphatasia.

    PubMed

    Zankl, Andreas; Mornet, Etienne; Wong, Shell

    2008-05-01

    Prenatal diagnosis of perinatal lethal hypophosphatasia (PL-HPH) by ultrasonography is difficult as PL-HPH must be differentiated from other skeletal dysplasias with short long bones and poor mineralization of the skeleton, such as osteogenesis imperfecta type II and achondrogenesis/hypochondrogenesis. Here we present a case of molecularly confirmed PL-HPH and illustrate specific ultrasonographic findings that help to distinguish PL-HPH from similar conditions. PMID:18386808

  6. Lethal Interpersonal Violence in the Middle Pleistocene

    PubMed Central

    Sala, Nohemi; Arsuaga, Juan Luis; Pantoja-Pérez, Ana; Pablos, Adrián; Martínez, Ignacio; Quam, Rolf M.; Gómez-Olivencia, Asier; Bermúdez de Castro, José María; Carbonell, Eudald

    2015-01-01

    Evidence of interpersonal violence has been documented previously in Pleistocene members of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force trauma. The type of injuries, their location, the strong similarity of the fractures in shape and size, and the different orientations and implied trajectories of the two fractures suggest they were produced with the same object in face-to-face interpersonal conflict. Given that either of the two traumatic events was likely lethal, the presence of multiple blows implies an intention to kill. This finding shows that the lethal interpersonal violence is an ancient human behavior and has important implications for the accumulation of bodies at the site, supporting an anthropic origin. PMID:26018668

  7. Lethal interpersonal violence in the Middle Pleistocene.

    PubMed

    Sala, Nohemi; Arsuaga, Juan Luis; Pantoja-Pérez, Ana; Pablos, Adrián; Martínez, Ignacio; Quam, Rolf M; Gómez-Olivencia, Asier; Bermúdez de Castro, José María; Carbonell, Eudald

    2015-01-01

    Evidence of interpersonal violence has been documented previously in Pleistocene members of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force trauma. The type of injuries, their location, the strong similarity of the fractures in shape and size, and the different orientations and implied trajectories of the two fractures suggest they were produced with the same object in face-to-face interpersonal conflict. Given that either of the two traumatic events was likely lethal, the presence of multiple blows implies an intention to kill. This finding shows that the lethal interpersonal violence is an ancient human behavior and has important implications for the accumulation of bodies at the site, supporting an anthropic origin. PMID:26018668

  8. Effectiveness of lethal, directed wolf-depredation control in Minnesota

    USGS Publications Warehouse

    Harper, E.K.; Paul, W.J.; Mech, L.D.; Weisberg, S.

    2008-01-01

    Wolf (Canis lupus) depredations on livestock in Minnesota, USA, are an economic problem for many livestock producers, and depredating wolves are lethally controlled. We sought to determine the effectiveness of lethal control through the analysis of data from 923 government-verified wolf depredations from 1979 to 1998. We analyzed the data by 1) assessing the correlations between the number of wolves killed in response to depredations with number of depredations the following year at state and local levels, and 2) the time to the next depredation. No analysis indicated that trapping wolves substantially reduced the following year's depredations at state or local levels. However, more specific analyses indicated that in certain situations, killing wolves was more effective than no action (i.e., not trapping). For example, trapping and killing adult males decreased the re-depredation risk. At sheep farms, killing wolves was generally effective. Attempting to trap, regardless of the results, seemed more effective at reducing depredations than not trapping, suggesting that mere human activity near depredation sites might deter future depredations.

  9. Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa.

    PubMed

    Jonkman, Marcel F; Pasmooij, Anna M G; Pasmans, Suzanne G M A; van den Berg, Maarten P; Ter Horst, Henk J; Timmer, Albertus; Pas, Hendri H

    2005-10-01

    The cytoplasmic plaque protein desmoplakin (DP), which is located in desmosomes, plays a major role in epithelial and muscle cell adhesion by linking the transmembrane cadherins to the cytoplasmic intermediate filament network. Mutations of DP may cause striate palmoplantar keratoderma, arrhythmogenic right ventricular dysplasia, skin fragility/woolly hair syndrome, Naxos-like disease, and Carvajal syndrome. DP must be indispensable, because DP-/- mice are early abortive. Here, we report a patient with severe fragility of skin and mucous membranes caused by genetic truncation of the DP tail. The new phenotype is lethal in the neonatal period because of immense transcutaneous fluid loss. The phenotype also comprised universal alopecia, neonatal teeth, and nail loss. Histology showed suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. Electron microscopy revealed disconnection of keratin intermediate filaments from desmosomes. Immunofluorescence staining of DP showed a distinct punctate intercellular pattern in the patient's skin. Protein analysis revealed expression of truncated DP polypeptides. Mutational analysis of the patient demonstrated compound heterozygosity for two DP mutations, 6079C-->T (R1934X) and 6370delTT, respectively. Aberrant mRNA transcripts that predict premature termination of translation with loss of the three intermediate filament-binding subdomains in the DP tail were detected by RT-PCR. The new dramatic phenotype, which we named "lethal acantholytic epidermolysis bullosa," underscores the paramount role of DP in epidermal integrity. PMID:16175511

  10. 5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

    PubMed Central

    Hohmann, Miriam S. N.; Cardoso, Renato D. R.; Pinho-Ribeiro, Felipe A.; Crespigio, Jefferson; Cunha, Thiago M.; Alves-Filho, José C.; da Silva, Rosiane V.; Pinge-Filho, Phileno; Ferreira, Sergio H.; Cunha, Fernando Q.; Casagrande, Rubia; Verri, Waldiceu A.

    2013-01-01

    5-Lipoxygenase (5-LO) converts arachidonic acid into leukotrienes (LTs) and is involved in inflammation. At present, the participation of 5-LO in acetaminophen (APAP)-induced hepatotoxicity and liver damage has not been addressed. 5-LO deficient (5-LO−/−) mice and background wild type mice were challenged with APAP (0.3–6 g/kg) or saline. The lethality, liver damage, neutrophil and macrophage recruitment, LTB4, cytokine production, and oxidative stress were assessed. APAP induced a dose-dependent mortality, and the dose of 3 g/kg was selected for next experiments. APAP induced LTB4 production in the liver, the primary target organ in APAP toxicity. Histopathological analysis revealed that 5-LO−/− mice presented reduced APAP-induced liver necrosis and inflammation compared with WT mice. APAP-induced lethality, increase of plasma levels of aspartate aminotransferase and alanine aminotransferase, liver cytokine (IL-1β, TNF-α, IFN-γ, and IL-10), superoxide anion, and thiobarbituric acid reactive substances production, myeloperoxidase and N-acetyl-β-D-glucosaminidase activity, Nrf2 and gp91phox mRNA expression, and decrease of reduced glutathione and antioxidant capacity measured by 2,2′-azinobis(3-ethylbenzothiazoline 6-sulfonate) assay were prevented in 5-LO−/− mice compared to WT mice. Therefore, 5-LO deficiency resulted in reduced mortality due to reduced liver inflammatory and oxidative damage, suggesting 5-LO is a promising target to reduce APAP-induced lethality and liver inflammatory/oxidative damage. PMID:24288682

  11. The mutational landscape of lethal castration-resistant prostate cancer.

    PubMed

    Grasso, Catherine S; Wu, Yi-Mi; Robinson, Dan R; Cao, Xuhong; Dhanasekaran, Saravana M; Khan, Amjad P; Quist, Michael J; Jing, Xiaojun; Lonigro, Robert J; Brenner, J Chad; Asangani, Irfan A; Ateeq, Bushra; Chun, Sang Y; Siddiqui, Javed; Sam, Lee; Anstett, Matt; Mehra, Rohit; Prensner, John R; Palanisamy, Nallasivam; Ryslik, Gregory A; Vandin, Fabio; Raphael, Benjamin J; Kunju, Lakshmi P; Rhodes, Daniel R; Pienta, Kenneth J; Chinnaiyan, Arul M; Tomlins, Scott A

    2012-07-12

    Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study. PMID

  12. Synthetic neurosteroids on brain protection

    PubMed Central

    Rey, Mariana; Coirini, Héctor

    2015-01-01

    Neurosteroids, like allopregnanolone and pregnanolone, are endogenous regulators of neuronal excitability. Inside the brain, they are highly selective and potent modulators of GABAA receptor activity. Their anticonvulsant, anesthetics and anxiolytic properties are useful for the treatments of several neurological and psychiatric disorders via reducing the risks of side effects obtained with the commercial drugs. The principal disadvantages of endogenous neurosteroids administration are their rapid metabolism and their low oral bioavailability. Synthetic steroids analogues with major stability or endogenous neurosteroids stimulation synthesis might constitute promising novel strategies for the treatment of several disorders. Numerous studies indicate that the 3α-hydroxyl configuration is the key for binding and activity, but modifications in the steroid nucleus may emphasize different pharmacophores. So far, several synthetic steroids have been developed with successful neurosteroid-like effects. In this work, we summarize the properties of various synthetic steroids probed in trials throughout the analysis of several neurosteroids-like actions. PMID:25788907

  13. Control theory meets synthetic biology.

    PubMed

    Del Vecchio, Domitilla; Dy, Aaron J; Qian, Yili

    2016-07-01

    The past several years have witnessed an increased presence of control theoretic concepts in synthetic biology. This review presents an organized summary of how these control design concepts have been applied to tackle a variety of problems faced when building synthetic biomolecular circuits in living cells. In particular, we describe success stories that demonstrate how simple or more elaborate control design methods can be used to make the behaviour of synthetic genetic circuits within a single cell or across a cell population more reliable, predictable and robust to perturbations. The description especially highlights technical challenges that uniquely arise from the need to implement control designs within a new hardware setting, along with implemented or proposed solutions. Some engineering solutions employing complex feedback control schemes are also described, which, however, still require a deeper theoretical analysis of stability, performance and robustness properties. Overall, this paper should help synthetic biologists become familiar with feedback control concepts as they can be used in their application area. At the same time, it should provide some domain knowledge to control theorists who wish to enter the rising and exciting field of synthetic biology. PMID:27440256

  14. Control theory meets synthetic biology

    PubMed Central

    2016-01-01

    The past several years have witnessed an increased presence of control theoretic concepts in synthetic biology. This review presents an organized summary of how these control design concepts have been applied to tackle a variety of problems faced when building synthetic biomolecular circuits in living cells. In particular, we describe success stories that demonstrate how simple or more elaborate control design methods can be used to make the behaviour of synthetic genetic circuits within a single cell or across a cell population more reliable, predictable and robust to perturbations. The description especially highlights technical challenges that uniquely arise from the need to implement control designs within a new hardware setting, along with implemented or proposed solutions. Some engineering solutions employing complex feedback control schemes are also described, which, however, still require a deeper theoretical analysis of stability, performance and robustness properties. Overall, this paper should help synthetic biologists become familiar with feedback control concepts as they can be used in their application area. At the same time, it should provide some domain knowledge to control theorists who wish to enter the rising and exciting field of synthetic biology. PMID:27440256

  15. Lethal and Sub-lethal Effects of UVB on Juvenile Biomphalaria glabrata (Mollusca: Pulmonata)

    PubMed Central

    Ruelas, Debbie S.; Karentz, Deneb; Sullivan, John T.

    2007-01-01

    Although Schistosoma mansoni occurs mainly in the tropics, where intense levels of solar radiation are present, the impact of ultraviolet (UV) light on schistosome transmission is not known. The purpose of this study was to investigate potential effects of UVB (290–320 nm) on juvenile Biomphalaria glabrata, the snail intermediate host of S. mansoni. Albino and wild type snails were exposed to doses of UVB from UV-fluorescent lamps, and the following were measured: survival, photoreactivation (light-mediated DNA repair), effects on feeding behavior, and morphological tissue abnormalities. Irradiation with UVB is lethal to B. glabrata in a dose-dependent manner. Exposure to white light subsequent to UVB irradiation enhances survival, probably by photoreactivation. The shell offers some, but not complete, protection. Experiments in which UVB transmittance through the shell was blocked with black nail polish suggest that injury to both exposed (headfoot) and shell-enclosed (mantle and visceral mass) tissues contributes to mortality in lethally-irradiated snails. Wild-type (pigmented) snails are less susceptible to lethal effects of UVB than albino snails, and they may be more capable of photoreactivation. UVB exposure inhibits snail feeding behavior, and causes tentacle forks and growths on the headfoot. Thus, UVB may influence the life cycle of S. mansoni by both lethal and sub-lethal damage to the snail intermediate host. However, the ability of snails to photoreactivate may mitigate these effects. PMID:16996081

  16. Structural Analysis of the Synthetic Duffy Binding Protein (DBP) Antigen DEKnull Relevant for Plasmodium vivax Malaria Vaccine Design

    PubMed Central

    Chen, Edwin; Salinas, Nichole D.; Ntumngia, Francis B.; Adams, John H.; Tolia, Niraj H.

    2015-01-01

    The Plasmodium vivax vaccine candidate Duffy Binding Protein (DBP) is a protein necessary for P. vivax invasion of reticulocytes. The polymorphic nature of DBP induces strain-specific immune responses that pose unique challenges for vaccine development. DEKnull is a synthetic DBP based antigen that has been engineered through mutation to enhance induction of blocking inhibitory antibodies. We determined the x-ray crystal structure of DEKnull to identify if any conformational changes had occurred upon mutation. Computational and experimental analyses assessed immunogenicity differences between DBP and DEKnull epitopes. Functional binding assays with monoclonal antibodies were used to interrogate the available epitopes in DEKnull. We demonstrate that DEKnull is structurally similar to the parental Sal1 DBP. The DEKnull mutations do not cause peptide backbone shifts within the polymorphic loop, or at either the DBP dimerization interface or DARC receptor binding pockets, two important structurally conserved protective epitope motifs. All B-cell epitopes, except for the mutated DEK motif, are conserved between DEKnull and DBP. The DEKnull protein retains binding to conformationally dependent inhibitory antibodies. DEKnull is an iterative improvement of DBP as a vaccine candidate. DEKnull has reduced immunogenicity to polymorphic regions responsible for strain-specific immunity while retaining conserved protein folds necessary for induction of strain-transcending blocking inhibitory antibodies. PMID:25793371

  17. [Capillary isotachophoresis--a new method in drug analysis. 2. Analytical capillary isotachophoresis of the synthetic peptide substance P].

    PubMed

    Jannasch, R

    1985-06-01

    For the synthetic undecapeptide substance P being object of actual pharmacological research and a potential peptide-drug experiments were carried out for the assessment of cation analyses by means of capillary isotachophoresis for the purpose of the development of test methods for pharmaceutical judgments of quality. Best conditions exist at a pH range from 6.2 to 6.3 of the leading electrolyte of the discontinuous electrolyte system by using of the counter ion morpholinoethansulfonic acid. The results confirm the high separation efficiency and rate of information of such analyses in the field of peptides. They served the control of purification methods for substance P as well as the determination of the contents in preparations for this peptide including simultaneously in case of need the preservative benzalkonium chloride with sufficient reproducibility (rel. S.D. 0.7-2.7% for substance P and less than or equal to 3% for benzalkonium chloride). It is also possible to estimate impurities and products of decomposition respectively down to the level of 0.1-1% and following that to make statements about the stability. PMID:2412242

  18. Performance Analysis of a Digital Image Synthesizer as a Counter-Measure Against Inverse Synthetic Aperture Radar

    NASA Astrophysics Data System (ADS)

    LeDantec, Fernando A.

    2002-09-01

    This thesis is concerned with the development of a model to analyze a Digital Image Synthesizer (DIS) integrated circuit designed to create false target images to deceive Inverse Synthetic Aperture Radar (ISAR). The DIS is able to recreate the scattering effect of a moving target by using appropriate phase and gain modulations on an intercepted ISAR chirp signal before retransmitting it with the proper time delay. The DIS signal processing and the ISAR compression of the modulated return are modeled to examine the range-Doppler profile of a synthesized false target image. The image is representative of the image that would appear on an ISAR display. ISAR image quality is used to evaluate different DIS architectures and bit formats. Evaluation of the image quality is based on the deviation from an infinite resolution false target image. The results obtained from evaluating different DIS architectures indicate that the design is tolerant of significant quantization errors. The model is used to validate the architecture of the integrated circuit being fabricated. Finally, various different ISAR integration times and pulse repetition frequencies are used to confirm the integrity of the model.

  19. Analysis of the synthetic pyrethroids, permethrin and 1(R)-phenothrin, in grain using a monoclonal antibody-based test

    SciTech Connect

    Skerritt, J.H.; Hill, A.S. ); McAdam, D.P. ); Stanker, L.H. )

    1992-07-01

    A monoclonal antibody generated to the synthetic pyrethroid-related hapten, (3-phenoxybenzyl)-2,2-dimethylcyclopropane-1, 3-dicarboxylate-protein conjugate, was used to develop assays for determinations of permethrin and 1(R)-phenothrin in wheat grain and flour milling fractions. The earlier 3-h assay was simplified using two approaches. The antibody was directly conjugated to the enzyme horseradish peroxidase (HRP), which removes a separate incubation and washing step from the assay. Also, an assay has been developed using microwell-bound monoclonal antibody and a HRP-labeled 3-phenoxybenzoic acid derivative. These assay formats have advantages in increased sensitivity and, in the case of the latter assay, accuracy with grain and flour samples. The most sensitive assay format could detect 1.5 ng/mL permethrin; 50% inhibition of antibody binding occurred at 10 ng/mL. These values corresponded to 75 and 500 ppb, respectively, in the original wheat sample. Methanol was the most effective pyrethroid extractant. Use of a simple cleanup procedure for ground grain extracts improved ELISA accuracy but could by omitted for screening purposes.

  20. Comparative analysis for detecting areas with building damage from several destructive earthquakes using satellite synthetic aperture radar images

    NASA Astrophysics Data System (ADS)

    Matsuoka, Masashi; Yamazaki, Fumio

    2010-11-01

    Earthquakes that have caused large-scale damage in developed areas, such as the 1994 Northridge and 1995 Kobe events, remind us of the importance of making quick damage assessments in order to facilitate the resumption of normal activities and restoration planning. Synthetic aperture radar (SAR) can be used to record physical aspects of the Earth's surface under any weather conditions, making it a powerful tool in the development of an applicable method for assessing damage following natural disasters. Detailed building damage data recorded on the ground following the 1995 Kobe earthquake may provide an invaluable opportunity to investigate the relationship between the backscattering properties and the degree of damage. This paper aims to investigate the differences between the backscattering coefficients and the correlations derived from pre- and post-earthquake SAR intensity images to smoothly detect areas with building damage. This method was then applied to SAR images recorded over the areas affected by the 1999 Kocaeli earthquake in Turkey, the 2001 Gujarat earthquake in India, and the 2003 Boumerdes earthquake in Algeria. The accuracy of the proposed method was examined and confirmed by comparing the results of the SAR analyses with the field survey data.

  1. Error in Radar-Derived Soil Moisture due to Roughness Parameterization: An Analysis Based on Synthetical Surface Profiles

    PubMed Central

    Lievens, Hans; Vernieuwe, Hilde; Álvarez-Mozos, Jesús; De Baets, Bernard; Verhoest, Niko E.C.

    2009-01-01

    In the past decades, many studies on soil moisture retrieval from SAR demonstrated a poor correlation between the top layer soil moisture content and observed backscatter coefficients, which mainly has been attributed to difficulties involved in the parameterization of surface roughness. The present paper describes a theoretical study, performed on synthetical surface profiles, which investigates how errors on roughness parameters are introduced by standard measurement techniques, and how they will propagate through the commonly used Integral Equation Model (IEM) into a corresponding soil moisture retrieval error for some of the currently most used SAR configurations. Key aspects influencing the error on the roughness parameterization and consequently on soil moisture retrieval are: the length of the surface profile, the number of profile measurements, the horizontal and vertical accuracy of profile measurements and the removal of trends along profiles. Moreover, it is found that soil moisture retrieval with C-band configuration generally is less sensitive to inaccuracies in roughness parameterization than retrieval with L-band configuration. PMID:22399956

  2. Analysis of ERS 1 synthetic aperture radar data of frozen lakes in northern Montana and implications for climate studies

    USGS Publications Warehouse

    Hall, Dorothy K.; Fagre, Daniel B.; Klasner, Fritz; Linebaugh, Gregg; Liston, Glen E.

