Sample records for synthetic dosage lethality

  1. Synthetic dosage lethality in the human metabolic network is highly predictive of tumor growth and cancer patient survival. (United States)

    Megchelenbrink, Wout; Katzir, Rotem; Lu, Xiaowen; Ruppin, Eytan; Notebaart, Richard A


    Synthetic dosage lethality (SDL) denotes a genetic interaction between two genes whereby the underexpression of gene A combined with the overexpression of gene B is lethal. SDLs offer a promising way to kill cancer cells by inhibiting the activity of SDL partners of activated oncogenes in tumors, which are often difficult to target directly. As experimental genome-wide SDL screens are still scarce, here we introduce a network-level computational modeling framework that quantitatively predicts human SDLs in metabolism. For each enzyme pair (A, B) we systematically knock out the flux through A combined with a stepwise flux increase through B and search for pairs that reduce cellular growth more than when either enzyme is perturbed individually. The predictive signal of the emerging network of 12,000 SDLs is demonstrated in five different ways. (i) It can be successfully used to predict gene essentiality in shRNA cancer cell line screens. Moving to clinical tumors, we show that (ii) SDLs are significantly underrepresented in tumors. Furthermore, breast cancer tumors with SDLs active (iii) have smaller sizes and (iv) result in increased patient survival, indicating that activation of SDLs increases cancer vulnerability. Finally, (v) patient survival improves when multiple SDLs are present, pointing to a cumulative effect. This study lays the basis for quantitative identification of cancer SDLs in a model-based mechanistic manner. The approach presented can be used to identify SDLs in species and cell types in which "omics" data necessary for data-driven identification are missing.

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

    Directory of Open Access Journals (Sweden)

    Faty Mahamadou


    Full Text Available Abstract 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.

  3. Synthetic lethality between gene defects affecting a single non-essential molecular pathway with reversible steps.

    Directory of Open Access Journals (Sweden)

    Andrei Zinovyev


    Full Text Available Systematic analysis of synthetic lethality (SL constitutes a critical tool for systems biology to decipher molecular pathways. The most accepted mechanistic explanation of SL is that the two genes function in parallel, mutually compensatory pathways, known as between-pathway SL. However, recent genome-wide analyses in yeast identified a significant number of within-pathway negative genetic interactions. The molecular mechanisms leading to within-pathway SL are not fully understood. Here, we propose a novel mechanism leading to within-pathway SL involving two genes functioning in a single non-essential pathway. This type of SL termed within-reversible-pathway SL involves reversible pathway steps, catalyzed by different enzymes in the forward and backward directions, and kinetic trapping of a potentially toxic intermediate. Experimental data with recombinational DNA repair genes validate the concept. Mathematical modeling recapitulates the possibility of kinetic trapping and revealed the potential contributions of synthetic, dosage-lethal interactions in such a genetic system as well as the possibility of within-pathway positive masking interactions. Analysis of yeast gene interaction and pathway data suggests broad applicability of this novel concept. These observations extend the canonical interpretation of synthetic-lethal or synthetic-sick interactions with direct implications to reconstruct molecular pathways and improve therapeutic approaches to diseases such as cancer.

  4. Synthetically lethal nanoparticles for treatment of endometrial cancer (United States)

    Ebeid, Kareem; Meng, Xiangbing; Thiel, Kristina W.; Do, Anh-Vu; Geary, Sean M.; Morris, Angie S.; Pham, Erica L.; Wongrakpanich, Amaraporn; Chhonker, Yashpal S.; Murry, Daryl J.; Leslie, Kimberly K.; Salem, Aliasger K.


    Uterine serous carcinoma, one of the most aggressive types of endometrial cancer, is characterized by poor outcomes and mutations in the tumour suppressor p53. Our objective was to engender synthetic lethality to paclitaxel (PTX), the frontline treatment for endometrial cancer, in tumours with mutant p53 and enhance the therapeutic efficacy using polymeric nanoparticles (NPs). First, we identified the optimal NP formulation through comprehensive analyses of release profiles and cellular-uptake and cell viability studies. Not only were PTX-loaded NPs superior to PTX in solution, but the combination of PTX-loaded NPs with the antiangiogenic molecular inhibitor BIBF 1120 (BIBF) promoted synthetic lethality specifically in cells with the loss-of-function (LOF) p53 mutation. In a xenograft model of endometrial cancer, this combinatorial therapy resulted in a marked inhibition of tumour progression and extended survival. Together, our data provide compelling evidence for future studies of BIBF- and PTX-loaded NPs as a therapeutic opportunity for LOF p53 cancers.