    1994-01-01

    Lakes that freeze each winter are good indicators of regional climate change if key parameters, such as freeze-up and breakup date and maximum ice thickness, are measured over a decade-scale time frame. Synthetic aperture radar (SAR) satellite data have proven to be especially useful for measurement of climatologically significant parameters characteristic of frozen lakes. In this paper, five lakes in Glacier National Park, Montana, have been studied both in the field and using Earth Remote-Sensing Satellite (ERS) 1 SAR data during the 1992-1993 winter. The lakes are characterized by clear ice, sometimes with tubular or rounded bubbles, and often with a layer of snow ice on top of the clear ice. They are also often snow covered. Freeze-up is detected quite easily using ERS 1 SAR data as soon as a thin layer of ice forms. The effect of snow ice on the backscatter is thought to be significant but is, as yet, undetermined. On the five lakes studied, relative backscatter was found to increase with ice thickness until a maximum was reached in February. Breakup, an often ill-defined occurrence, is difficult to detect because surface water causes the SAR signal to be absorbed, thus masking the ice below. Comparison of the bubble structure of thaw lakes in northern Alaska with lakes in northern Montana has shown that the ice structure is quite different, and this difference may contribute to differential SAR signature evolution in the lakes of the two areas.

  3. RKN Lethal DB: A database for the identification of Root Knot Nematode (Meloidogyne spp.) candidate lethal genes

    PubMed Central

    Ismail, Ahmed; Matthews, Benjamin F; Alkharouf, Nadim W

    2012-01-01

    Root Knot nematode (RKN; Meloidogyne spp.) is one of the most devastating parasites that infect the roots of hundreds of plant species. RKN cannot live independently from their hosts and are the biggest contributors to the loss of the world's primary foods. RNAi gene silencing studies have demonstrated that there are fewer galls and galls are smaller when RNAi constructs targeted to silence certain RKN genes are expressed in plant roots. We conducted a comparative genomics analysis, comparing RKN genes of six species: Meloidogyne Arenaria, Meloidogyne Chitwoodi, Meloidogyne Hapla, Meloidogyne Incognita, Meloidogyne Javanica, and Meloidogyne Paranaensis to that of the free living nematode Caenorhabditis elegans, to identify candidate genes that will be lethal to RKN when silenced or mutated. Our analysis yielded a number of such candidate lethal genes in RKN, some of which have been tested and proven to be effective in soybean roots. A web based database was built to house and allow scientists to search the data. This database will be useful to scientists seeking to identify candidate genes as targets for gene silencing to confer resistance in plants to RKN. Availability The database can be accessed from http://bioinformatics.towson.edu/RKN/ PMID:23144556

  4. Lethal and non-lethal violence against women in Australia: measurement challenges, conceptual frameworks, and limitations in knowledge.

    PubMed

    McPhedran, Samara; Baker, Jeanine

    2012-08-01

    Understanding pathways from non-lethal violence to lethal violence between intimate partners is a notable challenge for both policy and practice in partner violence prevention. Of particular interest is whether lethal violence represents an "escalation" of violence from "low" to "high" risk over time, or is best predicted by specific behavioral "typologies" of perpetrators. Testing the "escalation" and "typology" theories is hampered in Australia by limitations in knowledge about non-lethal and lethal violence against women. This article discusses data limitations, measurement problems, and conceptual shortcomings, and suggests approaches to improving evidence quality in the field of violence prevention and risk assessment. PMID:23008430

  5. Preparation of a verifiable peptide-protein immunogen: direction-controlled conjugation of a synthetic fragment of the monitor peptide with myoglobin and application for sequence analysis.

    PubMed

    Iwai, K; Fukuoka, S; Fushiki, T; Kido, K; Sengoku, Y; Semba, T

    1988-06-01

    A useful method for preparing a synthetic peptide-carrying protein for specific antibody production was established. The monitor peptide is a trypsin-sensitive cholecystokinin-releasing peptide purified from rat pancreatic juice on the basis of its stimulatory activity toward pancreatic enzyme secretion. The NH2-terminus fragment of the monitor peptide (residues 1-14) was synthesized by a solid phase method. Cysteine at the COOH terminus of the fragment was conjugated with amino groups of myoglobin using a hetero-bifunctional reagent. Sequence analysis of the fragment-myoglobin conjugate indicated that the peptide/myoglobin conjugation ratio was about 1/1 (mol/mol). Antiserum against the conjugate from a rabbit effectively abolished the stimulatory activity of the monitor peptide in the rat small intestine. PMID:3407924

  6. Mutation induced extinction in finite populations: lethal mutagenesis and lethal isolation.

    PubMed

    Wylie, C Scott; Shakhnovich, Eugene I

    2012-01-01

    Reproduction is inherently risky, in part because genomic replication can introduce new mutations that are usually deleterious toward fitness. This risk is especially severe for organisms whose genomes replicate "semi-conservatively," e.g. viruses and bacteria, where no master copy of the genome is preserved. Lethal mutagenesis refers to extinction of populations due to an unbearably high mutation rate (U), and is important both theoretically and clinically, where drugs can extinguish pathogens by increasing their mutation rate. Previous theoretical models of lethal mutagenesis assume infinite population size (N). However, in addition to high U, small N can accelerate extinction by strengthening genetic drift and relaxing selection. Here, we examine how the time until extinction depends jointly on N and U. We first analytically compute the mean time until extinction (τ) in a simplistic model where all mutations are either lethal or neutral. The solution motivates the definition of two distinct regimes: a survival phase and an extinction phase, which differ dramatically in both how τ scales with N and in the coefficient of variation in time until extinction. Next, we perform stochastic population-genetics simulations on a realistic fitness landscape that both (i) features an epistatic distribution of fitness effects that agrees with experimental data on viruses and (ii) is based on the biophysics of protein folding. More specifically, we assume that mutations inflict fitness penalties proportional to the extent that they unfold proteins. We find that decreasing N can cause phase transition-like behavior from survival to extinction, which motivates the concept of "lethal isolation." Furthermore, we find that lethal mutagenesis and lethal isolation interact synergistically, which may have clinical implications for treating infections. Broadly, we conclude that stably folded proteins are only possible in ecological settings that support sufficiently large populations

  7. Joint full-waveform analysis of off-ground zero-offset ground penetrating radar and electromagnetic induction synthetic data for estimating soil electrical properties

    NASA Astrophysics Data System (ADS)

    Moghadas, D.; André, F.; Slob, E. C.; Vereecken, H.; Lambot, S.

    2010-09-01

    A joint analysis of full-waveform information content in ground penetrating radar (GPR) and electromagnetic induction (EMI) synthetic data was investigated to reconstruct the electrical properties of multilayered media. The GPR and EMI systems operate in zero-offset, off-ground mode and are designed using vector network analyser technology. The inverse problem is formulated in the least-squares sense. We compared four approaches for GPR and EMI data fusion. The two first techniques consisted of defining a single objective function, applying different weighting methods. As a first approach, we weighted the EMI and GPR data using the inverse of the data variance. The ideal point method was also employed as a second weighting scenario. The third approach is the naive Bayesian method and the fourth technique corresponds to GPR-EMI and EMI-GPR sequential inversions. Synthetic GPR and EMI data were generated for the particular case of a two-layered medium. Analysis of the objective function response surfaces from the two first approaches demonstrated the benefit of combining the two sources of information. However, due to the variations of the GPR and EMI model sensitivities with respect to the medium electrical properties, the formulation of an optimal objective function based on the weighting methods is not straightforward. While the Bayesian method relies on assumptions with respect to the statistical distribution of the parameters, it may constitute a relevant alternative for GPR and EMI data fusion. Sequential inversions of different configurations for a two layered medium show that in the case of high conductivity or permittivity for the first layer, the inversion scheme can not fully retrieve the soil hydrogeophysical parameters. But in the case of low permittivity and conductivity for the first layer, GPR-EMI inversion provides proper estimation of values compared to the EMI-GPR inversion.

  8. Lethal predators: psychopathic, sadistic, and sane.

    PubMed

    Ochberg, Frank M; Brantley, Alan C; Hare, R D; Houk, Peter D; Ianni, Robert; James, Earl; O'Toole, Mary Ellen; Saathoff, Gregory

    2003-01-01

    The violent criminals defined in this article are a small, exceptionally dangerous group of offenders designated by the authors as "lethal predators." They have a history of sexual predation, have killed at least once, and are mentally abnormal but legally sane. They are highly likely to keep killing as long as they are free. Laws permitting civil commitment of dangerous and mentally abnormal sexual predators after they have completed criminal prison sentences have been upheld by the U.S. Supreme Court. Such laws can provide a legal means of keeping these highly dangerous killers confined so they cannot kill again. PMID:14608825

  9. Lethal mobilization of DDT by cowbirds

    USGS Publications Warehouse

    Van Velzen, A.C.; Stiles, W.B.; Stickel, L.F.

    1972-01-01

    This study is an experimental demonstration of lethal mobilization of DDT by brown-headed cowbirds (Molothrus ater) and the effects of food deprivation on the distribution and loss of DDT, DDD, and DDE. The principal experimental group consisted of 20 birds fed a dietary dosage of 100 ppm of DDT for 13 days. After 2 days of full rations of untreated food, they were subjected to food restriction. Food was reduced to 43 percent of normal. Seven of the 20 birds died within 4 days. No birds died in the three control groups, treated as follows: ( 1 ) 20 birds fed 100 ppm DDT for 13 days and full rations of untreated food thereafter, (2) 20 birds fed only untreated food but subjected to food restriction, and (3) 20 birds fed full rations of untreated food throughout. In a pilot study, birds were fed 100, 200, or 300 ppm of DDT and subjected to two periods of food restriction, the first of these immediately after dosage ceased and the second 4 months later. DDT-dosed birds from all dosage levels died in each period of food restriction. Before the weight loss that accompanied food restriction, the brains of DDT-dosed birds had concentrations of DDT and DDD that were far below the lethal range. Concentrations increased rapidly to lethal levels. In these birds, DDT in carcasses decreased while DDD increased. DDT-dosed birds that died during food restriction lost 16 percent of their total body burden of DDT + DDD + DDE, 21 percent of their weight, and 81 percent of their fat. The DDT-dosed birds that were subjected to food restriction but survived lost a significantly greater proportion of their body burden of residues than similarly dosed birds not subjected to weight loss. Brain levels of DDT and DDD in birds that died during food restriction soon after dosage did not differ significantly from brain levels of birds that died in a period of food restriction 4 months after dosage. Concentrations of DDE were significantly higher in the latter group, although they were lower

  10. Statistical analysis of results of carcinogenicity studies of synthetic vitreous fibres at Research and Consulting Company, Geneva.

    PubMed

    Rossiter, C E; Chase, J R

    1995-10-01

    Five inhalation studies of synthetic vitreous fibres have recently investigated experimental tumorigenic responses to four different refractory ceramic fibres (RCF), two fibre glasses, one stone (rock) wool and one slag wool. Except for one RCF, the source materials were typical commercial products. Three studies included positive control groups exposed to chrysotile or crocidolite asbestos. The studies were conducted using state-of-the-art technologies for fibre size separation, fibre lofting and nose-only inhalation exposure. The target average fibre size was 20 microns long by 1 micron diameter. Hamsters exposed to a kaolin RCF yielded a mesothelioma rate of 38%, but no lung cancers. There were no tumours among the chrysotile-exposed hamsters. At the highest dose of 30 mg m-3 in rat studies, the commercial RCF all produced significant numbers of lung tumours, and some mesotheliomas. The fourth RCF, which had been heat-treated to simulate an after-service fibre, did not produce a significant excess of lung cancers, but did produce one mesothelioma. A rat multi-dose experiment with three lower doses of the kaolin RCF yielded one mesothelioma among 379 rats, but no excess of lung tumours. The overall dose-response relation for lung cancer did not appear to be linear, consistent with the possibility of a threshold close to the Maximum Tolerated Dose. No insulation wool (glass, stone or slag) exposure group had a lung tumour rate that differed statistically significantly from the tumour rate for the respective concurrent control groups, sham-exposed to filtered air. There was no significant difference in the total tumour rates between the four insulation wool groups and the control animals, and no significant dose-response relation above the respective sham-exposed control tumour rates. The total lung tumour rates for rats in both chrysotile and crocidolite exposure groups were significantly raised. One animal in each asbestos-exposed group developed a mesothelioma

  11. Free energy analysis of conductivity and charge selectivity of M2GlyR-derived synthetic channels.

    PubMed

    Chen, Jianhan; Tomich, John M

    2014-09-01

    Significant progresses have been made in the design, synthesis, modeling and in vitro testing of channel-forming peptides derived from the second transmembrane domain of the α-subunit of the glycine receptor (GlyR). The latest designs, including p22 (KKKKP ARVGL GITTV LTMTT QS), are highly soluble in water with minimal aggregation propensity and insert efficiently into cell membranes to form highly conductive ion channels. The last obstacle to a potential lead sequence for channel replacement treatment of CF patients is achieving adequate chloride selectivity. We have performed free energy simulation to analyze the conductance and charge selectivity of M2GlyR-derived synthetic channels. The results reveal that the pentameric p22 pore is non-selective. Moderate barriers for permeation of both K(+) and Cl(-) are dominated by the desolvation cost. Despite previous evidence suggesting a potential role of threonine side chains in anion selectivity, the hydroxyl group is not a good surrogate of water for coordinating these ions. We have also tested initial ideas of introducing additional rings of positive changes to various positions along the pore to increase anion selectivity. The results support the feasibility of achieving anion selectivity by modifying the electrostatic properties of the pore, but at the same time suggest that the peptide assembly and pore topology may also be dramatically modified, which could abolish the effects of modified electrostatics on anion selectivity. This was confirmed by subsequent two-electrode voltage clamp measurements showing that none of the tested mono-, di- and tri-Dap substituted sequences was selective. The current study thus highlights the importance of controlling channel topology besides modifying pore electrostatics for achieving anion selectivity. Several strategies are now being explored in our continued efforts to design an anion selective peptide channel with suitable biophysical, physiological and pharmacological

  12. Synthetic cathinone abuse

    PubMed Central

    Capriola, Michael

    2013-01-01

    The abuse of synthetic cathinones, widely known as bath salts, has been increasing since the mid-2000s. These substances are derivatives of the naturally occurring compound cathinone, which is the primary psychoactive component of khat. The toxicity of synthetic cathinones includes significant sympathomimetic effects, as well as psychosis, agitation, aggression, and sometimes violent and bizarre behavior. Mephedrone and methylenedioxypyrovalerone are currently the predominantly abused synthetic cathinones. PMID:23869180

  13. Evolvable synthetic neural system

    NASA Technical Reports Server (NTRS)

    Curtis, Steven A. (Inventor)

    2009-01-01

    An evolvable synthetic neural system includes an evolvable neural interface operably coupled to at least one neural basis function. Each neural basis function includes an evolvable neural interface operably coupled to a heuristic neural system to perform high-level functions and an autonomic neural system to perform low-level functions. In some embodiments, the evolvable synthetic neural system is operably coupled to one or more evolvable synthetic neural systems in a hierarchy.

  14. [SYNTHETIC PEPTIDE VACCINES].

    PubMed

    Sergeyev, O V; Barinsky, I F

    2016-01-01

    An update on the development and trials of synthetic peptide vaccines is reviewed. The review considers the successful examples of specific protection as a result of immunization with synthetic peptides using various protocols. The importance of conformation for the immunogenicity of the peptide is pointed out. An alternative strategy of the protection of the organism against the infection using synthetic peptides is suggested. PMID:27145593

  15. Bacillus anthracis Lethal Toxin Reduces Human Alveolar Epithelial Barrier Function

    PubMed Central

    Langer, Marybeth; Duggan, Elizabeth Stewart; Booth, John Leland; Patel, Vineet Indrajit; Zander, Ryan A.; Silasi-Mansat, Robert; Ramani, Vijay; Veres, Tibor Zoltan; Prenzler, Frauke; Sewald, Katherina; Williams, Daniel M.; Coggeshall, Kenneth Mark; Awasthi, Shanjana; Lupu, Florea; Burian, Dennis; Ballard, Jimmy Dale; Braun, Armin

    2012-01-01

    The lung is the site of entry for Bacillus anthracis in inhalation anthrax, the deadliest form of the disease. Bacillus anthracis produces virulence toxins required for disease. Alveolar macrophages were considered the primary target of the Bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target of Bacillus anthracis lethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination of Bacillus anthracis from the lung in early disease and promoting edema in late stages of the illness. PMID:23027535

  16. Prothrombin complex concentrate use in coagulopathy of lethal brain injuries increases organ donation.

    PubMed

    Joseph, Bellal; Aziz, Hassan; Pandit, Viraj; Hays, Daniel; Kulvatunyou, Narong; Tang, Andrew; Wynne, Julie; O' Keeffe, Terence; Green, Donald J; Friese, Randall S; Gruessner, Rainer; Rhee, Peter

    2014-04-01

    Coagulopathy is a defined barrier for organ donation in patients with lethal traumatic brain injuries. The purpose of this study was to document our experience with the use of prothrombin complex concentrate (PCC) to facilitate organ donation in patients with lethal traumatic brain injuries. We performed a 4-year retrospective analysis of all patients with devastating gunshot wounds to the brain. The data were analyzed for demographics, change in international normalized ratio (INR), and subsequent organ donation. The primary end point was organ donation. Eighty-eight patients with lethal traumatic brain injury were identified from the trauma registry of whom 13 were coagulopathic at the time of admission (mean INR 2.2 ± 0.8). Of these 13 patients, 10 patients received PCC in an effort to reverse their coagulopathy. Mean INR before PCC administration was 2.01 ± 0.7 and 1.1 ± 0.7 after administration (P < 0.006). Correction of coagulopathy was attained in 70 per cent (seven of 10) patients. Of these seven patients, consent for donation was obtained in six patients and resulted in 19 solid organs being procured. The cost of PCC per patient was $1022 ± 544. PCC effectively reveres coagulopathy associated with lethal traumatic brain injury and enabled patients to proceed to organ donation. Although various methodologies exist for the treatment of coagulopathy to facilitate organ donation, PCC provides a rapid and cost-effective therapy for reversal of coagulopathy in patients with lethal traumatic brain injuries. PMID:24887662

  17. Characterizing synthetic gypsum

    SciTech Connect

    Henkels, P.J.; Gaynor, J.C.

    1996-10-01

    Each gypsum wallboard manufacturer has developed its own general guidelines for synthetic gypsum. The guidelines vary accordingly for each manufacturer and are often modified to suite a particular source and end use. In addition, the physical and chemical properties of synthetic gypsum are characterized by several proprietary and published test methods. Characterizing a synthetic gypsum and determining its acceptability is a time consuming process and can be confusing, particularly to those outside the gypsum wallboard industry. This paper describes some of the more important characteristics and practical aspects of synthetic gypsum usage based on USG`s extensive experience in wall board manufacture.

  18. [The forensic medical assessment of injury prevention characteristics of limited-lethality weapons].

    PubMed

    Makarov, I Iu; Kovalev, A V; Kutsenko, K I; Evteeva, I A

    2012-01-01

    The results of analysis of the data presented in the special literature and normative legal documentation indicate that the forensic medical aspects of the injuries inflicted by gunshots of limited-lethality weapons either need to be clarified or remain virtually unexplored. There is the long overdue necessity to consolidate efforts of forensic medical experts and specialists from other agencies and institutions for the comprehensive solution of the problems related to the injury prevention characteristics of limited-lethality weapons and participation in the interdepartmental activities for the improvement of the legislation regulating weapon trafficking. PMID:23272558

  19. Relative toxicity testing of spacecraft materials. 1: Spacecraft materials. [lethality of pyrolysates

    NASA Technical Reports Server (NTRS)

    Lawrence, W. H.

    1980-01-01

    In chamber thermodegradation procedures were used to access the lethality to rats of the pyrolysis/combustion products of three foams, an adhesive backed metallic tape and RTV silicone rubber adhesive sealant used in spacecraft construction. The role of carbon monoxide in the overall pyrolysate toxicity was also investigated. Post exposure observation of the rats, histological evaluation of selected organs, carbon monoxide concentration in the chamber atmosphere during exposure and the percent carboxyhemoglobin in the animals expiring in the chamber are discussed. Thermogravimetric analysis and dosage response results are given. The lethal effect of the RTV silicon appears to be due to physical obstruction of the respiratory system by particulate matter from pyrolysis.

  20. Potential lethal and non-lethal effects of predators on dispersal of spider mites.

    PubMed

    Otsuki, Hatsune; Yano, Shuichi

    2014-11-01

    Predators can affect prey dispersal lethally by direct consumption or non-lethally by making prey hesitate to disperse. These lethal and non-lethal effects are detectable only in systems where prey can disperse between multiple patches. However, most studies have drawn their conclusions concerning the ability of predatory mites to suppress spider mites based on observations of their interactions on a single patch or on heavily infested host plants where spider mites could hardly disperse toward intact patches. In these systems, specialist predatory mites that penetrate protective webs produced by spider mites quickly suppress the spider mites, whereas generalist predators that cannot penetrate the webs were ineffective. By using a connected patch system, we revealed that a generalist ant, Pristomyrmex punctatus Mayr (Hymenoptera: Formicidae), effectively prevented dispersal of spider mites, Tetranychus kanzawai Kishida (Acari: Tetranychidae), by directly consuming dispersing individuals. We also revealed that a generalist predatory mite, Euseius sojaensis Ehara (Acari: Phytoseiidae), prevented between-patch dispersal of T. kanzawai by making them hesitate to disperse. In contrast, a specialist phytoseiid predatory mite, Neoseiulus womersleyi Schicha, allowed spider mites to escape an initial patch, increasing the number of colonized patches within the system. Our results suggest that ants and generalist predatory mites can effectively suppress Tetranychus species under some conditions, and should receive more attention as agents for conservation biological control in agroecosystems. PMID:24867061

  1. [Acute lethal alcohol intoxication (author's transl)].

    PubMed

    Kringsholm, B

    1976-01-01

    In 14,744 autopsy cases from an 18-year period 92 cases (of which 7 were ruled out because of decomposition were observed in which death was supposed to be due to direct acute alcoholic intoxication. In the police reports 81 persons were designated as chronic alcoholics or abusers of spirits. The blood alcohol level ranged between 2.04 and 4.92 o/oo. The cases studied were divided into two groups, one with low and the other with high lethal alcohol level. Fatty liver and cirrhosis were found with identical frequency in the two groups, whereas cardiac hypertrophy of obscure origin occurred markedly more often in the group with low lethal blood alcohol level. On the basis the possible mechanism of death in the cases with cardiac hypertrophy is discussed. Finally, the relation between the blood and urine alcohol concentrations observed in 72 cases is discussed. On the assumption that the water phase of the blood was 75 per cent of the total blood, death occurred in the persons without cardiac hypertrophy with fairly identical frequency either in the phase of absorption or the phase of elimination, whereas in the persons with cardiac hypertrophy death most often occurred in the phase of absorption. These statements should, however, be taken with some reservation, partly because the water phase of the blood may vary considerably post mortem (60-90 per cent) and partly because the urine alcohol concentration depends on serval variable factors. PMID:137612

  2. Tityus serrulatus venom--A lethal cocktail.

    PubMed

    Pucca, Manuela Berto; Cerni, Felipe Augusto; Pinheiro Junior, Ernesto Lopes; Bordon, Karla de Castro Figueiredo; Amorim, Fernanda Gobbi; Cordeiro, Francielle Almeida; Longhim, Heloisa Tavoni; Cremonez, Caroline Marroni; Oliveira, Guilherme Honda; Arantes, Eliane Candiani

    2015-12-15

    Tityus serrulatus (Ts) is the main scorpion species of medical importance in Brazil. Ts venom is composed of several compounds such as mucus, inorganic salts, lipids, amines, nucleotides, enzymes, kallikrein inhibitor, natriuretic peptide, proteins with high molecular mass, peptides, free amino acids and neurotoxins. Neurotoxins are considered the most responsible for the envenoming syndrome due to their pharmacological action on ion channels such as voltage-gated sodium (Nav) and potassium (Kv) channels. The major goal of this review is to present important advances in Ts envenoming research, correlating both the crude Ts venom and isolated toxins with alterations observed in all human systems. The most remarkable event lies in the Ts induced massive releasing of neurotransmitters influencing, directly or indirectly, the entire body. Ts venom proved to extremely affect nervous and muscular systems, to modulate the immune system, to induce cardiac disorders, to cause pulmonary edema, to decrease urinary flow and to alter endocrine, exocrine, reproductive, integumentary, skeletal and digestive functions. Therefore, Ts venom possesses toxins affecting all anatomic systems, making it a lethal cocktail. However, its low lethality may be due to the low venom mass injected, to the different venom compositions, the body characteristics and health conditions of the victim and the local of Ts sting. Furthermore, we also described the different treatments employed during envenoming cases. In particular, throughout the review, an effort will be made to provide information from an extensive documented studies concerning Ts venom in vitro, in animals and in humans (a total of 151 references). PMID:26522893

  3. Antenatal diagnosis of lethal skeletal dysplasias.

    PubMed

    Tretter, A E; Saunders, R C; Meyers, C M; Dungan, J S; Grumbach, K; Sun, C C; Campbell, A B; Wulfsberg, E A

    1998-02-17

    Lethal skeletal dysplasias (LSD) are a heterogeneous group of rare but important genetic disorders characterized by abnormal growth and development of bone and cartilage. We describe the diagnosis and outcome of 29 cases of lethal skeletal dysplasias evaluated between January 1989 and December 1996 at the University of Maryland Medical Center and the Ultrasound Institute of Baltimore. Two cases presented at delivery with no prenatal care while the remaining 27 cases were identified by antenatal sonography. Final diagnoses included thanatophoric dysplasia (14), osteogenesis imperfecta, type II (6), achondrogenesis (2), short rib syndromes (3), campomelic syndrome (2), atelosteogenesis (1), and no evidence of a skeletal dysplasia (1). Twenty out of 27 pregnancies were terminated with an average at detection of 21.6 weeks. The other 7 pregnancies that went on to deliver had an average age at detection of 29.2 weeks. Fetal abnormalities in the terminated pregnancies were identified at a significantly earlier gestational age (P = 0.0016) than the pregnancies that continued. While the identification of LSD by sonography was excellent (26/27), only 13/27 (48%) were given an accurate specific antenatal diagnosis. In 8/14 (57%) cases with an inaccurate or nonspecific diagnosis there was a significant or crucial change in the genetic counseling. Thus, while antenatal sonography is an excellent method for discovering LSD, clinical examination, radiographs, and autopsy are mandatory for making a specific diagnosis. PMID:9489797

  4. Lethal outcomes in Klippel-Trenaunay syndrome.

    PubMed

    Karunamurthy, Arivarasan; Pantanowitz, Liron; Lepe, Jorge Guzman; Reyes-Múgica, Miguel

    2013-01-01

    Klippel-Trenaunay syndrome (KTS) is an uncommon congenital angiodysplasia that manifests in infancy and is characterized by venous and lymphatic malformations of the skin, soft tissue, and bone causing limb hypertrophy. We report 2 patients with long-term KTS who developed lethal complications from uncommon and unusual manifestations. The 1st patient was a female with KTS who at 2 years of age underwent a below-the-knee amputation for a massively hypertrophied and malformed left foot. Two years later she required additional surgical removal of vascular malformations involving her left calf with extension to the groin, pubis, and ipsilateral abdomen. Fifteen years later she underwent splenectomy (400 g) revealing multifocal, cystically dilated vascular channels distorting the splenic architecture and died suddenly of massive intra-abdominal hemorrhage on the 2nd postoperative day. The 2nd patient was a 72-year-old male with long-standing KTS who presented with debilitating chronic penile and scrotal edema. Surgical excision of his lymphedematous scrotal and penile skin revealed a low-grade angiosarcoma arising in the setting of chronic lymphedema. The patient died shortly after surgery from massive hemorrhage due to traumatic rupture of malformed leg vessels. KTS may lead to significant morbidity and mortality, and pathologic consequences from long-term KTS have been rarely reported. These cases illustrate the risk of lethal hemorrhage, organomegaly from protracted vascular malformation, and development of vascular neoplasia associated with chronic lymphedema in KTS. PMID:23915076

  5. Enhancing CHK1 inhibitor lethality in glioblastoma.

    PubMed

    Tang, Yong; Dai, Yun; Grant, Steven; Dent, Paul

    2012-04-01

    The present studies were initiated to determine whether inhibitors of MEK1/2 or SRC signaling, respectively, enhance CHK1 inhibitor lethality in primary human glioblastoma cells. Multiple MEK1/2 inhibitors (CI-1040 (PD184352); AZD6244 (ARRY-142886)) interacted with multiple CHK1 inhibitors (UCN-01, AZD7762) to kill multiple primary human glioma cell isolates that have a diverse set of genetic alterations typically found in the disease. Inhibition of SRC family proteins also enhanced CHK1 inhibitor lethality. Combined treatment of glioma cells with (MEK1/2 + CHK1) inhibitors enhanced radiosensitivity. Combined (MEK1/2 + CHK1) inhibitor treatment led to dephosphorylation of ERK1/2 and S6 ribosomal protein, whereas the phosphorylation of JNK and p38 was increased. MEK1/2 + CHK1 inhibitor-stimulated cell death was associated with the cleavage of pro-caspases 3 and 7 as well as the caspase substrate (PARP). We also observed activation of pro-apoptotic BCL-2 effector proteins BAK and BAX and reduced levels of pro-survival BCL-2 family protein BCL-XL. Overexpression of BCL-XL alleviated but did not completely abolish MEK1/2 + CHK1 inhibitor cytotoxicity in GBM cells. These findings argue that multiple inhibitors of the SRC-MEK pathway have the potential to interact with multiple CHK1 inhibitors to kill glioma cells. PMID:22313687

  6. Feature extraction and fusion for protein structure identification in cryo-electron microscopic images using independent component analysis and the projection-slice synthetic filter

    NASA Astrophysics Data System (ADS)

    Riasati, Vahid R.; Braunreiter, Dennis

    2006-04-01

    In this paper we utilize the Projection-Slice Synthetic Discriminant Function Filters, PSDF, in concert with an Independent Component Analysis technique to simultaneously reduce the data set that represents each of the training images and to emphasize subtle differences in each of the training images. These differences are encoded into the PSDF in order to improve the filter sensitivity for the recognition and identification of protein images formed from a cryo-electron microscopic imaging process. The PSDF and Independent Component Analysis provide a premise not only for the identification of the class of structures under consideration, but also for detecting the orientation of the structures in these images. The protein structures found in cryo-electron microscopic imaging represent a class of objects that have low resolution and contrast and subtle variation. This poses a challenge in design of filters to recognize these structures due to false targets that often have similar characteristics as the protein structures. The incorporation of a component analysis and eigen values conditioning in forming the filter provides an enhanced approach of de-correlating images prior to their incorporation into the filter. We present our method of filter synthesis and the results of the application of this modified filter to a protein structure recognition problem.

  7. Characterization of desmoglein-3 epitope region peptides as synthetic antigens: analysis of their in vitro T cell stimulating efficacy, cytotoxicity, stability, and their conformational features.

    PubMed

    Szabados, Hajnalka; Uray, Katalin; Majer, Zsuzsa; Silló, Pálma; Kárpáti, Sarolta; Hudecz, Ferenc; Bősze, Szilvia

    2015-09-01

    Desmoglein-3 (Dsg3) adhesion protein is the main target of autoantibodies and autoreactive T cells in Pemphigus vulgaris (PV) autoimmune skin disorder. Several mapping studies of Dsg3 T cell epitope regions were performed, and based on those data, we designed and synthesized four peptide series corresponding to Dsg3 T cell epitope regions. Each peptide series consists of a 17mer full-length peptide (Dsg3/189-205, Dsg3/206-222, Dsg3/342-358, and Dsg3/761-777) and its N-terminally truncated derivatives, resulting in 15 peptides altogether. The peptides were prepared on solid phase and were chemically characterized. In order to establish a structure-activity relationship, the solution conformation of the synthetic peptides has been investigated using electronic circular dichroism spectroscopy. The in vitro T cell stimulating efficacy of the peptides has been determined on peripheral blood mononuclear cells isolated from whole blood of PV patients and also from healthy donors. After 20 h of stimulation, the interferon (IFN)-γ content of the supernatants was measured by enzyme-linked immunosorbent assay. In the in vitro conditions, peptides were stable and non-cytotoxic. The in vitro IFN-γ production profile of healthy donors and PV patients, induced by peptides as synthetic antigens, was markedly different. The most unambiguous differences were observed after stimulation with 17mer peptide Dsg3/342-358, and three truncated derivatives from two other peptide series, namely, peptides Dsg3/192-205, Dsg3/763-777, and Dsg3/764-777. Comparative analysis of in vitro activity and the capability of oligopeptides to form ordered or unordered secondary structure showed that peptides bearing high solvent sensibility and backbone flexibility were the most capable to distinguish between healthy and PV donors. PMID:26250896

  8. Synthetic lethal screening with small molecule inhibitors provides a pathway to rational combination therapies for melanoma

    PubMed Central

    Roller, Devin; Axelrod, Mark; Capaldo, Brian; Jensen, Karin; Mackey, Aaron; Weber, Michael J; Gioeli, Daniel

    2012-01-01

    Recent data demonstrate that extracellular signals are transmitted through a network of proteins rather than hierarchical signaling pathways suggesting why inhibition of a single component of a canonical pathway is insufficient for the treatment of cancer. The biological outcome of signaling through a network is inherently more robust and resistant to inhibition of a single network component. In this study, we performed a functional chemical genetic screen to identify novel interactions between signaling inhibitors that would not be predicted based on our current understanding of signaling networks. We screened over 300 drug combinations in nine melanoma cell lines and have identified pairs of compounds that show synergistic cytotoxicity. The synergistic cytotoxicities identified did not correlate with the known RAS and BRAF mutational status of the melanoma cell lines. Among the most robust results was synergy between sorafenib, a multi-kinase inhibitor with activity against RAF, and diclofenac, a non-steroidal anti-inflammatory drug (NSAID). Drug substitution experiments using the NSAIDs celecoxib and ibuprofen or the MEK inhibitor PD325901 and the RAF inhibitor RAF265 suggest that inhibition of cyclooxygenase (COX) and MAP kinase signaling are targets for the synergistic cytotoxicity of sorafenib and diclofenac. Co-treatment with sorafenib and diclofenac interrupts a positive feedback signaling loop involving ERK, cPLA2, and COX. Genome-wide expression profiling demonstrates synergy-specific down-regulation of survival-related genes. This study has uncovered novel functional drug combinations and suggests that the underlying signaling networks that control responses to targeted agents can vary substantially depending on unexplored components of the cell genotype. PMID:22962324

  9. Autophagy induction causes a synthetic lethal sensitization to ribonucleotide reductase inhibition in breast cancer cells

    PubMed Central

    Chen, Yun-Ru; Tsou, Brittany; Hu, Shuya; Ma, Huimin; Liu, Xiyong; Yen, Yun; Ann, David K.

    2016-01-01

    Macroautophagy can promote cellular survival or death depending on the cellular context and its extent. We hypothesized that autophagy induction would synergize with a therapeutic agent targeting the autophagic cargo. To test this hypothesis, we treated breast cancer MDA-MB-231 cells with tamoxifen (TMX), which induces autophagy through an estrogen receptor-independent pathway. Induction of autophagy reduced cellular levels of RRM2, a subunit of ribonucleotide reductase (RR), the rate limiting enzyme in the production of deoxyribonucleotide triphosphates (dNTPs). This autophagy inducer was combined with COH29, an inhibitor developed in our laboratory that targets RR through a novel mechanism. The combination therapy showed synergistic effects on cytotoxicity in vitro and in an in vivo xenograft model. This cytotoxicity was blocked by knockdown of the autophagy protein ATG5 or addition of chloroquine, an autophagy inhibitor. The combined therapy also induced dNTP depletion and massive genomic instability, leading us to hypothesize that combining autophagy induction with RR inhibition can lead to mitotic catastrophe in rapidly dividing cells. We propose that this TMX + COH29 combined therapy may have clinical benefit. Furthermore, autophagy induction may be a general mechanism for augmenting the effects of chemotherapeutic agents PMID:26675256

  10. Lethal domestic violence in eastern North Carolina.

    PubMed

    Gilliland, M G; Spence, P R; Spence, R L

    2000-01-01

    Strategies for preventing domestic violence can be tailored to a particular geographic or socioeconomic area if the patterns of domestic violence in the area are known. National statistics, although widely available, may not be applicable to a specific region. We reviewed homicide deaths in Eastern North Carolina between 1978 and 1999 to identify patterns in this rural area. Approximately 20% of the homicide deaths in eastern North Carolina are caused by intimate partners. Women accounted for 53% of the victims in 1976, similar to national figures but not rising to 72% as seen nationally in 1998. Latinos are an increasing presence in the area, but had only one recorded episode of lethal violence against an intimate partner. Gunshots accounted for most of the deaths (59% in men, 72% in women). Knowledge of such patterns can assist in selecting prevention strategies for this particular area. Over the last 25 years increasing attention has been devoted to domestic violence (DV), initially defined as abuse committed against a spouse, former spouse, fiancée, boy- or girlfriend, or cohabitant. As time has passed, the definition has been broadened to include other family members--elders, children, and siblings. The Centers for Disease Control and Prevention (CDC) now uses the term "intimate partner violence" for intentional emotional or physical abuse inflicted by a spouse, ex-spouse, a present or former boy- or girlfriend, or date. For the purposes of this paper, we consider DV interchangeable with intimate partner violence. There has been a national concern that abusive events are under-reported. The National Crime Victimization Survey, an anonymous household survey, indicated nearly 1 million incidents of non-lethal intimate partner violence per year between 1992 and 1996. The number decreased from 1.1 million in 1993 to 840,000 in 1996. Attempts to validate such data for a given geographic area often require subjects to violate anonymity--this may account for lower

  11. The Spatial Concentration of Southern Whites and Argument-Based Lethal Violence

    ERIC Educational Resources Information Center

    Lee, Matthew R.; Shihadeh, Edward S.

    2009-01-01

    This analysis examines how the spatial concentration of Southern whites is associated with white argument-based lethal violence. Using a well-known measure of spatial segregation (V, the adjusted P* index) among Southern-born whites in U.S. counties in 2000, the results reveal that the spatial concentration of Southern-born whites is only…

  12. Designing synthetic biology.

    PubMed

    Agapakis, Christina M

    2014-03-21

    Synthetic biology is frequently defined as the application of engineering design principles to biology. Such principles are intended to streamline the practice of biological engineering, to shorten the time required to design, build, and test synthetic gene networks. This streamlining of iterative design cycles can facilitate the future construction of biological systems for a range of applications in the production of fuels, foods, materials, and medicines. The promise of these potential applications as well as the emphasis on design has prompted critical reflection on synthetic biology from design theorists and practicing designers from many fields, who can bring valuable perspectives to the discipline. While interdisciplinary connections between biologists and engineers have built synthetic biology via the science and the technology of biology, interdisciplinary collaboration with artists, designers, and social theorists can provide insight on the connections between technology and society. Such collaborations can open up new avenues and new principles for research and design, as well as shed new light on the challenging context-dependence-both biological and social-that face living technologies at many scales. This review is inspired by the session titled "Design and Synthetic Biology: Connecting People and Technology" at Synthetic Biology 6.0 and covers a range of literature on design practice in synthetic biology and beyond. Critical engagement with how design is used to shape the discipline opens up new possibilities for how we might design the future of synthetic biology. PMID:24156739

  13. Synthetic facial implants.

    PubMed

    Quatela, Vito C; Chow, Jen

    2008-02-01

    This article presents a range of synthetic implant materials for use in facial plastic surgery. The authors discuss alternatives to autogenous tissue transfer in terms of biocompatibility, technique, complications, controversies, and cautions. The reader is presented information about a range of synthetic implant materials such as silicone, polyester fiber, polyamide mesh, metal, polyethylene, polyacrylamide gel, hydroxyapatite, polylactic acid, collagen, and others. PMID:18063244

  14. Variable Synthetic Capacitance

    NASA Technical Reports Server (NTRS)

    Kleinberg, L. L.

    1986-01-01

    Feedback amplifier circuit synthesizes electronically variable capacitance. Variable Synthetic Capacitor is amplifier circuit with follower/feedback configuration. Effective input capacitance depends on input set current. If synthetic capacitor is connected across resonant element of oscillator, oscillator frequency controlled via input set current. Circuit especially suitable for fine frequency adjustments of piezoelectric-crystal or inductor/capacitor resonant oscillators.

  15. Testing of candidate non-lethal sampling methods for detection of Renibacterium salmoninarum in juvenile Chinook salmon Oncorhynchus tshawytscha

    USGS Publications Warehouse

    Elliott, Diane G.; McKibben, Constance L.; Conway, Carla M.; Purcell, Maureen K.; Chase, Dorothy M.; Applegate, Lynn M.

    2015-01-01

    Non-lethal pathogen testing can be a useful tool for fish disease research and management. Our research objectives were to determine if (1) fin clips, gill snips, surface mucus scrapings, blood draws, or kidney biopsies could be obtained non-lethally from 3 to 15 g Chinook salmon Oncorhynchus tshawytscha, (2) non-lethal samples could accurately discriminate between fish exposed to the bacterial kidney disease agent Renibacterium salmoninarum and non-exposed fish, and (3) non-lethal samples could serve as proxies for lethal kidney samples to assess infection intensity. Blood draws and kidney biopsies caused ≥5% post-sampling mortality (Objective 1) and may be appropriate only for larger fish, but the other sample types were non-lethal. Sampling was performed over 21 wk following R. salmoninarum immersion challenge of fish from 2 stocks (Objectives 2 and 3), and nested PCR (nPCR) and real-time quantitative PCR (qPCR) results from candidate non-lethal samples were compared with kidney tissue analysis by nPCR, qPCR, bacteriological culture, enzyme-linked immunosorbent assay (ELISA), fluorescent antibody test (FAT) and histopathology/immunohistochemistry. R. salmoninarum was detected by PCR in >50% of fin, gill, and mucus samples from challenged fish. Mucus qPCR was the only non-lethal assay exhibiting both diagnostic sensitivity and specificity estimates >90% for distinguishing between R. salmoninarum-exposed and non-exposed fish and was the best candidate for use as an alternative to lethal kidney sample testing. Mucus qPCR R. salmoninarum quantity estimates reflected changes in kidney bacterial load estimates, as evidenced by significant positive correlations with kidney R. salmoninaruminfection intensity scores at all sample times and in both fish stocks, and were not significantly impacted by environmentalR. salmoninarum concentrations.

  16. Testing of candidate non-lethal sampling methods for detection of Renibacterium salmoninarum in juvenile Chinook salmon Oncorhynchus tshawytscha.

    PubMed

    Elliott, Diane G; McKibben, Constance L; Conway, Carla M; Purcell, Maureen K; Chase, Dorothy M; Applegate, LynnMarie J

    2015-05-11

    Non-lethal pathogen testing can be a useful tool for fish disease research and management. Our research objectives were to determine if (1) fin clips, gill snips, surface mucus scrapings, blood draws, or kidney biopsies could be obtained non-lethally from 3 to 15 g Chinook salmon Oncorhynchus tshawytscha, (2) non-lethal samples could accurately discriminate between fish exposed to the bacterial kidney disease agent Renibacterium salmoninarum and non-exposed fish, and (3) non-lethal samples could serve as proxies for lethal kidney samples to assess infection intensity. Blood draws and kidney biopsies caused ≥5% post-sampling mortality (Objective 1) and may be appropriate only for larger fish, but the other sample types were non-lethal. Sampling was performed over 21 wk following R. salmoninarum immersion challenge of fish from 2 stocks (Objectives 2 and 3), and nested PCR (nPCR) and real-time quantitative PCR (qPCR) results from candidate non-lethal samples were compared with kidney tissue analysis by nPCR, qPCR, bacteriological culture, enzyme-linked immunosorbent assay (ELISA), fluorescent antibody test (FAT) and histopathology/immunohistochemistry. R. salmoninarum was detected by PCR in >50% of fin, gill, and mucus samples from challenged fish. Mucus qPCR was the only non-lethal assay exhibiting both diagnostic sensitivity and specificity estimates>90% for distinguishing between R. salmoninarum-exposed and non-exposed fish and was the best candidate for use as an alternative to lethal kidney sample testing. Mucus qPCR R. salmoninarum quantity estimates reflected changes in kidney bacterial load estimates, as evidenced by significant positive correlations with kidney R. salmoninarum infection intensity scores at all sample times and in both fish stocks, and were not significantly impacted by environmental R. salmoninarum concentrations. PMID:25958804

  17. Apparent lethal concentrations of pyrolysis products of some polymeric materials

    NASA Technical Reports Server (NTRS)

    Hilado, C. J.; Marcussen, W. H.; Furst, A.; Kourtides, D. A.; Parker, J. A.

    1976-01-01

    Thirty-nine samples of polymeric materials were evaluated to determine the apparent lethal concentrations of their pyrolysis products. The materials were compared on the basis of the apparent lethal concentration for 50 percent of the test animals. Relative toxicity rankings based o apparent lethal concentration values can differ significantly depending on whether they are based on weight of sample charged or weight of sample pyrolyzed. The ranking of polyphenylene sulfide is particularly sensitive to this difference.

  18. Interferometric synthetic aperture microscopy

    NASA Astrophysics Data System (ADS)

    Ralston, Tyler S.; Marks, Daniel L.; Scott Carney, P.; Boppart, Stephen A.

    2007-02-01

    State-of-the-art methods in high-resolution three-dimensional optical microscopy require that the focus be scanned through the entire region of interest. However, an analysis of the physics of the light-sample interaction reveals that the Fourier-space coverage is independent of depth. Here we show that, by solving the inverse scattering problem for interference microscopy, computed reconstruction yields volumes with a resolution in all planes that is equivalent to the resolution achieved only at the focal plane for conventional high-resolution microscopy. In short, the entire illuminated volume has spatially invariant resolution, thus eliminating the compromise between resolution and depth of field. We describe and demonstrate a novel computational image-formation technique called interferometric synthetic aperture microscopy (ISAM). ISAM has the potential to broadly impact real-time three-dimensional microscopy and analysis in the fields of cell and tumour biology, as well as in clinical diagnosis where in vivo imaging is preferable to biopsy.

  19. Embryonic lethality after combined inactivation of Fancd2 and Mlh1 in mice

    PubMed Central

    van de Vrugt, Henri J.; Eaton, Laura; Newell, Amy Hanlon; Al-Dhalimy, Mushen; Liskay, R. Michael; Olson, Susan B.; Grompe, Markus

    2009-01-01

    DNA repair defects are frequently encountered in human cancers. These defects are utilized by traditional therapeutics but also offer novel cancer treatment strategies based on synthetic lethality. To determine the consequences of combined Fanconi anemia and mismatch repair pathway inactivation, defects in Fancd2 and Mlh1 were combined in one mouse model. Fancd2/Mlh1 double mutant embryos displayed growth retardation resulting in embryonic lethality and significant under-representation among progeny. Additional inactivation of Trp53 failed to improve the survival of Fancd2/Mlh1 deficient embryos. Mouse fibroblasts were obtained and challenged with crosslinking agents. Fancd2-deficient cells displayed the FA-characteristic growth inhibition after mitomycin C exposure. In primary fibroblasts, absence of Mlh1 did not greatly affect the mitomycin C sensitivity of Fancd2-deficient and proficient cells. However, in Trp53 mutant immortalized fibroblasts Mlh1-deficiency reduced the growth-inhibiting effect of mitomycin C in Fancd2 mutant and complemented cells. Similar data were obtained using psoralen/UVA, signifying that MLH1 influences the cellular sensitivity to DNA interstrand crosslinks. Next, the effect of MLH1-deficiency on the formation of chromosomal aberrations in response to crosslinking agents was determined. Surprisingly, Mlh1 mutant fibroblasts displayed a modest, but noticeable decrease in induced chromosomal breakage and interchange frequencies, suggesting that MLH1 promotes ICL repair catastrophe. In conclusion, the combined inactivation of Fancd2 and Mlh1 did not result in synthetic lethality at the cellular level. Although, absence of Fancd2 sensitized Mlh1 / Trp53 mutant fibroblasts to mitomycin C, the differential survival of primary and immortalized fibroblasts advocates against systemic inactivation of FANCD2 to enhance treatment of MLH1-deficient tumors. PMID:19934329

  20. Time-dependent analysis of visible helium line-ratios for electron temperature and density diagnostic using synthetic simulations on NSTX-U

    DOE PAGESBeta

    Muñoz Burgos, J. M.; Barbui, T.; Schmitz, O.; Stutman, D.; Tritz, K.

    2016-07-11

    Helium line-ratios for electron temperature (Te) and density (ne) plasma diagnostic in the Scrape-Off-Layer (SOL) and Edge regions of tokamaks are widely used. Due to their intensities and proximity of wavelengths, the singlet 667.8 and 728.1 nm, and triplet 706.5 nm visible lines have been typically preferred. Time-dependency of the triplet line (706.5 nm) has been previously analyzed in detail by including transient effects on line-ratios during gas-puff diagnostic applications. In this work, several line-ratio combinations within each of the two spin systems are analyzed with the purpose of eliminating transient effects to extend the application of this powerful diagnosticmore » to high temporal resolution characterization of plasmas. The analysis is done using synthetic emission modeling and diagnostic for low electron density NSTX SOL plasma conditions by several visible lines. Quasi-static equilibrium, and time-dependent models are employed to evaluate transient effects of the atomic population levels that may affect the derived electron temperatures and densities as the helium gas-puff penetrates the plasma. Ultimately, the analysis of a wider range of spectral lines will help to extend this powerful diagnostic to experiments where the wavelength range of the measured spectra may be constrained either by limitations of the spectrometer, or by other conflicting lines from different ions.« less

  1. Quantitative Analysis of Cereulide Toxin from Bacillus cereus in Rice and Pasta Using Synthetic Cereulide Standard and 13C6-Cereulide Standard—A Short Validation Study

    PubMed Central

    Zuberovic Muratovic, Aida; Tröger, Rikard; Granelli, Kristina; Hellenäs, Karl-Erik

    2014-01-01

    A single laboratory validation study of a rapid and sensitive quantitative method for the analysis of cereulide toxin produced by Bacillus cereus using ultra high performance liquid chromatography-electrospray-tandem mass spectrometry is presented. The analysis of this cyclic peptide toxin was validated for pasta and rice samples using a newly presented synthetic cereulide peptide standard, together with 13C6-cereulide that previously have not been commercially available. The use of cereulide standard was also compared to the most frequently used surrogate standard, the antibiotic valinomycin. The performance of the method was evaluated by analyzing spiked sample pools from different types of rice and pasta, as well as 21 individual rice and pasta samples from differently prepared meals. Inoculation of samples with three cereulide toxin-producing strains of Bacillus cereus was finally used to mimic naturally contaminated foods. The quantification range of the method was 1–500 ng/g (R2 = 0.999) and the limits of detection and quantification were 0.1 and 1 ng/g, respectively. The precision varied from 3% to 7% relative standard deviation and the trueness from −2% to +6% relative bias at different concentration levels in cooked rice and pasta. PMID:25514093

  2. Studies on radiosensitive lines of Drosophila. IX. Analysis of fertility and frequency of dominant lethal mutations in the gamma-irradiated females of the mutant line rad(2)201/sup G1/

    SciTech Connect

    Varentsova, E.R.; Sharygin, V.I.; Khromykh, Yu.M.

    1986-03-01

    Fertility and frequency of dominant lethal mutations (DLM) induced by gamma rays in females at the age of 0-5 h and 5-7 days were studied in the radiosensitive mutant rad(2)201/sup G1/ of Drosophila. It has been found that the oocytes of mutant lines are more radiosensitive as compared to those of the wild type flies when compared on the basis of DLM frequency obtained through the entire maturation period. The early oocytes of stages 2-7, i.e., at the stages corresponding to the recombination-defective properties of mutation rad(2)201/sup g1/ are the most sensitive. It has also been demonstrated that the gamma-ray doses exceeding 10 Gy cause a strong sterilizing effect in the mutant females as a result of destruction and resorption of the egg chamber, irradiated at the stages of previtellogenic growth of oocytes. In the radiosensitive mutant females, the sensitivity of the oocytes for DLM induction does not correlate with the sensitivity of the ovarian follicles toward the resorbing effect of gamma rays. The possible involvement of the mutant locus in the genetic processes in different specialized cells of the sexual pathway in Drosophila is discussed.

  3. Lethal photosensitization of biofilm-grown bacteria

    NASA Astrophysics Data System (ADS)

    Wilson, Michael

    1997-12-01

    Antibacterial agents are increasingly being used for the prophylaxis and treatment of oral diseases. As these agents can be rendered ineffective by resistance development in the target organisms there is a need to develop alternative antimicrobial approaches. Light-activated antimicrobial agents release singlet oxygen and free radicals which can kill adjacent bacteria and a wide range of cariogenic and periodontopathogenic bacteria has been shown to be susceptible to such agents. In the oral cavity these organisms are present as biofilms (dental plaques) which are less susceptible to traditional antimicrobial agents than bacterial suspensions. The results of these studies have shown that biofilm-grown oral bacteria are also susceptible to lethal photosensitization although the light energy doses required are grater than those needed to kill the organisms when they are grown as aqueous suspensions.

  4. Ants defend aphids against lethal disease.

    PubMed

    Nielsen, Charlotte; Agrawal, Anurag A; Hajek, Ann E

    2010-04-23

    Social insects defend their own colonies and some species also protect their mutualist partners. In mutualisms with aphids, ants typically feed on honeydew produced by aphids and, in turn guard and shelter aphid colonies from insect natural enemies. Here we report that Formica podzolica ants tending milkweed aphids, Aphis asclepiadis, protect aphid colonies from lethal fungal infections caused by an obligate aphid pathogen, Pandora neoaphidis. In field experiments, bodies of fungal-killed aphids were quickly removed from ant-tended aphid colonies. Ant workers were also able to detect infective conidia on the cuticle of living aphids and responded by either removing or grooming these aphids. Our results extend the long-standing view of ants as mutualists and protectors of aphids by demonstrating focused sanitizing and quarantining behaviour that may lead to reduced disease transmission in aphid colonies. PMID:19923138

  5. Alleged lethal sorcery in East Timor.

    PubMed

    Pollanen, Michael S

    2004-01-01

    A wide range of cultural and social perspectives exists on the concept of sudden and unexpected death. In countries, without a formal system of death investigation, sudden death is shrouded in mysticism often based on traditional belief systems. This cultural perspective on sudden death is often at variance with medical and forensic concepts and may include explanations such as sorcery, magic, and voodoo. In this case report, the postmortem findings in an alleged victim of lethal 'black magic', known as ema halo by the indigenous people of East Timor, is described. The alleged victim died suddenly in front of witnesses. At autopsy, marked dilation of a bicuspid aortic valve with annuloaortic ectasia and a sinus of Valsalva aneurysm was found after exhumation of the body. The findings mitigated the local belief in witchcraft and established a natural manner of death. PMID:14687768

  6. Analytical heat transfer of a porous media: An analysis of the thermal characteristics of synthetic lightweight aggregate

    NASA Astrophysics Data System (ADS)

    Hellickson, Timothy H.

    The thermal insulative properties of a sustainable concrete-based aggregate infused with recycling waste plus fly-ash are investigated to define the effective thermal conductivity based upon optimal volume ratio of the constituent materials. The complex structures were characterized with the use of metallographic sectioning and image processing by exploiting the information given by the gradient of the color held within the image. Next, a tri-skeleton mesh was mapped over the image and a finite element analysis was conducted. The output of the finite element analysis was the temperature contour and an integrated flux over each surface from which the effective thermal conductivity of the material could be calculated via Fourier's Law. The development of a new methodology that evaluates the effective thermal conductivity for a conductivity ratio of less than 10 and a volume density of 0.60 was developed based upon the material properties, the microscopic geometry and a non-interaction approximation. Lastly, the results of the thermal test were used validate the finite element program.

  7. Synthetic hydroxyapatites doped with Zn(II) studied by X-ray diffraction, infrared, Raman and thermal analysis

    NASA Astrophysics Data System (ADS)

    Guerra-López, José R.; Echeverría, Gustavo A.; Güida, Jorge A.; Viña, Raúl; Punte, Graciela

    2015-06-01

    Calcium hydroxyapatite (CaHap) formation when different amounts of Zn(II) are present in the mother solution has been investigated by atomic absorption, infrared and Raman spectroscopies, X-ray diffraction and thermal analysis (DTA and TG). The studied samples have been synthesized at T=95 °C and pH 9 in air. The analysis of the results have shown that the pure CaHap sample crystallizes in the monoclinic form P21/b. Concentrations up to 20% of Zn(II) in the mother solution, equivalent to smaller concentrations in solid (up to 9.1% in wt), favor the formation of the hexagonal apatite, P63/m, while Zn(II) concentrations higher than 20% in solution help an amorphous phase development where vibrational spectra indicated coexistence of two phases: an apatite and ZnNH4PO4·H2O. Infrared data of thermal treated samples endorse that HPO42- ion had not been incorporated in Zn(II) doped samples during the synthesis process. Present results also allow to conclude that Zn(II) cation exhibits a preference to occupy the Ca2 site of the apatite structure and induces water adsorption and a small quantity of CO32- cation incorporation, leading to formation of a less crystalline Ca deficient apatite.

  8. Identification of a De Novo Heterozygous Missense FLNB Mutation in Lethal Atelosteogenesis Type I by Exome Sequencing

    PubMed Central

    Jeon, Ga Won; Lee, Mi-Na; Jung, Ji Mi; Hong, Seong Yeon; Kim, Young Nam; Sin, Jong Beom

    2014-01-01

    Background Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic disorder characterized by severe short-limbed dwarfism and dislocated hips, knees, and elbows. AO-I is caused by mutations in the filamin B (FLNB) gene; however, several other genes can cause AO-like lethal skeletal dysplasias. Methods In order to screen all possible genes associated with AO-like lethal skeletal dysplasias simultaneously, we performed whole-exome sequencing in a female newborn having clinical features of AO-I. Results Exome sequencing identified a novel missense variant (c.517G>A; p.Ala173Thr) in exon 2 of the FLNB gene in the patient. Sanger sequencing validated this variant, and genetic analysis of the patient's parents suggested a de novo occurrence of the variant. Conclusions This study shows that exome sequencing can be a useful tool for the identification of causative mutations in lethal skeletal dysplasia patients. PMID:24624349

  9. Inhibition of Hepatitis C Virus in Chimeric Mice by Short Synthetic Hairpin RNAs: Sequence Analysis of Surviving Virus Shows Added Selective Pressure of Combination Therapy

    PubMed Central

    Dallas, Anne; Ilves, Heini; Ma, Han; Chin, Daniel J.; MacLachlan, Ian; Klumpp, Klaus

    2014-01-01

    ABSTRACT We have recently shown that a cocktail of two short synthetic hairpin RNAs (sshRNAs), targeting the internal ribosome entry site of hepatitis C virus (HCV) formulated with lipid nanoparticles, was able to suppress viral replication in chimeric mice infected with HCV GT1a by up to 2.5 log10 (H. Ma et al., Gastroenterology 146:63–66.e5, http://dx.doi.org/10.1053/j.gastro.2013.09.049) Viral load remained about 1 log10 below pretreatment levels 21 days after the end of dosing. We have now sequenced the HCV viral RNA amplified from serum of treated mice after the 21-day follow-up period. Viral RNA from the HCV sshRNA-treated groups was altered in sequences complementary to the sshRNAs and nowhere else in the 500-nucleotide sequenced region, while the viruses from the control group that received an irrelevant sshRNA had no mutations in that region. The ability of the most commonly selected mutations to confer resistance to the sshRNAs was confirmed in vitro by introducing those mutations into HCV-luciferase reporters. The mutations most frequently selected by sshRNA treatment within the sshRNA target sequence occurred at the most polymorphic residues, as identified from an analysis of available clinical isolates. These results demonstrate a direct antiviral activity with effective HCV suppression, demonstrate the added selective pressure of combination therapy, and confirm an RNA interference (RNAi) mechanism of action. IMPORTANCE This study presents a detailed analysis of the impact of treating a hepatitis C virus (HCV)-infected animal with synthetic hairpin-shaped RNAs that can degrade the virus's RNA genome. These RNAs can reduce the viral load in these animals by over 99% after 1 to 2 injections. The study results confirm that the viral rebound that often occurred a few weeks after treatment is due to emergence of a virus whose genome is mutated in the sequences targeted by the RNAs. The use of two RNA inhibitors, which is more effective than use of either

  10. Validation and application of an UPLC-MS/MS method for the quantification of synthetic cannabinoids in urine samples and analysis of seized materials from the Portuguese market.

    PubMed

    Simões, Susana Sadler; Silva, Inês; Ajenjo, Antonio Castañera; Dias, Mário João

    2014-10-01

    An UPLC-MS/MS method using ESI+ionization and MRM was developed and fully validated according to international guidelines for the qualitative and quantitative analysis of nine synthetic cannabinoids and/or their metabolites in urine samples (1mL). Prior to extraction the samples were subjected to an enzymatic hydrolysis using β-glucuronidase followed by a SPE procedure using Oasis(®) HLB 3cc (60mg) columns. The chromatographic separation was performed with an Acquity UPLC(®) HSS T3 (50mm×2.1mm i.d., 1.8μm) reversed-phase column using a gradient with methanol-ammonium formate 2mM (0.1% formic acid) and with a run time of 9.5min. The method was validated in terms of selectivity, capacity of identification, limits of detection (0.01-0.5ng/mL) and quantification (0.05-0.5ng/mL), recovery (58-105%), carryover, matrix effect, linearity (0.05-50ng/mL), intra-assay precision, inter-assay accuracy and precision (CV<20%). The method was applied to 80 authentic samples, five of them (6.2%) were confirmed or suspected to be positive for the metabolites JWH-018 N-hydroxypentyl and JWH-018 N-pentanoic acid of JWH-018 and for the metabolite JWH-122 N-(5-hydroxypentyl) of JWH-122, and three of them in association with THC and/or THCCOOH (substances included in the method, together with the 11-OH-THC). Additionally, 17 spice products were analyzed, for which were confirmed the presence of the following substances: AM-2201, JWH-018, JWH-022 JWH-073, JWH-122, JWH-203, JWH-210, JWH-250, HU-210 and RCS-4, according to the comparison with authentic reference material and published data. The analytical method developed allowed the analysis of synthetic cannabinoids and the notification of the first cases in Portugal. PMID:25127518

  11. Early Cytokine Dysregulation and Viral Replication Are Associated with Mortality During Lethal Influenza Infection

    PubMed Central

    Vogel, Alexander J.; Harris, Seth; Marsteller, Nathan; Condon, Shirley A.

    2014-01-01

    Abstract Infection with influenza A virus (IAV) leads to acute lung injury and possibly fatal complications, especially in immunocompromised, elderly, or chronically infected individuals. Therefore, it is important to study the factors that lead to pathology and mortality in infected hosts. In this report, we analyze immune responses to infection at a sublethal (0.1 LD50) and lethal (1 LD50) dose of the highly pathogenic IAV A/Puerto Rico/8/34 (PR8). Our experiments revealed that infection with a 1 LD50 dose induced peak viral titers at day 2 compared to day 4 in the 0.1 LD50 dose. Moreover, early cytokine dysregulation was observed in the lethal dose with significantly elevated levels of IFN-α, TNF-α, CXCL9, IL-6, and MCP-1 produced at day 2. Early inflammatory responses following infection with 1 LD50 correlated with a greater influx of neutrophils into the lung. However, depletion of neutrophils enhanced morbidity following IAV infection. Though no differences in CD8+ cell function were observed, CD4+ effector responses were impaired in the lungs 8 days after infection with 1 LD50. Histological analysis revealed significant pathology in lethally infected mice at day 2 and day 6 postinfection, when viral titers remained high. Treating lethally infected mice with oseltamivir inhibited viral titers to sublethal levels, and abrogated the pathology associated with the lethal dose. Together, these results suggest that early cytokine dysregulation and viral replication play a role in pulmonary damage and high mortality in lethally infected mice. PMID:24787235

  12. Building synthetic memory

    PubMed Central

    Inniss, Mara C.; Silver, Pamela A.

    2013-01-01

    Synopsis Cellular memory – conversion of a transient signal into a sustained response – is a common feature of biological systems. Synthetic biologists aim to understand and reengineer such systems in a reliable and predictable manner. Synthetic memory circuits have been designed and built in vitro and in vivo based on diverse mechanisms such as oligonucleotide hybridization, recombination, transcription, phosphorylation, and RNA editing. Thus far, building these circuits has helped us explore the basic principles required for stable memory and ask novel biological questions. Here we discuss strategies for building synthetic memory circuits, their use as research tools, and future applications of these devices in medicine and industry. PMID:24028965

  13. Building synthetic memory.

    PubMed

    Inniss, Mara C; Silver, Pamela A

    2013-09-01

    Cellular memory - conversion of a transient signal into a sustained response - is a common feature of biological systems. Synthetic biologists aim to understand and re-engineer such systems in a reliable and predictable manner. Synthetic memory circuits have been designed and built in vitro and in vivo based on diverse mechanisms, such as oligonucleotide hybridization, recombination, transcription, phosphorylation, and RNA editing. Thus far, building these circuits has helped us explore the basic principles required for stable memory and ask novel biological questions. Here we discuss strategies for building synthetic memory circuits, their use as research tools, and future applications of these devices in medicine and industry. PMID:24028965

  14. Synthetic Base Fluids

    NASA Astrophysics Data System (ADS)

    Brown, M.; Fotheringham, J. D.; Hoyes, T. J.; Mortier, R. M.; Orszulik, S. T.; Randles, S. J.; Stroud, P. M.

    The chemical nature and technology of the main synthetic lubricant base fluids is described, covering polyalphaolefins, alkylated aromatics, gas-to-liquid (GTL) base fluids, polybutenes, aliphatic diesters, polyolesters, polyalkylene glycols or PAGs and phosphate esters.Other synthetic lubricant base oils such as the silicones, borate esters, perfluoroethers and polyphenylene ethers are considered to have restricted applications due to either high cost or performance limitations and are not considered here.Each of the main synthetic base fluids is described for their chemical and physical properties, manufacture and production, their chemistry, key properties, applications and their implications when used in the environment.

  15. Lethal and sub-lethal effects of spinosad on bumble bees (Bombus impatiens Cresson).

    PubMed

    Morandin, Lora A; Winston, Mark L; Franklin, Michelle T; Abbott, Virginia A

    2005-07-01

    Recent developments of new families of pesticides and growing awareness of the importance of wild pollinators for crop pollination have stimulated interest in potential effects of novel pesticides on wild bees. Yet pesticide toxicity studies on wild bees remain rare, and few studies have included long-term monitoring of bumble bee colonies or testing of foraging ability after pesticide exposure. Larval bees feeding on exogenous pollen and exposed to pesticides during development may result in lethal or sub-lethal effects during the adult stage. We tested the effects of a naturally derived biopesticide, spinosad, on bumble bee (Bombus impatiens Cresson) colony health, including adult mortality, brood development, weights of emerging bees and foraging efficiency of adults that underwent larval development during exposure to spinosad. We monitored colonies from an early stage, over a 10-week period, and fed spinosad to colonies in pollen at four levels: control, 0.2, 0.8 and 8.0 mg kg(-1), during weeks 2 through 5 of the experiment. At concentrations that bees would likely encounter in pollen in the wild (0.2-0.8 mg kg(-1)) we detected minimal negative effects to bumble bee colonies. Brood and adult mortality was high at 8.0 mg kg(-1) spinosad, about twice the level that bees would be exposed to in a 'worst case' field scenario, resulting in colony death two to four weeks after initial pesticide exposure. At more realistic concentrations there were potentially important sub-lethal effects. Adult worker bees exposed to spinosad during larval development at 0.8 mg kg(-1) were slower foragers on artificial complex flower arrays than bees from low or no spinosad treated colonies. Inclusion of similar sub-lethal assays to detect effects of pesticides on pollinators would aid in development of environmentally responsible pest management strategies. PMID:15880684

  16. Chronic exposure of corals to fine sediments: lethal and sub-lethal impacts.

    PubMed

    Flores, Florita; Hoogenboom, Mia O; Smith, Luke D; Cooper, Timothy F; Abrego, David; Negri, Andrew P

    2012-01-01

    Understanding the sedimentation and turbidity thresholds for corals is critical in assessing the potential impacts of dredging projects in tropical marine systems. In this study, we exposed two species of coral sampled from offshore locations to six levels of total suspended solids (TSS) for 16 weeks in the laboratory, including a 4 week recovery period. Dose-response relationships were developed to quantify the lethal and sub-lethal thresholds of sedimentation and turbidity for the corals. The sediment treatments affected the horizontal foliaceous species (Montipora aequituberculata) more than the upright branching species (Acropora millepora). The lowest sediment treatments that caused full colony mortality were 30 mg l(-1) TSS (25 mg cm(-2) day(-1)) for M. aequituberculata and 100 mg l(-1) TSS (83 mg cm(-2) day(-1)) for A. millepora after 12 weeks. Coral mortality generally took longer than 4 weeks and was closely related to sediment accumulation on the surface of the corals. While measurements of damage to photosystem II in the symbionts and reductions in lipid content and growth indicated sub-lethal responses in surviving corals, the most reliable predictor of coral mortality in this experiment was long-term sediment accumulation on coral tissue. PMID:22662225

  17. Chronic Exposure of Corals to Fine Sediments: Lethal and Sub-Lethal Impacts

    PubMed Central

    Flores, Florita; Hoogenboom, Mia O.; Smith, Luke D.; Cooper, Timothy F.; Abrego, David; Negri, Andrew P.

    2012-01-01

    Understanding the sedimentation and turbidity thresholds for corals is critical in assessing the potential impacts of dredging projects in tropical marine systems. In this study, we exposed two species of coral sampled from offshore locations to six levels of total suspended solids (TSS) for 16 weeks in the laboratory, including a 4 week recovery period. Dose-response relationships were developed to quantify the lethal and sub-lethal thresholds of sedimentation and turbidity for the corals. The sediment treatments affected the horizontal foliaceous species (Montipora aequituberculata) more than the upright branching species (Acropora millepora). The lowest sediment treatments that caused full colony mortality were 30 mg l−1 TSS (25 mg cm−2 day−1) for M. aequituberculata and 100 mg l−1 TSS (83 mg cm−2 day−1) for A. millepora after 12 weeks. Coral mortality generally took longer than 4 weeks and was closely related to sediment accumulation on the surface of the corals. While measurements of damage to photosystem II in the symbionts and reductions in lipid content and growth indicated sub-lethal responses in surviving corals, the most reliable predictor of coral mortality in this experiment was long-term sediment accumulation on coral tissue. PMID:22662225

  18. Analysis of the role of antibody-dependent cellular cytotoxic antibody activity in murine neonatal herpes simplex virus infection with antibodies to synthetic peptides of glycoprotein D and monoclonal antibodies to glycoprotein B.

    PubMed Central

    Kohl, S; Strynadka, N C; Hodges, R S; Pereira, L

    1990-01-01

    The role of antibody in neonatal herpes simplex virus (HSV) infection remains controversial. A battery of well-characterized monoclonal antibodies to HSV glycoprotein B (gB), and polyclonal antibodies against synthetic peptides of predicted epitopes of HSV glycoprotein D (gD) were used to determine in vitro functional activity and association with protection against lethal infection in a murine model of neonatal HSV disease. Antiviral neutralization activity of HSV was not associated with antibody-dependent cellular cytotoxicity (ADCC) activity to HSV-infected cells in vitro. In a model of high dose challenge (10(4) PFU), protection was not afforded by any antibody alone, but was by antibody plus human mononuclear cells, and highly associated with ADCC functional activity (P less than 0.001). In a low dose challenge model, neutralizing activity of antibody alone was associated with protection in vivo (P less than 0.001). Of the nine neutralizing epitopes of gD in vitro, eight were predicted surface regions. Four of the five epitopic sites of gD (2-21, 267-276, 288-297, and 303-312) that were determined to be important targets of ADCC and in vivo protection were also predicted to be surface regions. The only exception was the antiserum to region 52-61 which was predicted to be buried and also showed these activities. ADCC as well as neutralizing antibody activity are important in protection against neonatal HSV infection. PMID:2164044

  19. Proteomic analysis of Bacillus thuringiensis ΔphaC mutant BMB171/PHB(-1) reveals that the PHB synthetic pathway warrants normal carbon metabolism.

    PubMed

    Chen, Deju; Xu, Dong; Li, Mingshun; He, Jin; Gong, Yuhua; Wu, Dandan; Sun, Ming; Yu, Ziniu

    2012-09-18

    A phaC knockout mutant from Bacillus thuringiensis (Bt) strain BMB171, named BMB171/PHB(-1), was constructed. A physiological and metabolic investigation and a proteomic analysis were conducted for both ΔphaC mutant and its parent strain. Grown in peptone medium with 5 gram glucose per liter as sole carbon source, BMB171/PHB(-1) produced various organic acids. Here the excreted pyruvate, citrate, lactate, acetate and glutamate were quantitatively analyzed. Deletion of phaC gene from the BMB171 strain resulted in 1) growth delay; 2) higher consumption of dioxigen but lower cell yield; 3) stagnation of pH movement; 4) overproduction of organic acids; 5) rapid descent of cell density in the stationary phase; and 6) a sporulation-deficient phenotype. Our proteomic study with qPCR reconfirmation reveals that the absence of PhaC led to a metabolic turmoil which showed repressed glycolysis, and over-expressed TCA cycle, various futile pathways and amino acid synthesis during vegetative growth. It is thus thought that B. thuringiensis BMB171 effectively regulated its carbon metabolism upon the presence of the functional PHB synthetic pathway. The presence of this pathway warrants a PHB-producing bacterium better surviving under different environmental conditions. PMID:22705120

  20. Analysis of synthetic cannabinoids using high-resolution mass spectrometry and mass defect filtering: Implications for non-targeted screening of designer drugs

    PubMed Central

    Grabenauer, Megan; Krol, Wojciech L.; Wiley, Jenny L.; Thomas, Brian F.

    2012-01-01

    Detection of new designer drugs remains an analytical challenge due to the ability of manufacturers to rapidly substitute closely related analogs for banned substances. Traditional targeted mass spectrometry methods rely on library searches, known masses, or multiple reaction monitoring (MRM) transitions and are therefore often unable to detect or identify recently discovered or yet unreported designer drug analogs. Here, high-resolution mass spectrometry in conjunction with mass defect filtering is presented as a method for non-targeted analysis to detect both known and novel analogs of designer drugs. The technique is applied in depth to a family of designer drugs composed of indole-derived synthetic cannabinoids closely related to JWH-018, a substance recently controlled in the United States. A single mass defect filter with a 50 mDa window encompasses over 80% of all currently published structures in this family. Searching for precursor ions of common fragment ions enables detection of compounds with mass defects that fall outside the range of mass defect filter parameters. Application of a mass defect filter to fragment ions prior to precursor ion searching increases the breadth of analogs that can be detected. The combined approach defines a broad-spectrum search for related molecules. PMID:22724537

  1. Continuous flow analysis of iron in zinc electrowinning electrolyte using an iron chalcogenide glass ion-selective electrode Part I. Synthetic media.

    PubMed

    De Marco, Roland; Pejcic, Bobby; Loan, Mitch; Wilcox, Matthew

    2002-04-22

    It is shown that the iron(III) chalcogenide glass membrane ion-selective electrode (ISE) can be calibrated in continuous flow analysis (CFA) using acidified iron(III) nitrate standards, yielding a 60+/-3 mV per decade change in activity of Fe(3+) response in the range 10(-7)-10(-2) M total iron(III). Extended ageing of the iron(III) ISE in 2 M zinc(II) sulphate did not alter the potentiometric response characteristics of the electrode. Furthermore, electrochemical impedance spectroscopy and X-ray photoelectron spectroscopy in the presence and absence of zinc(II) sulphate failed to detect a zinc(II) interference on the iron(III) ISE. CFA/ISE determined activities of Fe(3+) in synthetic zinc electrolyte containing 2x10(-3)-2x10(-1) M total iron(III) yielded results falling within +/-0.2logaFe(3+) unit of the corresponding iron speciation data calculated using the minteqa2 program. PMID:18968611

  2. Metalloproteinase Inhibitors, Nonantimicrobial Chemically Modified Tetracyclines, and Ilomastat Block Bacillus anthracis Lethal Factor Activity in Viable Cells

    PubMed Central

    Kocer, Salih S.; Walker, Stephen G.; Zerler, Brad; Golub, Lorne M.; Simon, Sanford R.

    2005-01-01

    Lethal toxin, produced by the bacterium Bacillus anthracis, is a major contributor to morbidity and mortality in animals and humans who have contracted anthrax. One component of this toxin, lethal factor (LF), proteolytically inactivates members of the mitogen-activated protein kinase kinase (MAPKK or MEK) family. In this study we show that CMT-300, CMT-308, and Ilomastat, agents initially characterized as matrix metalloproteinase inhibitors which are in early stages of development as pharmaceuticals, effectively inhibit the zinc metalloproteinase activity of LF. All three inhibitors, CMT-300, CMT-308, and Ilomastat, inhibit LF-mediated cleavage of a synthetic peptide substrate based on the N-terminal domain of MEKs. Inhibition of LF-mediated MEK proteolysis by all three agents was also achieved using lysates of the human monocytoid line MonoMac 6 as sources of MAPKKs and visualization of the extent of cleavage after separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by detection by Western blotting. Finally, we have demonstrated inhibition of intracellular MEKs in viable human monocytes and MonoMac 6 cells by these agents after incubation of the cells with a reconstituted preparation of recombinant lethal toxin. All three agents are effective inhibitors when incubated with LF prior to exposure to cells, while the CMTs, but not Ilomastat, are also effective when added after LF has already entered the viable cell targets. These results offer promise for strategies to combat effects of the lethal toxin of B. anthracis. PMID:16239558

  3. What Are Synthetic Cannabinoids?

    MedlinePlus

    ... those produced by marijuana: elevated mood relaxation altered perception —awareness of surrounding objects and conditions symptoms of ... those produced by marijuana: elevated mood relaxation altered perception symptoms of psychosis Synthetic cannabinoids can also cause ...

  4. Models for synthetic biology

    PubMed Central

    Kaznessis, Yiannis N

    2007-01-01

    Synthetic biological engineering is emerging from biology as a distinct discipline based on quantification. The technologies propelling synthetic biology are not new, nor is the concept of designing novel biological molecules. What is new is the emphasis on system behavior. The objective is the design and construction of new biological devices and systems to deliver useful applications. Numerous synthetic gene circuits have been created in the past decade, including bistable switches, oscillators, and logic gates, and possible applications abound, including biofuels, detectors for biochemical and chemical weapons, disease diagnosis, and gene therapies. More than fifty years after the discovery of the molecular structure of DNA, molecular biology is mature enough for real quantification that is useful for biological engineering applications, similar to the revolution in modeling in chemistry in the 1950s. With the excitement that synthetic biology is generating, the engineering and biological science communities appear remarkably willing to cross disciplinary boundaries toward a common goal. PMID:17986347

  5. Synthetic microbial communities☆

    PubMed Central

    Großkopf, Tobias; Soyer, Orkun S

    2014-01-01

    While natural microbial communities are composed of a mix of microbes with often unknown functions, the construction of synthetic microbial communities allows for the generation of defined systems with reduced complexity. Used in a top-down approach, synthetic communities serve as model systems to ask questions about the performance and stability of microbial communities. In a second, bottom-up approach, synthetic microbial communities are used to study which conditions are necessary to generate interaction patterns like symbiosis or competition, and how higher order community structure can emerge from these. Besides their obvious value as model systems to understand the structure, function and evolution of microbial communities as complex dynamical systems, synthetic communities can also open up new avenues for biotechnological applications. PMID:24632350

  6. Oxidative degradation of cholesteryl esters in low-density lipoproteins: analysis by liquid chromatography-light scattering and protection by a new synthetic antioxidant, S20478.

    PubMed

    Arborati, M; Benchorba, D; Lesieur, I; Bizot-Espiard, J G; Guardiola-Lemaitre, B; Chapman, M J; Ninio, E

    1997-01-01

    Cholesteryl esters in the hydrophobic core of low-density lipoprotein (LDL) particles constitute a major molecular target during copper-mediated oxidation. To facilitate the rapid analysis and quantitation of the oxidative degradation of LDL cholesteryl esters, we describe a new approach based on light scattering detection following separation by HPLC. We have applied this approach to the evaluation of the protective capacity of a new synthetic antioxidant, S20478, during oxidation of LDL in the presence of copper ions. HPLC separation of cholesterol and the four major molecular species of cholesteryl esters (C16:0, C18:1, C18:2 and C20:4) of LDL was achieved in a single run of 20 min with high sensitivity (50 ng) and low background. Time course studies of the oxidative modification of LDL (ratio LDL protein: copper, 100 micrograms/mL: 1 microM) revealed that the content of unsaturated cholesteryl esters (C20:4 and C18:2) decreased (-30% and -15%, respectively) within 90 min of copper-mediated oxidation, while only minor degradation (up to 15%) of monounsaturated (C18:1) and saturated (C16:0) esters occurred. At 24 hours of oxidation, only traces (< 5%) of the C20:4 and C18:2 esters were detectable; whereas 52% of the C18:1 ester remained (P < 0.01). Of the saturated esters, only minor proportions (35% or less) underwent oxidative modification. In addition, some 81% of free cholesterol was conserved as the native sterol. The synthetic antioxidant, S20478 (50 microM) was capable of inhibiting the initiation and the propagation of copper-mediated LDL oxidation as determined by the time- and dose-dependent inhibition of the formation of conjugated dienes and thiobarbituric acid-reactive substances, as well as the conservation of the net electrical charge of LDL; indeed S20478 conserved cholesteryl esters in their native form up to 24 hours. However, after prolonged exposure to copper ions (48 hours), only 47% of the unsaturated esters remained (C18:2, P < 0

  7. Synthetic biology and biosecurity.

    PubMed

    Robienski, Jürgen; Simon, Jürgen

    2014-01-01

    This article discusses the conflict fields and legal questions of synthetic biology, esp. concerning biosecurity. A respective jurisprudential discussion has not taken place yet in Germany apart from few statements and recommendations. But in Germany, Europe and the USA, it is generally accepted that a broad discussion is necessary. This is esp. true for the question of biosecurity and the possible dangers arising from Synthetic Biology. PMID:25845204

  8. Synthetic Vision Systems

    NASA Technical Reports Server (NTRS)

    Prinzel, L.J.; Kramer, L.J.

    2009-01-01

    A synthetic vision system is an aircraft cockpit display technology that presents the visual environment external to the aircraft using computer-generated imagery in a manner analogous to how it would appear to the pilot if forward visibility were not restricted. The purpose of this chapter is to review the state of synthetic vision systems, and discuss selected human factors issues that should be considered when designing such displays.

  9. Active synthetic soil

    NASA Technical Reports Server (NTRS)

    Ming, Douglas W. (Inventor); Henninger, Donald L. (Inventor); Allen, Earl R. (Inventor); Golden, Dadigamuwage C. (Inventor)

    1995-01-01

    A synthetic soil/fertilizer for horticultural application having all the agronutrients essential for plant growth is disclosed. The soil comprises a synthetic apatite fertilizer having sulfur, magnesium and micronutrients dispersed in a calcium phosphate matrix, a zeolite cation exchange medium saturated with a charge of potassium and nitrogen cations, and an optional pH buffer. Moisture dissolves the apatite and mobilizes the nutrient elements from the apatite matrix and the zeolite charge sites.

  10. Active synthetic soil

    NASA Technical Reports Server (NTRS)

    Ming, Douglas W. (Inventor); Henninger, Donald L. (Inventor); Allen, Earl R. (Inventor); Golden, Dadigamuwage C. (Inventor)

    1995-01-01

    A synthetic soil/fertilizer for horticultural application having all the agronutrients essential for plant growth is disclosed. The soil comprises a synthetic apatite fertilizer having sulfur, magnesium, and micronutrients dispersed in a calcium phosphate matrix, a zeolite cation exchange medium saturated with a charge of potassium and nitrogen cations, and an optional pH buffer. Moisture dissolves the apatite and mobilizes the nutrient elements from the apatite matrix and the zeolite charge sites.

  11. Second interlaboratory comparison study for the analysis of 239Pu in synthetic urine at the microBq (-100 aCi) level by mass spectrometry

    SciTech Connect

    McCurdy, D; Lin, Z; Inn, K W; Bell III, R; Wagner, S; Efurd, D W; Steiner, R; Duffy, C; Hamilton, T F; Brown, T A; Marchetti, A A

    2005-01-28

    As a follow up to the initial 1998 intercomparison study, a second study was initiated in 2001 as part of the ongoing evaluation of the capabilities of various ultra-sensitive methods to analyze {sup 239}Pu in urine samples. The initial study was sponsored by the Department of Energy, Office of International Health Programs to evaluate and validate new technologies that may supersede the existing fission tract analysis (FTA) method for the analysis of {sup 239}Pu in urine at the {micro}Bq/l level. The ultra-sensitive techniques evaluated in the second study included accelerator mass spectrometry (AMS) by LLNL, thermal ionization mass spectrometry (TIMS) by LANL and FTA by the University of Utah. Only the results for the mass spectrometric methods will be presented. For the second study, the testing levels were approximately 4, 9, 29 and 56 {micro}Bq of {sup 239}Pu per liter of synthetic urine. Each test sample also contained {sup 240}Pu at a {sup 240}Pu/{sup 239}Pu atom ratio of {approx}0.15 and natural uranium at a concentration of 50 {micro}Bq/ml. From the results of the two studies, it can be inferred that the best performance at the {micro}Bq level is more laboratory specific than method specific. The second study demonstrated that LANL-TIMS and LLNL-AMS had essentially the same quantification level for both isotopes. Study results for bias and precision and acceptable performance compared to ANSI N13.30 and ANSI N42.22 have been compiled.

  12. Tumor clone dynamics in lethal prostate cancer

    PubMed Central

    Carreira, Suzanne; Romanel, Alessandro; Goodall, Jane; Grist, Emily; Ferraldeschi, Roberta; Miranda, Susana; Prandi, Davide; Lorente, David; Frenel, Jean-Sebastien; Pezaro, Carmel; Omlin, Aurelius; Rodrigues, Daniel Nava; Flohr, Penelope; Tunariu, Nina; de Bono, Johann S.; Demichelis, Francesca; Attard, Gerhardt

    2015-01-01

    It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers. PMID:25232177

  13. Lethal body burdens of polar narcotics: Chlorophenols

    SciTech Connect

    Wezel, A.P. van; Punte, S.S.; Opperhuizen, A.

    1995-09-01

    The goal of the present study was to measure in fathead minnow (Pimephales promelas) the lethal body burden (LBB) of three chlorophenols that are known as polar narcotic chemicals. The LBBs of the chlorophenols were compared to LBBs of nonpolar narcotic chemicals to consider if the two classes of narcotic chemicals differ on a body burden level. The LBB of the most acidic chlorophenol was measured at two different levels of pH exposure to determine the influence of the degree of ionization on the magnitude of the LBB. Both n-octanol/water partition coefficients and n-hexane/water partition coefficients of the chlorophenols were determined at different pH levels to consider the influence of ionization on the partition coefficient and to determine the importance of a polar group in the organic phase on the partitioning behavior. Partitioning to n-octanol and n-hexane was used as input in a model to simulate the equilibrium partitioning between hydrophobic and nonhydrophobic and target and nontarget compartments in the fish.

  14. Inhibitors of the Metalloproteinase Anthrax Lethal Factor.

    PubMed

    Goldberg, Allison B; Turk, Benjamin E

    2016-01-01

    Bacillus anthracis, a rod shaped, spore forming, gram positive bacteria, is the etiological agent of anthrax. B. anthracis virulence is partly attributable to two secreted bipartite protein toxins, which act inside host cells to disrupt signaling pathways important for host defense against infection. These toxins may also directly contribute to mortality in late stage infection. The zinc-dependent metalloproteinase anthrax lethal factor (LF) is a critical component of one of these protein toxins and a prime target for inhibitor development to produce anthrax therapeutics. Here, we describe recent efforts to identify specific and potent LF inhibitors. Derivatization of peptide substrate analogs bearing zinc-binding groups has produced potent and specific LF inhibitors, and X-ray crystallography of LFinhibitor complexes has provided insight into features required for high affinity binding. Novel inhibitor scaffolds have been identified through several approaches, including fragment-based drug discovery, virtual screening, and highthroughput screening of diverse compound libraries. Lastly, efforts to discover LF inhibitors have led to the development of new screening strategies, such as the use of full-length proteins as substrates, that may prove useful for other proteases as well. Overall, these efforts have led to a collection of chemically and mechanistically diverse molecules capable of inhibiting LF activity in vitro and in cells, as well as in animal models of anthrax infection. PMID:27072692

  15. Examining lethality risk for rodent studies of primary blast lung injury.

    PubMed

    Hubbard, William Brad; Hall, Christina; Siva Sai Suijith Sajja, Venkata; Lavik, Erink; VandeVord, Pamela

    2014-01-01

    While protective measures have been taken to mitigate injury to the thorax during a blast exposure, primary blast lung injury (PBLI) is still evident in mounted/in vehicle cases during military conflicts. Moreover, civilians, who are unprotected from blast exposure, can be severely harmed by terrorist attacks that use improvised explosive devices (IEDs). Since the lungs are the most susceptible organ due to their air-filled nature, PBLI is one of the most serious injuries seen in civilian blast cases. Determining lethality threshold for rodent studies is crucial to guide experimental designs centered on therapies for survival after PBLI or mechanistic understanding of the injury itself. Using an Advanced Blast Simulator, unprotected rats were exposed to a whole body blast to induce PBLI. The one-hour survival rate was assessed to determine operating conditions for a 50% lethality rate. Macroscopic and histological analysis of lung was conducted using hematoxylin and eosin staining. Results demonstrated lethality risk trends based on static blast overpressure (BOP) for rodent models, which may help standardized animal studies and contribute to scaling to the human level. The need for a standardized method of producing PBLI is pressing and establishing standard curves, such as a lethality risk curve for lung blasts, is crucial for this condensing of BOP methods. PMID:25405409

  16. Differential Synthetic Aperture Ladar

    SciTech Connect

    Stappaerts, E A; Scharlemann, E

    2005-02-07

    We report a differential synthetic aperture ladar (DSAL) concept that relaxes platform and laser requirements compared to conventional SAL. Line-of-sight translation/vibration constraints are reduced by several orders of magnitude, while laser frequency stability is typically relaxed by an order of magnitude. The technique is most advantageous for shorter laser wavelengths, ultraviolet to mid-infrared. Analytical and modeling results, including the effect of speckle and atmospheric turbulence, are presented. Synthetic aperture ladars are of growing interest, and several theoretical and experimental papers have been published on the subject. Compared to RF synthetic aperture radar (SAR), platform/ladar motion and transmitter bandwidth constraints are especially demanding at optical wavelengths. For mid-IR and shorter wavelengths, deviations from a linear trajectory along the synthetic aperture length have to be submicron, or their magnitude must be measured to that precision for compensation. The laser coherence time has to be the synthetic aperture transit time, or transmitter phase has to be recorded and a correction applied on detection.

  17. Cation substitution in synthetic meridianiite (MgSO4·11H2O) I: X-ray powder diffraction analysis of quenched polycrystalline aggregates

    NASA Astrophysics Data System (ADS)

    Fortes, A. Dominic; Browning, Frank; Wood, Ian G.

    2012-05-01

    Meridianiite, MgSO4·11H2O, is the most highly hydrated phase in the binary MgSO4-H2O system. Lower hydrates in the MgSO4-H2O system have end-member analogues containing alternative divalent metal cations (Ni2+, Zn2+, Mn2+, Cu2+, Fe2+, and Co2+) and exhibit extensive solid solution with MgSO4 and with one another, but no other undecahydrate is known. We have prepared aqueous MgSO4 solutions doped with these other cations in proportions up to and including the pure end-members. These liquids have been solidified into fine-grained polycrystalline blocks of metal sulfate hydrate + ice by rapid quenching in liquid nitrogen. The solid products have been characterised by X-ray powder diffraction, and the onset of partial melting has been quantified using a thermal probe. We have established that of the seven end-member metal sulfates studied, only MgSO4 forms an undecahydrate; ZnSO4 forms an orthorhombic heptahydrate (synthetic goslarite), MnSO4, FeSO4, and CoSO4 form monoclinic heptahydrates (syn. mallardite, melanterite, bieberite, respectively), and CuSO4 crystallises as the well-known triclinic pentahydrate (syn. chalcanthite). NiSO4 forms a new hydrate which has been indexed with a triclinic unit cell of dimensions a = 6.1275(1) Å, b = 6.8628(1) Å, c = 12.6318(2) Å, α = 92.904(2)°, β = 97.678(2)°, and γ = 96.618(2)°. The unit-cell volume of this crystal, V = 521.74(1) Å3, is consistent with it being an octahydrate, NiSO4·8H2O. Further analysis of doped specimens has shown that synthetic meridianiite is able to accommodate significant quantities of foreign cations in its structure; of the order 50 mol. % Co2+ or Mn2+, 20-30 mol. % Ni2+ or Zn2+, but less than 10 mol. % of Cu2+ or Fe2+. In three of the systems we examined, an `intermediate' phase occurred that differed in hydration state both from the Mg-bearing meridianiite end-member and the pure dopant end-member hydrate. In the case of CuSO4, we observed a melanterite-structured heptahydrate at Cu

  18. Combined diazepam and MK-801 therapy provides synergistic protection from tetramethylenedisulfotetramine-induced tonic-clonic seizures and lethality in mice.

    PubMed

    Shakarjian, Michael P; Ali, Mahil S; Velíšková, Jana; Stanton, Patric K; Heck, Diane E; Velíšek, Libor

    2015-05-01

    The synthetic rodenticide, tetramethylenedisulfotetramine (TMDT), is a persistent and highly lethal GABA-gated Cl(-) channel blocker. TMDT is clandestinely produced, remains popular in mainland China, and causes numerous unintentional and deliberate poisonings worldwide. TMDT is odorless, tasteless, and easy to manufacture, features that make it a potential weapon of terrorism. There is no effective treatment. We previously characterized the effects of TMDT in C57BL/6 mice and surveyed efficacies of GABAergic and glutamatergic anticonvulsant treatments. At 0.4 mg/kg i.p., TMDT produced neurotoxic symptomatology consisting of twitches, clonic and tonic-clonic seizures, often progressing to status epilepticus and death. If administered immediately after the occurrence of the first clonic seizure, the benzodiazepine diazepam (DZP) effectively prevented all subsequent seizure symptoms, whereas the NMDA receptor antagonist dizocilpine (MK-801) primarily prevented tonic-clonic seizures. The latter agent, however, appeared to be more effective at preventing delayed death. The present study further explored these phenomena, and characterized the therapeutic actions of DZP and MK-801 as combinations. Joint treatment with both DZP and MK-801 displayed synergistic protection against tonic-clonic seizures and 24 h lethality as determined by isobolographic analysis. Clonic seizures, however, remained poorly controlled. A modification of the treatment regimen, where DZP was followed 10 min later by MK-801, yielded a reduction in both types of seizures and improved overall outcome. Simultaneous monitoring of subjects via EEG and videography confirmed effectiveness of this sequential regimen. We conclude that TMDT blockage at GABAA receptors involves early activation of NMDA receptors, which contribute to persistent ictogenic activity. Our data predict that a sequential combination treatment with DZP followed by MK-801 will be superior to either individual therapy with, or

  19. Combined Diazepam and MK-801 Therapy Provides Synergistic Protection from Tetramethylenedisulfotetramine-induced Tonic-Clonic Seizures and Lethality in Mice

    PubMed Central

    Shakarjian, Michael P.; Ali, Mahil S.; Velíšková, Jana; Stanton, Patric K.; Heck, Diane E.; Velíšek, Libor

    2015-01-01

    The synthetic rodenticide, tetramethylenedisulfotetramine (TMDT), is a persistent and highly lethal GABA-gated Cl− channel blocker. TMDT is clandestinely produced, remains popular in mainland China, and causes numerous unintentional and deliberate poisonings worldwide. TMDT is odorless, tasteless, and easy to manufacture, features that make it a potential weapon of terrorism. There is no effective treatment. We previously characterized the effects of TMDT in C57BL/6 mice and surveyed efficacies of GABAergic and glutamatergic anticonvulsant treatments. At 0.4 mg/kg i.p., TMDT produced neurotoxic symptomatology consisting of twitches, clonic and tonic-clonic seizures, often progressing to status epilepticus and death. If administered immediately after the occurrence of the first clonic seizure, the benzodiazepine diazepam (DZP) effectively prevented all subsequent seizure symptoms, whereas the NMDA receptor antagonist dizocilpine (MK-801) primarily prevented tonic-clonic seizures. The latter agent, however, appeared to be more effective at preventing delayed death. The present study further explored these phenomena, and characterized the therapeutic actions of DZP and MK-801 as combinations. Joint treatment with both DZP and MK-801 displayed synergistic protection against tonic-clonic seizures and 24 hour lethality as determined by isobolographic analysis. Clonic seizures, however, remained poorly controlled. A modification of the treatment regimen, where DZP was followed 10 min later by MK-801, yielded a reduction in both types of seizures and improved overall outcome. Simultaneous monitoring of subjects via EEG and videography confirmed effectiveness of this sequential regimen. We conclude that TMDT blockage at GABAA receptors involves early activation of NMDA receptors, which contribute to persistent ictogenic activity. Our data predict that a sequential combination treatment with DZP followed by MK-801 will be superior to either individual therapy with, or

  20. Development of a rapid method for the analysis of synthetic growth promoters in bovine muscle using liquid chromatography tandem mass spectrometry.

    PubMed

    Malone, E M; Elliott, C T; Kennedy, D G; Regan, L

    2009-04-01

    A rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the simultaneous identification, confirmation and quantitation of thirteen synthetic growth promoters in bovine muscle. The method was validated in accordance with the criteria defined in Commission Decision 2002/657/EC. A value of 1mugkg(-1) was chosen as the required performance level (RPL) for all analytes. The growth promoters investigated were alpha and beta trenbolone, 16-beta-OH stanozolol, methylboldenone, fluoxymesterone, methyltestosterone, medroxyprogesterone acetate, megestrol acetate, melengestrol acetate, dexamethasone, flumethasone, dienestrol and hexestrol. The method involved enzymatic hydrolysis, purification by solid phase extraction followed by analysis by UPLC-MS/MS using electrospray ionization operated in both positive and negative polarities with a total run time of 14 min. The decision limit (CCalpha) values obtained, ranged from 0.09 to 0.19 microgkg(-1) and the detection capability (CCbeta) values obtained, ranged from 0.15 to 0.32 microgkg(-1). The results of the inter-assay study, which was performed by fortifying bovine muscle samples (n=18) on three separate days, show the accuracy calculated for the various analytes to range between 98% and 102%. The precision of the method, expressed as R.S.D. values for the inter-assay variation of each analyte at the three levels of fortification (1, 1.5 and 2.0 microgkg(-1)), ranged between 3.1% and 5.8%. A Day 4 assay was carried out to examine variations due to different animals and different muscle types. PMID:19286019

  1. The Virtual Observatory Service TheoSSA: Establishing a Database of Synthetic Stellar Flux Standards II. NLTE Spectral Analysis of the OB-Type Subdwarf Feige 110

    NASA Technical Reports Server (NTRS)

    Rauch, T.; Rudkowski, A.; Kampka, D.; Werner, K.; Kruk, J. W.; Moehler, S.

    2014-01-01

    Context. In the framework of the Virtual Observatory (VO), the German Astrophysical VO (GAVO) developed the registered service TheoSSA (Theoretical Stellar Spectra Access). It provides easy access to stellar spectral energy distributions (SEDs) and is intended to ingest SEDs calculated by any model-atmosphere code, generally for all effective temperatures, surface gravities, and elemental compositions. We will establish a database of SEDs of flux standards that are easily accessible via TheoSSA's web interface. Aims. The OB-type subdwarf Feige 110 is a standard star for flux calibration. State-of-the-art non-local thermodynamic equilibrium stellar-atmosphere models that consider opacities of species up to trans-iron elements will be used to provide a reliable synthetic spectrum to compare with observations. Methods. In case of Feige 110, we demonstrate that the model reproduces not only its overall continuum shape from the far-ultraviolet (FUV) to the optical wavelength range but also the numerous metal lines exhibited in its FUV spectrum. Results. We present a state-of-the-art spectral analysis of Feige 110. We determined Teff =47 250 +/- 2000 K, log g=6.00 +/- 0.20, and the abundances of He, N, P, S, Ti, V, Cr, Mn, Fe, Co, Ni, Zn, and Ge. Ti, V, Mn, Co, Zn, and Ge were identified for the first time in this star. Upper abundance limits were derived for C, O, Si, Ca, and Sc. Conclusions. The TheoSSA database of theoretical SEDs of stellar flux standards guarantees that the flux calibration of astronomical data and cross-calibration between different instruments can be based on models and SEDs calculated with state-of-the-art model atmosphere codes.

  2. Applicability of accelerated solvent extraction for synthetic colorants analysis in meat products with ultrahigh performance liquid chromatography-photodiode array detection.

    PubMed

    Liao, Qie Gen; Li, Wei Hong; Luo, Lin Guang

    2012-02-24

    Accelerated solvent extraction (ASE) coupled with ultrahigh performance liquid chromatography (UHPLC) with photodiode array detection (PDA) has been used for the quantitative determination of synthetic colorants in meat products. Samples were extracted with ethanol-water-ammonia with a ratio of 75:24:1 (v/v/v) using ASE instrument at 85°C. As a result, all the colorants in meat products were separated using an optimized gradient elution within 3.5 min. Detection and quantification limits of synthetic colorants were in the ranges of 0.01-0.02 mg kg(-1) and 0.05 mg kg(-1), respectively. The intra-day and inter-day precision of the synthetic colorants were ranged between 1.7% (E123) to 5.2% (E124) and 3.2% (E124) to 6.0% (E129), respectively. The intra-day and inter-day recoveries of the synthetic colorants were ranged between 76.9% (E124) to 84.9% (E102) and 76.3% (E124) to 84.3% (E127), respectively. The method has been applied for the determination of seven synthetic colorants in meat products. PMID:22284887

  3. Automated synthetic scene generation

    NASA Astrophysics Data System (ADS)

    Givens, Ryan N.

    Physics-based simulations generate synthetic imagery to help organizations anticipate system performance of proposed remote sensing systems. However, manually constructing synthetic scenes which are sophisticated enough to capture the complexity of real-world sites can take days to months depending on the size of the site and desired fidelity of the scene. This research, sponsored by the Air Force Research Laboratory's Sensors Directorate, successfully developed an automated approach to fuse high-resolution RGB imagery, lidar data, and hyperspectral imagery and then extract the necessary scene components. The method greatly reduces the time and money required to generate realistic synthetic scenes and developed new approaches to improve material identification using information from all three of the input datasets.

  4. Factors Affecting Lethal Isotherms During Cryoablation Procedures

    PubMed Central

    Rau, Andrew C.; Siskey, Ryan; Ochoa, Jorge A.; Good, Tracy

    2016-01-01

    Background: Creating appropriately-sized, lethal isotherms during cryoablation of renal tumors is critical in order to achieve sufficiently-sized zones of cell death. To ensure adequate cell death in target treatment locations, surgeons must carefully select the type, size, location, and number of probes to be used, as well as various probe operating parameters. Objective: The current study investigates the effects of probe type, operating pressure, and clinical method on the resulting sizes of isotherms in an in vitro gelatin model. Method: Using a total of four cryoprobes from two manufacturers, freeze procedures were conducted in gelatin in order to compare resulting sizes of constant temperature zones (isotherms). The effects of certain procedural parameters which are clinically adjustable were studied. Results: Test results show that the sizes of 0 °C,-20 °C and -40 °C isotherms created by similarly-sized probes from two different manufacturers were significantly different for nearly all comparisons made, and that size differences resulting from changing the operating pressure were not as prevalent. Furthermore, isotherm sizes created using a multiple freeze procedure (a ten minute freeze, followed by a five minute passive thaw, followed by another ten minute freeze) did not result in statistically-significant differences when compared to those created using a single freeze procedure in all cases. Conclusion: These results indicate that selection of the probe manufacturer and probe size may be more important for dictating the size of kill zones during cryoablation than procedural adjustments to operating pressures or freeze times.

  5. Synthetic battery cycling techniques

    NASA Technical Reports Server (NTRS)

    Leibecki, H. F.; Thaller, L. H.

    1982-01-01

    Synthetic battery cycling makes use of the fast growing capability of computer graphics to illustrate some of the basic characteristics of operation of individual electrodes within an operating electrochemical cell. It can also simulate the operation of an entire string of cells that are used as the energy storage subsystem of a power system. The group of techniques that as a class have been referred to as Synthetic Battery Cycling is developed in part to try to bridge the gap of understanding that exists between single cell characteristics and battery system behavior.

  6. Synthetic guide star generation

    DOEpatents

    Payne, Stephen A [Castro Valley, CA; Page, Ralph H [Castro Valley, CA; Ebbers, Christopher A [Livermore, CA; Beach, Raymond J [Livermore, CA

    2008-06-10

    A system for assisting in observing a celestial object and providing synthetic guide star generation. A lasing system provides radiation at a frequency at or near 938 nm and radiation at a frequency at or near 1583 nm. The lasing system includes a fiber laser operating between 880 nm and 960 nm and a fiber laser operating between 1524 nm and 1650 nm. A frequency-conversion system mixes the radiation and generates light at a frequency at or near 589 nm. A system directs the light at a frequency at or near 589 nm toward the celestial object and provides synthetic guide star generation.

  7. Synthetic guide star generation

    DOEpatents

    Payne, Stephen A.; Page, Ralph H.; Ebbers, Christopher A.; Beach, Raymond J.

    2004-03-09

    A system for assisting in observing a celestial object and providing synthetic guide star generation. A lasing system provides radiation at a frequency at or near 938 nm and radiation at a frequency at or near 1583 nm. The lasing system includes a fiber laser operating between 880 nm and 960 nm and a fiber laser operating between 1524 nm and 1650 nm. A frequency-conversion system mixes the radiation and generates light at a frequency at or near 589 nm. A system directs the light at a frequency at or near 589 nm toward the celestial object and provides synthetic guide star generation.

  8. Two different forms of lethal chondrodysplasias caused by COL2A1 gene mutations

    SciTech Connect

    Winterpacht, A.; Hilbert, K.; Schwarze, U.

    1994-09-01

    Two bone dysplasia families seem to be due to mutations in the type II procollagen gene (COL2A1): the so-called spondyloepiphyseal dysplasia congenita (SEDC) group with achondrogenesis II, hypochondrogenesis, SEDC, osteoarthrosis and the Stickler-Kniest pattern that include different forms of Kniest and Stickler dysplasia. Both groups comprise a clinical spectrum ranging from lethal to mild. COL2A1-mutations have been identified in lethal forms of the SEDC family but not in lethal forms of the Stickler/Kniest group. We now report a COL2A-1 mutation in an additional case of hypochondrogenesis (patient S) and in a lethal case of Kniest dysplasia (patient B). We amplified all 54 exons of the COL2A1 gene in both patients and screened the PCR products for mutations by SSCP analysis and sequencing. In patient B, we identified an 18 bp deletion in exon 34 which removes 6 amino acids from the mature protein. In patient S, we were able to identify a two base pair exchange (GG to AT) in exon 31, which leads to the very unusual conversion of Gly to Ile. To our knowledge, this is the first report of a Gly to Ile conversion in the COL2A1 gene, and the first report of a COL2A1 gene mutation in a lethal form of Kniest dysplasia. On the basis of the known COL2A1 gene mutations and the genotype-phenotype correlations established so far, we provide molecular data (an in frame deletion in patient B and a Gly conversion in patient S) that support their clinical classification as Kniest dysplasia and hypochondrogenesis, respectively.

  9. CD4+ T Cells Targeting Dominant and Cryptic Epitopes from Bacillus anthracis Lethal Factor

    PubMed Central

    Ascough, Stephanie; Ingram, Rebecca J.; Chu, Karen K. Y.; Musson, Julie A.; Moore, Stephen J.; Gallagher, Theresa; Baillie, Les; Williamson, Ethel D.; Robinson, John H.; Maillere, Bernard; Boyton, Rosemary J.; Altmann, Daniel M.

    2016-01-01

    Anthrax is an endemic infection in many countries, particularly in the developing world. The causative agent, Bacillus anthracis, mediates disease through the secretion of binary exotoxins. Until recently, research into adaptive immunity targeting this bacterial pathogen has largely focused on the humoral response to these toxins. There is, however, growing recognition that cellular immune responses involving IFNγ producing CD4+ T cells also contribute significantly to a protective memory response. An established concept in adaptive immunity to infection is that during infection of host cells, new microbial epitopes may be revealed, leading to immune recognition of so called ‘cryptic’ or ‘subdominant’ epitopes. We analyzed the response to both cryptic and immunodominant T cell epitopes derived from the toxin component lethal factor and presented by a range of HLA-DR alleles. Using IFNγ-ELISpot assays we characterized epitopes that elicited a response following immunization with synthetic peptide and the whole protein and tested their capacities to bind purified HLA-DR molecules in vitro. We found that DR1 transgenics demonstrated T cell responses to a greater number of domain III cryptic epitopes than other HLA-DR transgenics, and that this pattern was repeated with the immunodominant epitopes, as a greater proportion of these epitopes induced a T cell response when presented within the context of the whole protein. Immunodominant epitopes LF457-476 and LF467-487 were found to induce a T cell response to the peptide, as well as to the whole native LF protein in DR1 and DR15, but not in DR4 transgenics. The analysis of Domain I revealed the presence of several unique cryptic epitopes all of which showed a strong to moderate relative binding affinity to HLA-DR4 molecules. However, none of the cryptic epitopes from either domain III or I displayed notably high binding affinities across all HLA-DR alleles assayed. These responses were influenced by the

  10. CD4+ T Cells Targeting Dominant and Cryptic Epitopes from Bacillus anthracis Lethal Factor.

    PubMed

    Ascough, Stephanie; Ingram, Rebecca J; Chu, Karen K Y; Musson, Julie A; Moore, Stephen J; Gallagher, Theresa; Baillie, Les; Williamson, Ethel D; Robinson, John H; Maillere, Bernard; Boyton, Rosemary J; Altmann, Daniel M

    2015-01-01

    Anthrax is an endemic infection in many countries, particularly in the developing world. The causative agent, Bacillus anthracis, mediates disease through the secretion of binary exotoxins. Until recently, research into adaptive immunity targeting this bacterial pathogen has largely focused on the humoral response to these toxins. There is, however, growing recognition that cellular immune responses involving IFNγ producing CD4+ T cells also contribute significantly to a protective memory response. An established concept in adaptive immunity to infection is that during infection of host cells, new microbial epitopes may be revealed, leading to immune recognition of so called 'cryptic' or 'subdominant' epitopes. We analyzed the response to both cryptic and immunodominant T cell epitopes derived from the toxin component lethal factor and presented by a range of HLA-DR alleles. Using IFNγ-ELISpot assays we characterized epitopes that elicited a response following immunization with synthetic peptide and the whole protein and tested their capacities to bind purified HLA-DR molecules in vitro. We found that DR1 transgenics demonstrated T cell responses to a greater number of domain III cryptic epitopes than other HLA-DR transgenics, and that this pattern was repeated with the immunodominant epitopes, as a greater proportion of these epitopes induced a T cell response when presented within the context of the whole protein. Immunodominant epitopes LF457-476 and LF467-487 were found to induce a T cell response to the peptide, as well as to the whole native LF protein in DR1 and DR15, but not in DR4 transgenics. The analysis of Domain I revealed the presence of several unique cryptic epitopes all of which showed a strong to moderate relative binding affinity to HLA-DR4 molecules. However, none of the cryptic epitopes from either domain III or I displayed notably high binding affinities across all HLA-DR alleles assayed. These responses were influenced by the specific HLA

  11. Pseudomonas aeruginosa UV-A-induced lethal effect: influence of salts, nutritional stress and pyocyanine.

    PubMed

    Fernández, R O; Pizarro, R A

    1999-05-01

    The presence of NaCl in plating media shows an important protection against the Pseudomonas aeruginosa UV-A-induced lethal effect, contrasting with the known sensitizing action of salts on UV-A-irradiated Escherichia coli cells. MgSO4 exhibits a similar protection, but lower concentrations than for NaCl are needed to achieve the same effect. NaCl protection from lethal effects involves an osmotic mechanism, while MgSO4 could act by a different process. On the other hand, when cells grown in a complete medium are then incubated for 20 min in a synthetic medium and irradiated with UV-A, a very marked protection is obtained. This protection is dependent on protein synthesis, since treatment with tetracycline, during the nutritional stress, blocks its induction. These results offer a new example of cross-protection among different stressing agents. In our experimental conditions, natural phenazines of P. aeruginosa are not present in the cells, ruling out the possibility that these pigments act as photosensitizers. Conversely, pyocyanine (the major phenazine produced by this microorganism) prevents the UV-A killing effect in a concentration-dependent way when present in the irradiation media. Finally, UV-A irradiation induces, as in E. coli, the accumulation of guanosine tetraphosphate and guanosine pentaphosphate, although the physiological meaning of this finding has yet to be determined. PMID:10443032

  12. Lethal Netherton syndrome due to homozygous p.Arg371X mutation in SPINK5.

    PubMed

    Diociaiuti, Andrea; Castiglia, Daniele; Fortugno, Paola; Bartuli, Andrea; Pascucci, Monica; Zambruno, Giovanna; El Hachem, May

    2013-01-01

    Here we report a lethal case of Netherton syndrome presenting with neurologic complications, hypernatremic dehydration, failure to thrive, and episodes of sepsis. Molecular analysis of the serine protease inhibitor Kazal-type 5 gene identified a homozygous mutation (c.1111C>T, p.Arg371X). This case highlights the importance of early diagnosis to start appropriate care in a timely fashion and prevent disease complications. PMID:23331056

  13. In vitro breast cancer cell lethality of Brazilian plant extracts.

    PubMed

    Suffredini, I B; Paciencia, M L B; Frana, S A; Varella, A D; Younes, R N

    2007-10-01

    In this study we screened the cytotoxicity of 1220 plant extracts obtained from 351 plants belonging to 74 families occurring in the Amazon and Atlantic rain forests against MCF-7 human breast adenocarcinoma cell lines. All extracts were tested at a dose of 100 microg/mL. Only 11 aqueous or organic extracts belonging to the Annonaceae, Apocynaceae, Araceae, Clusiaceae, Flacourtiaceae, Leguminosae, Olacaceae and Violaceae showed marked lethal activity. Vismia guianensis and Annona hypoglauca extracts showed the greatest lethal activity. PMID:18236788

  14. Biodegradable synthetic bone composites

    DOEpatents

    Liu, Gao; Zhao, Dacheng; Saiz, Eduardo; Tomsia, Antoni P.

    2013-01-01

    The invention provides for a biodegradable synthetic bone composition comprising a biodegradable hydrogel polymer scaffold comprising a plurality of hydrolytically unstable linkages, and an inorganic component; such as a biodegradable poly(hydroxyethylmethacrylate)/hydroxyapatite (pHEMA/HA) hydrogel composite possessing mineral content approximately that of human bone.

  15. Synthetic Aperture Radar Interferometry

    NASA Technical Reports Server (NTRS)

    Rosen, P. A.; Hensley, S.; Joughin, I. R.; Li, F.; Madsen, S. N.; Rodriguez, E.; Goldstein, R. M.

    1998-01-01

    Synthetic aperture radar interferometry is an imaging technique for measuring the topography of a surface, its changes over time, and other changes in the detailed characteristics of the surface. This paper reviews the techniques of interferometry, systems and limitations, and applications in a rapidly growing area of science and engineering.

  16. Perinatal-lethal Gaucher disease presenting as hydrops fetalis

    PubMed Central

    BenHamida, Emira; Ayadi, Imene; Ouertani, Ines; Chammem, Maroua; Bezzine, Ahlem; BenTmime, Riadh; Attia, Leila; Mrad, Ridha; Marrakchi, Zahra

    2015-01-01

    Perinatal-lethal Gaucher disease is very rare and is considered a variant of type 2 Gaucher disease that occurs in the neonatal period. The most distinct features of perinatal-lethal Gaucher disease are non-immune hydrops fetalis. Less common signs of the disease are hepatosplenomegaly, ichthyosis and arthrogryposis. We report a case of Gaucher's disease (type 2) diagnosed in a newborn who presented with Hydrops Fetalis. PMID:26327947

  17. Late-acting dominant lethal genetic systems and mosquito control

    PubMed Central

    Phuc, Hoang Kim; Andreasen, Morten H; Burton, Rosemary S; Vass, Céline; Epton, Matthew J; Pape, Gavin; Fu, Guoliang; Condon, Kirsty C; Scaife, Sarah; Donnelly, Christl A; Coleman, Paul G; White-Cooper, Helen; Alphey, Luke

    2007-01-01

    Background Reduction or elimination of vector populations will tend to reduce or eliminate transmission of vector-borne diseases. One potential method for environmentally-friendly, species-specific population control is the Sterile Insect Technique (SIT). SIT has not been widely used against insect disease vectors such as mosquitoes, in part because of various practical difficulties in rearing, sterilization and distribution. Additionally, vector populations with strong density-dependent effects will tend to be resistant to SIT-based control as the population-reducing effect of induced sterility will tend to be offset by reduced density-dependent mortality. Results We investigated by mathematical modeling the effect of manipulating the stage of development at which death occurs (lethal phase) in an SIT program against a density-dependence-limited insect population. We found late-acting lethality to be considerably more effective than early-acting lethality. No such strains of a vector insect have been described, so as a proof-of-principle we constructed a strain of the principal vector of the dengue and yellow fever viruses, Aedes (Stegomyia) aegypti, with the necessary properties of dominant, repressible, highly penetrant, late-acting lethality. Conclusion Conventional SIT induces early-acting (embryonic) lethality, but genetic methods potentially allow the lethal phase to be tailored to the program. For insects with strong density-dependence, we show that lethality after the density-dependent phase would be a considerable improvement over conventional methods. For density-dependent parameters estimated from field data for Aedes aegypti, the critical release ratio for population elimination is modeled to be 27% to 540% greater for early-acting rather than late-acting lethality. Our success in developing a mosquito strain with the key features that the modeling indicated were desirable demonstrates the feasibility of this approach for improved SIT for disease

  18. Synthetic Vision Workshop 2

    NASA Technical Reports Server (NTRS)

    Kramer, Lynda J. (Compiler)

    1999-01-01

    The second NASA sponsored Workshop on Synthetic/Enhanced Vision (S/EV) Display Systems was conducted January 27-29, 1998 at the NASA Langley Research Center. The purpose of this workshop was to provide a forum for interested parties to discuss topics in the Synthetic Vision (SV) element of the NASA Aviation Safety Program and to encourage those interested parties to participate in the development, prototyping, and implementation of S/EV systems that enhance aviation safety. The SV element addresses the potential safety benefits of synthetic/enhanced vision display systems for low-end general aviation aircraft, high-end general aviation aircraft (business jets), and commercial transports. Attendance at this workshop consisted of about 112 persons including representatives from industry, the FAA, and other government organizations (NOAA, NIMA, etc.). The workshop provided opportunities for interested individuals to give presentations on the state of the art in potentially applicable systems, as well as to discuss areas of research that might be considered for inclusion within the Synthetic Vision Element program to contribute to the reduction of the fatal aircraft accident rate. Panel discussions on topical areas such as databases, displays, certification issues, and sensors were conducted, with time allowed for audience participation.

  19. Synthetic Bursae for Robots

    NASA Technical Reports Server (NTRS)

    Lovchik, Christopher S.

    2005-01-01

    Synthetic bursae are under development for incorporation into robot joints that are actuated by motor-driven cables in a manner similar to that of arthropod joints actuated by muscle-driven tendons. Like natural bursae, the synthetic bursae would serve as cushions and friction reducers. A natural bursa is a thin bladder filled with synovial fluid, which serves to reduce friction and provide a cushion between a bone and a muscle or a tendon. A synthetic bursa would be similar in form and function: It would be, essentially, a compact, soft roller consisting of a bladder filled with a non-Newtonian fluid. The bladder would be constrained to approximately constant volume. The synthetic bursa would cushion an actuator cable against one of the members of a robot joint and would reduce the friction between the cable and the member. Under load, the pressure in the bladder would hold the opposite walls of the bladder apart, making it possible for them to move freely past each other without rubbing.

  20. Protective Effects of Hong Shan Capsule against Lethal Total-Body Irradiation-Induced Damage in Wistar Rats.

    PubMed

    Li, Jianzhong; Xu, Jing; Xu, Weiheng; Qi, Yang; Lu, Yiming; Qiu, Lei; Hu, Zhenlin; Chu, Zhiyong; Chai, Yifeng; Zhang, Junping

    2015-01-01

    Hong Shan Capsule (HSC), a crude drug of 11 medicinal herbs, was used in clinical practice for the treatment of radiation injuries in China. In this study, we investigated its protection in rats against acute lethal total-body irradiation (TBI). Pre-administration of HSC reduced the radiation sickness characteristics, while increasing the 30-day survival of the irradiated rats. Administration of HSC also reduced the radiation sickness characteristics and increased the 30-day survival of mice after exposure to lethal TBI. Ultrastructural observation illustrated that the pretreatment of rats with HSC significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed the dramatic effect of HSC on alterations of gene expression caused by lethal TBI. Pretreatment with HSC prevented differential expression of 66% (1398 genes) of 2126 genes differentially expressed in response to TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 32 pathways, such as pathways in cancer and the mitogen-activated protein kinase (MAPK) signaling pathway. Our analysis indicated that the pretreatment of rats with HSC modulated these pathways induced by lethal TBI, such as multiple MAPK pathways, suggesting that pretreatment with HSC might provide protective effects on lethal TBI mainly or partially through the modulation of these pathways. Our data suggest that HSC has the potential to be used as an effective therapeutic or radio-protective agent to minimize irradiation damage. PMID:26274957

  1. Protective Effects of Hong Shan Capsule against Lethal Total-Body Irradiation-Induced Damage in Wistar Rats

    PubMed Central

    Li, Jianzhong; Xu, Jing; Xu, Weiheng; Qi, Yang; Lu, Yiming; Qiu, Lei; Hu, Zhenlin; Chu, Zhiyong; Chai, Yifeng; Zhang, Junping

    2015-01-01

    Hong Shan Capsule (HSC), a crude drug of 11 medicinal herbs, was used in clinical practice for the treatment of radiation injuries in China. In this study, we investigated its protection in rats against acute lethal total-body irradiation (TBI). Pre-administration of HSC reduced the radiation sickness characteristics, while increasing the 30-day survival of the irradiated rats. Administration of HSC also reduced the radiation sickness characteristics and increased the 30-day survival of mice after exposure to lethal TBI. Ultrastructural observation illustrated that the pretreatment of rats with HSC significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed the dramatic effect of HSC on alterations of gene expression caused by lethal TBI. Pretreatment with HSC prevented differential expression of 66% (1398 genes) of 2126 genes differentially expressed in response to TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 32 pathways, such as pathways in cancer and the mitogen-activated protein kinase (MAPK) signaling pathway. Our analysis indicated that the pretreatment of rats with HSC modulated these pathways induced by lethal TBI, such as multiple MAPK pathways, suggesting that pretreatment with HSC might provide protective effects on lethal TBI mainly or partially through the modulation of these pathways. Our data suggest that HSC has the potential to be used as an effective therapeutic or radio-protective agent to minimize irradiation damage. PMID:26274957

  2. Synthetic River Valleys

    NASA Astrophysics Data System (ADS)

    Brown, R.; Pasternack, G. B.

    2011-12-01

    The description of fluvial form has evolved from anecdotal descriptions to artistic renderings to 2D plots of cross section or longitudinal profiles and more recently 3D digital models. Synthetic river valleys, artificial 3D topographic models of river topography, have a plethora of potential applications in fluvial geomorphology, and the earth sciences in general, as well as in computer science and ecology. Synthetic river channels have existed implicitly since approximately the 1970s and can be simulated from a variety of approaches spanning the artistic and numerical. An objective method of synthesizing 3D stream topography based on reach scale attributes would be valuable for sizing 3D flumes in the physical and numerical realms, as initial input topography for morphodynamic models, stream restoration design, historical reconstruction, and mechanistic testing of interactions of channel geometric elements. Quite simply - simulation of synthetic channel geometry of prescribed conditions can allow systematic evaluation of the dominant relationships between river flow and geometry. A new model, the control curve method, is presented that uses hierarchically scaled parametric curves in over-lapping 2D planes to create synthetic river valleys. The approach is able to simulate 3D stream geometry from paired 2D descriptions and can allow experimental insight into form-process relationships in addition to visualizing past measurements of channel form that are limited to two dimension descriptions. Results are presented that illustrate the models ability to simulate fluvial topography representative of real world rivers as well as how channel geometric elements can be adjusted. The testing of synthetic river valleys would open up a wealth of knowledge as to why some 3D attributes of river channels are more prevalent than others as well as bridging the gap between the 2D descriptions that have dominated fluvial geomorphology the past century and modern, more complete, 3D

  3. IN SITU SOLID-PHASE EXTRACTION AND ANALYSIS OF ULTRA-TRACE SYNTHETIC MUSKS IN MUNICIPAL SEWAGE EFFLUENT USING GAS CHROMATOGRAPHY-MASS SPECTROMETRY, FULL-SCAN MODE

    EPA Science Inventory



    Fragrance materials, such as synthetic musks in aqueous samples, are normally analyzed by GC/MS in the selected ion monitoring (SIM) mode to provide maximum sensitivity after liquid-liquid extraction of 1-L samples. A 1-L sample, however, usually provides too little ana...

  4. CLOSED-LOOP STRIPPING ANALYSIS (CLSA) OF SYNTHETIC MUSK COMPOUNDS FROM FISH TISSUES WITH MEASUREMENT BY GAS CHROMATOGRAPHY-MASS SPECTROMETRY WITH SELECTED-ION MONITORING

    EPA Science Inventory

    Synthetic musk compounds have been found in surface water, fish tissues, and human breast milk. Current techniques for separating these compounds from fish tissues require tedious sample clean-upprocedures A simple method for the deterrnination of these compounds in fish tissues ...

  5. Deletion of Indian hedgehog gene causes dominant semi-lethal Creeper trait in chicken

    PubMed Central

    Jin, Sihua; Zhu, Feng; Wang, Yanyun; Yi, Guoqiang; Li, Junying; Lian, Ling; Zheng, Jiangxia; Xu, Guiyun; Jiao, Rengang; Gong, Yu; Hou, Zhuocheng; Yang, Ning

    2016-01-01

    The Creeper trait, a classical monogenic phenotype of chicken, is controlled by a dominant semi-lethal gene. This trait has been widely cited in the genetics and molecular biology textbooks for illustrating autosomal dominant semi-lethal inheritance over decades. However, the genetic basis of the Creeper trait remains unknown. Here we have utilized ultra-deep sequencing and extensive analysis for targeting causative mutation controlling the Creeper trait. Our results indicated that the deletion of Indian hedgehog (IHH) gene was only found in the whole-genome sequencing data of lethal embryos and Creeper chickens. Large scale segregation analysis demonstrated that the deletion of IHH was fully linked with early embryonic death and the Creeper trait. Expression analysis showed a much lower expression of IHH in Creeper than wild-type chickens. We therefore suggest the deletion of IHH to be the causative mutation for the Creeper trait in chicken. Our findings unravel the genetic basis of the longstanding Creeper phenotype mystery in chicken as the same gene also underlies bone dysplasia in human and mouse, and thus highlight the significance of IHH in animal development and human haploinsufficiency disorders. PMID:27439785

  6. Deletion of Indian hedgehog gene causes dominant semi-lethal Creeper trait in chicken.

    PubMed

    Jin, Sihua; Zhu, Feng; Wang, Yanyun; Yi, Guoqiang; Li, Junying; Lian, Ling; Zheng, Jiangxia; Xu, Guiyun; Jiao, Rengang; Gong, Yu; Hou, Zhuocheng; Yang, Ning

    2016-01-01

    The Creeper trait, a classical monogenic phenotype of chicken, is controlled by a dominant semi-lethal gene. This trait has been widely cited in the genetics and molecular biology textbooks for illustrating autosomal dominant semi-lethal inheritance over decades. However, the genetic basis of the Creeper trait remains unknown. Here we have utilized ultra-deep sequencing and extensive analysis for targeting causative mutation controlling the Creeper trait. Our results indicated that the deletion of Indian hedgehog (IHH) gene was only found in the whole-genome sequencing data of lethal embryos and Creeper chickens. Large scale segregation analysis demonstrated that the deletion of IHH was fully linked with early embryonic death and the Creeper trait. Expression analysis showed a much lower expression of IHH in Creeper than wild-type chickens. We therefore suggest the deletion of IHH to be the causative mutation for the Creeper trait in chicken. Our findings unravel the genetic basis of the longstanding Creeper phenotype mystery in chicken as the same gene also underlies bone dysplasia in human and mouse, and thus highlight the significance of IHH in animal development and human haploinsufficiency disorders. PMID:27439785

  7. The Use of Coincident Synthetic Aperture Radar and Visible Imagery to Aid in the Analysis of Photon-Counting Lidar Data Sets Over Complex Ice/Snow Surfaces

    NASA Astrophysics Data System (ADS)

    Horan, Kimberly H.

    Qualitative and quantitative analysis of multi-sensor data is becoming increasingly useful as a method of improving our understanding of complex environments, and can be an effective tool in the arsenal to help climate scientists to predict sea level rise due to change in the mass balance of large glaciers in the Arctic and Antarctic. A novel approach to remote sensing of the continuously changing polar environment involves the use of coincident RADARSAT-2 synthetic aperture radar (SAR) imagery and Landsat 7 visible/near-infrared imagery, combined with digital elevation models (DEM) developed from Multiple Altimeter Beam Experimental Lidar (MABEL) data sets. MABEL is a scaled down model of the lidar altimeter that will eventually be flown on ICESat-2, and provides dense along-track and moderate slope (cross-track) elevation data over narrow (~198 m) aircraft transects. Because glacial terrain consists of steep slopes, crevices, glacial lakes, and outflow into the sea, accurate slope information is critical to our understanding of any changes that may be happening in the ice sheets. RADARSAT-2 operates in the C-band, at a wavelength of 5.55 cm, and was chosen partly for its ability to image the Earth under all atmospheric conditions, including clouds. The SAR images not only provide spatial context for the elevation data found using the lidar, but also offer key insights into the consistency of the snow and ice making up the glacier, giving us some idea of mean temperature and surface conditions on the ice sheet. Finally, Landsat 7 images provide us with information on the extent of the glacier, and additional understanding of the state of the glacial surface. To aid in the analysis of the three data sets, proper preparation of each data set must first be performed. For the lidar data, this required the development of a new data reduction technique, based on statistical analysis, to reduce the number of received photons to those representing only the surface return

  8. Comparative analysis of the biaxial mechanical behavior of carotid wall tissue and biological and synthetic materials used for carotid patch angioplasty.

    PubMed

    Kamenskiy, Alexey V; Pipinos, Iraklis I; MacTaggart, Jason N; Kazmi, Syed A Jaffar; Dzenis, Yuris A

    2011-11-01

    Patch angioplasty is the most common technique used for the performance of carotid endarterectomy. A large number of patching materials are available for use while new materials are being continuously developed. Surprisingly little is known about the mechanical properties of these materials and how these properties compare with those of the carotid artery wall. Mismatch of the mechanical properties can produce mechanical and hemodynamic effects that may compromise the long-term patency of the endarterectomized arterial segment. The aim of this paper was to systematically evaluate and compare the biaxial mechanical behavior of the most commonly used patching materials. We compared PTFE (n  =  1), Dacron (n  =  2), bovine pericardium (n  =  10), autogenous greater saphenous vein (n  =  10), and autogenous external jugular vein (n  =  9) with the wall of the common carotid artery (n  =  18). All patching materials were found to be significantly stiffer than the carotid wall in both the longitudinal and circumferential directions. Synthetic patches demonstrated the most mismatch in stiffness values and vein patches the least mismatch in stiffness values compared to those of the native carotid artery. All biological materials, including the carotid artery, demonstrated substantial nonlinearity, anisotropy, and variability; however, the behavior of biological and biologically-derived patches was both qualitatively and quantitatively different from the behavior of the carotid wall. The majority of carotid arteries tested were stiffer in the circumferential direction, while the opposite anisotropy was observed for all types of vein patches and bovine pericardium. The rates of increase in the nonlinear stiffness over the physiological stress range were also different for the carotid and patching materials. Several carotid wall samples exhibited reverse anisotropy compared to the average behavior of the carotid tissue. A similar characteristic was

  9. The virtual observatory service TheoSSA: Establishing a database of synthetic stellar flux standards . II. NLTE spectral analysis of the OB-type subdwarf Feige 110

    NASA Astrophysics Data System (ADS)

    Rauch, T.; Rudkowski, A.; Kampka, D.; Werner, K.; Kruk, J. W.; Moehler, S.

    2014-06-01

    Context. In the framework of the Virtual Observatory (VO), the German Astrophysical VO (GAVO) developed the registered service TheoSSA (Theoretical Stellar Spectra Access). It provides easy access to stellar spectral energy distributions (SEDs) and is intended to ingest SEDs calculated by any model-atmosphere code, generally for all effective temperatures, surface gravities, and elemental compositions. We will establish a database of SEDs of flux standards that are easily accessible via TheoSSA's web interface. Aims: The OB-type subdwarf Feige 110 is a standard star for flux calibration. State-of-the-art non-local thermodynamic equilibrium stellar-atmosphere models that consider opacities of species up to trans-iron elements will be used to provide a reliable synthetic spectrum to compare with observations. Methods: In case of Feige 110, we demonstrate that the model reproduces not only its overall continuum shape from the far-ultraviolet (FUV) to the optical wavelength range but also the numerous metal lines exhibited in its FUV spectrum. Results: We present a state-of-the-art spectral analysis of Feige 110. We determined , log g = 6.00 ± 0.20, and the abundances of He, N, P, S, Ti, V, Cr, Mn, Fe, Co, Ni, Zn, and Ge. Ti, V, Mn, Co, Zn, and Ge were identified for the first time in this star. Upper abundance limits were derived for C, O, Si, Ca, and Sc. Conclusions: The TheoSSA database of theoretical SEDs of stellar flux standards guarantees that the flux calibration of astronomical data and cross-calibration between different instruments can be based on models and SEDs calculated with state-of-the-art model-atmosphere codes. Based on observations with the NASA/ESA Hubble Space Telescope, obtained at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS5-26666. Based on observations made with the NASA-CNES-CSA Far Ultraviolet Spectroscopic Explorer. Table 2, Figs. 3 and

  10. Lethal Mutagenesis of HIV with Mutagenic Nucleoside Analogs

    NASA Astrophysics Data System (ADS)

    Loeb, Lawrence A.; Essigmann, John M.; Kazazi, Farhad; Zhang, Jue; Rose, Karl D.; Mullins, James I.

    1999-02-01

    The human immunodeficiency virus (HIV) replicates its genome and mutates at exceptionally high rates. As a result, the virus is able to evade immunological and chemical antiviral agents. We tested the hypothesis that a further increase in the mutation rate by promutagenic nucleoside analogs would abolish viral replication. We evaluated deoxynucleoside analogs for lack of toxicity to human cells, incorporation by HIV reverse transcriptase, resistance to repair when incorporated into the DNA strand of an RNA\\cdot DNA hybrid, and mispairing at high frequency. Among the candidates tested, 5-hydroxydeoxycytidine (5-OH-dC) fulfilled these criteria. In seven of nine experiments, the presence of this analog resulted in the loss of viral replicative potential after 9-24 sequential passages of HIV in human CEM cells. In contrast, loss of viral replication was not observed in 28 control cultures passaged in the absence of the nucleoside analog, nor with other analogs tested. Sequence analysis of a portion of the HIV reverse transcriptase gene demonstrated a disproportionate increase in G -> A substitutions, mutations predicted to result from misincorporation of 5-OH-dC into the cDNA during reverse transcription. Thus, "lethal mutagenesis" driven by the class of deoxynucleoside analogs represented by 5-OH-dC could provide a new approach to treating HIV infections and, potentially, other viral infections.

  11. Lethal and sub-lethal effects of faecal deltamethrin residues on dung-feeding insects.

    PubMed

    Mann, C M; Barnes, S; Offer, B; Wall, R

    2015-06-01

    Endectocides administered to livestock to facilitate pest and parasite control may be excreted in the faeces at concentrations that are toxic to coprophagous insects, including species of ecological importance. Although much research has focused on the effects of macrocyclic lactones, relatively less attention has been given to any similar impacts of the widely used pyrethroid insecticides. Here, the effects of faecal residues of the pyrethroid deltamethrin after application to Holstein-Friesian cattle in a proprietary pour-on formulation are examined. Freshly dropped dung was collected 1, 3, 5 and 7 days after treatment and from an untreated control group. In laboratory bioasssays, female Lucilia sericata (Diptera: Calliphoridae) blow flies matured significantly smaller egg batches and had a lower percentage of eggs hatch after feeding on dung collected for up to 5 days after treatment, compared with flies feeding on dung from untreated cattle. In the field, artificial dung pats were constructed from the collected dung and left on pastureland for 7 days before being retrieved and searched for insects. Significantly more adult Diptera emerged from the faeces of untreated cattle than from the dung of treated cattle collected on days 1 and 3 after treatment. Adult Coleoptera were found in lower numbers in the dung of treated animals compared with control dung, suggesting a repellent effect. The results indicate that deltamethrin residues in cattle faeces have a range of lethal and sub-lethal effects on dung-feeding insects for up to a week after treatment, but that the precise duration and nature of toxicity varies depending on the sensitivity of the insect in question. PMID:25594879

  12. Application of the Organic Synthetic Designs to Astrobiology

    NASA Astrophysics Data System (ADS)

    Kolb, V. M.

    2009-12-01

    In this paper we propose a synthesis of the heterocyclic compounds and the insoluble materials on the meteorites. Our synthetic scheme involves the reaction of sugars and amino acids, the so-called Maillard reaction. We have developed this scheme based on the combined analysis of the regular and retrosynthetic organic synthetic principles. The merits of these synthetic methods for the prebiotic design are addressed.

  13. EXPEDITIOUS SYNTHETIC TRANSFORMATIONS USING MICROWAVES

    EPA Science Inventory

    Microwave-expedited solvent-free synthetic processes will be described for the synthesis of a variety of industrially significant compounds and intermediates namely, enamines, nitroalkenes, enones, oxidized sulfur compounds and ionic liquids. This solvent-free synthetic methodolo...

  14. The danger assessment: validation of a lethality risk assessment instrument for intimate partner femicide.

    PubMed

    Campbell, Jacquelyn C; Webster, Daniel W; Glass, Nancy

    2009-04-01

    The Danger Assessment (DA) is an instrument designed to assess the likelihood of lethality or near lethality occurring in a case of intimate partner violence. This article describes the development, psychometric validation, and suggestions for use of the DA. An 11-city study of intimate partner femicide used multivariate analysis to test the predictive validity of the risk factors on the DA from intimate partner femicide cases (N = 310) compared with 324 abused women in the same cities (controls). The results were used to revise the DA (four items added; one "double-barreled" item divided into two), and the calculated weights (adjusted odds ratios) used to develop a scoring algorithm with levels of risk. These levels of risk were then tested with an independent sample of attempted femicides (N = 194) with a final outcome of .90 of the cases included in the area under the receiver operating characteristic (ROC) curve. PMID:18667689

  15. Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicans.

    PubMed Central

    Blasi, E; Mazzolla, R; Pitzurra, L; Barluzzi, R; Bistoni, F

    1993-01-01

    We have studied the effects of picolinic acid (PLA), a product of tryptophan degradation, on mouse susceptibility to intracerebral infection with Candida albicans. We show that intraperitoneal administration of PLA significantly enhances the median survival time of mice inoculated with the lethal challenge. Furthermore, intracerebral administration of this agent induces a protective state against the local lethal infection, the phenomenon depending upon the administration schedule and doses of PLA employed. According to survival data, yeast growth in the brain as well as yeast colonization of the kidneys are drastically reduced in PLA-treated mice compared with those for untreated controls. Northern (RNA) blot analysis of brain tissues demonstrates that mRNA levels specific for tumor necrosis factor and interleukin 1 are augmented and induced, respectively, after inoculation of PLA. These results indicate that PLA has a protective effect likely involving elicitation of a cytokine response in vivo against fungal infections. Images PMID:7506894

  16. Growth, photosynthetic and respiratory responses to sub-lethal copper concentrations in Scenedesmus incrassatulus (Chlorophyceae).

    PubMed

    Perales-Vela, Hugo Virgilio; González-Moreno, Sergio; Montes-Horcasitas, Carmen; Cañizares-Villanueva, Rosa Olivia

    2007-05-01

    In the present paper we investigated the effects of sub-lethal concentrations of Cu2+ in the growth and metabolism of Scenedesmus incrassatulus. We found that the effect of Cu2+ on growth, photosynthetic pigments (chlorophylls and carotenoids) and metabolism do not follow the same pattern. Photosynthesis was more sensitive than respiration. The analysis of chlorophyll a fluorescence transient shows that the effect of sub-lethal Cu2+ concentration in vivo, causes a reduction of the active PSII reaction centers and the primary charge separation, decreasing the quantum yield of PSII, the electron transport rate and the photosynthetic O2 evolution. The order of sensitivity found was: Growth>photosynthetic pigments content=photosynthetic O2 evolution>photosynthetic electron transport>respiration. The uncoupled relationship between growth and metabolism is discussed. PMID:17267014

  17. Synthetic Foveal Imaging Technology

    NASA Technical Reports Server (NTRS)

    Monacos, Steve P. (Inventor); Hoenk, Michael E. (Inventor); Nikzad, Shouleh (Inventor)

    2013-01-01

    Apparatuses and methods are disclosed that create a synthetic fovea in order to identify and highlight interesting portions of an image for further processing and rapid response. Synthetic foveal imaging implements a parallel processing architecture that uses reprogrammable logic to implement embedded, distributed, real-time foveal image processing from different sensor types while simultaneously allowing for lossless storage and retrieval of raw image data. Real-time, distributed, adaptive processing of multi-tap image sensors with coordinated processing hardware used for each output tap is enabled. In mosaic focal planes, a parallel-processing network can be implemented that treats the mosaic focal plane as a single ensemble rather than a set of isolated sensors. Various applications are enabled for imaging and robotic vision where processing and responding to enormous amounts of data quickly and efficiently is important.

  18. Synthetic ligaments. Current status.

    PubMed

    Funk, F J

    1987-06-01

    Many techniques for ligamentous reconstruction have been developed in recent years. In the United States, injuries of the knee have been increasingly treated with innovative methods of surgical reconstruction, most of which have used normal structures. There are obvious theoretic advantages in using synthetic materials that might simplify surgery, spare normal tissues, and possibly facilitate stronger repairs. To these ends, several synthetic substances have been used experimentally and clinically. This is a brief summary of eight of the materials that have been or are being investigated in the United States. Some are no longer in use, others are currently being used in clinical trials. As of this writing, only the Gortex ligament has received a general device release from the Food and Drug Administration (FDA). PMID:3034461

  19. Wholly Synthetic Molecular Machines.

    PubMed

    Cheng, Chuyang; Stoddart, J Fraser

    2016-06-17

    The past quarter of a century has witnessed an increasing engagement on the part of physicists and chemists in the design and synthesis of molecular machines de novo. This minireview traces the development of artificial molecular machines from their prototypes in the form of shuttles and switches to their emergence as motors and pumps where supplies of energy in the form of chemical fuel, electrochemical potential and light activation become a minimum requirement for them to function away from equilibrium. The challenge facing this rapidly growing community of scientists and engineers today is one of putting wholly synthetic molecules to work, both individually and as collections. Here, we highlight some of the recent conceptual and practical advances relating to the operation of wholly synthetic rotary and linear motors. PMID:26833859

  20. Engineered Asymmetric Synthetic Vesicles

    NASA Astrophysics Data System (ADS)

    Lu, Li; Chiarot, Paul

    2013-11-01

    Synthetic vesicles are small, fluid-filled spheres that are enclosed by a bilayer of lipid molecules. They can be used as models for investigating membrane biology and as delivery vehicles for pharmaceuticals. In practice, it is difficult to simultaneously control membrane asymmetry, unilamellarity, vesicle size, vesicle-to-vesicle uniformity, and luminal content. Membrane asymmetry, where each leaflet of the bilayer is composed of different lipids, is of particular importance as it is a feature of most natural membranes. In this study, we leverage microfluidic technology to build asymmetric vesicles at high-throughput. We use the precise flow control offered by microfluidic devices to make highly uniform emulsions, with controlled internal content, that serve as templates to build the synthetic vesicles. Flow focusing, dielectrophoretic steering, and interfacial lipid self-assembly are critical procedures performed on-chip to produce the vesicles. Fluorescent and confocal microscopy are used to evaluate the vesicle characteristics.