  5. Antiangiogenic Resistance and Cancer Metabolism: Opportunities for Synthetic Lethality. (United States)

    Lord, Simon; Funes, Juan M; Harris, Adrian L; Quintela-Fandino, Miguel


    Antiangiogenic resistance is a major problem in cancer therapeutics. Preclinical research has identified several compensatory proangiogenic pathways that arise upon vascular endothelial growth factor inhibition, several of which have led to the development of novel drugs. However, the combination of two or more targeted agents in the angiogenesis system is hampered by toxicity, as the system is involved in normal physiology. We propose a different approach for improving the efficacy of this drug class, which takes advantage of aberrant cancer metabolism. Several features distinguish cancer metabolism from that of normal cells, including increased glycolysis, glutaminolysis, and pentose-phosphate shunt, as well as an anaplerotic shift of the Krebs cycle. In addition, these aberrations are driven by most of the common mutations that can be targeted by drugs. Antiangiogenics may hamper the ability of cancer to sustain aberrant metabolism due to their impacts on nutrient and oxygen supplies, and thus they may induce some metabolic pathways to become essential for tumor survival (induced essentiality or contextual lethality, a type of synthetic lethality). Thus, some metabolic and signaling pathways that are otherwise nonessential may induce synthetic lethality when inhibited in combination with antiangiogenics. The key problems, however, are interpatient and intratumor heterogeneity, as not all patients with the same tumor type show the same metabolic traits and the same metabolic reprogramming in response to antiangiogenics. With each cancer there are heterogeneous hypoxic areas. Integrating dynamic tracking of metabolism may allow us to tailor our choices of companion drugs with antiangiogenics, taking advantage of window-of-opportunity designs.

  6. Synthetic Lethality Triggered by Combining Olaparib with BRCA2-Rad51 Disruptors. (United States)

    Falchi, Federico; Giacomini, Elisa; Masini, Tiziana; Boutard, Nicolas; Di Ianni, Lorenza; Manerba, Marcella; Farabegoli, Fulvia; Rossini, Lara; Robertson, Janet; Minucci, Saverio; Pallavicini, Isabella; Di Stefano, Giuseppina; Roberti, Marinella; Pellicciari, Roberto; Cavalli, Andrea


    In BRCA2-defective cells, poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors can trigger synthetic lethality, as two independent DNA-repairing mechanisms are simultaneously impaired. Here, we have pharmacologically induced synthetic lethality, which was triggered by combining two different small organic molecules. When administered with a BRCA2-Rad51 disruptor in nonmutant cells, Olaparib showed anticancer activity comparable to that shown when administered alone in BRCA2-defective cells. This strategy could represent an innovative approach to anticancer drug discovery and could be extended to other synthetic lethality pathways.

  7. Malignancy of Cancers and Synthetic Lethal Interactions Associated With Mutations of Cancer Driver Genes. (United States)

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


    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 experiments to validate

  8. Anti-Cancer Drug Discovery Using Synthetic Lethal Chemogenetic (SLC) Analysis

    National Research Council Canada - National Science Library

    Bellows, David S


    I am developing a novel cell-based small-molecule screening approach that can identify inhibitors of any non-essential protein function through a surrogate synthetic lethal phenotype in the baker's...

  9. Anti-Cancer Drug Discovery Using Synthetic Lethal Chemogenetic (SLC) Analysis

    National Research Council Canada - National Science Library

    Bellows, David S


    I am developing a novel cell-based small-molecule screening approach that can identify inhibitors of any non-essential protein function through a surrogate synthetic lethal phenotype in the baker's...

  10. The interaction between daughterless and sex-lethal in triploids: a lethal sex-transforming maternal effect linking sex determination and dosage compensation in Drosophila melanogaster. (United States)

    Cline, T W


    Regulation of Drosophila sex determination and X-chromosome dosage compensation in response to the X-chromosome/autosome (X/A) balance of the zygote is shown to require proper functioning of both the da+ gene in the mother and the Sxl+ gene in the zygote. Previous studies led to the hypothesis that zygotic Sxl+ alleles are differentially active in females (XXAA) vs males (XYAA) in response to the X/A balance, and that maternal da+ gene product acts as a positive regulator in this connection. Sxl+ activity was proposed to impose the female developmental sequence on cells which would follow the male sequence in its absence. Important predictions of this proposal are verified. This study focuses primarily on the phenotype of triploid intersexes (XXAAA, X/A = 0.67). They are shown here to survive effects of da and Sxl mutations that would be lethal to diploids. The ambiguous X/A signal of intersexes normally causes them to develop as phenotypic mosaics of male and female tissue. Loss of maternal da+ or zygotic Sxl+ gene function shifts their somatic sexual phenotype to the male alternative. A gain-of-function mutation at Sxl has the opposite effect, imposing female development regardless of the maternal genotype with respect to da. It also reduces their rate of X-linked gene expression. The effects of a duplication of Sxl+ resemble those of the constitutive Sxl allele, but are less extreme. The role of these genes in the process of X-chromosome dosage compensation is inferred indirectly from the strict dependence of the mutations' lethal effects on the X/A balance in haploids, diploids, and triploids, and more directly from the effects of the mutations on the phenotypes of the X-linked neomorphic mutations, Bar and Hairy-wing. The relationship of da+ and Sxl+ gene functions to those of other sex-specific lethal loci in D. melanogaster, and to sex determination mechanisms in other species, is discussed.

  11. The population genetics of X-autosome synthetic lethals and steriles. (United States)

    Lachance, Joseph; Johnson, Norman A; True, John R


    Epistatic interactions are widespread, and many of these interactions involve combinations of alleles at different loci that are deleterious when present in the same individual. The average genetic environment of sex-linked genes differs from that of autosomal genes, suggesting that the population genetics of interacting X-linked and autosomal alleles may be complex. Using both analytical theory and computer simulations, we analyzed the evolutionary trajectories and mutation-selection balance conditions for X-autosome synthetic lethals and steriles. Allele frequencies follow a set of fundamental trajectories, and incompatible alleles are able to segregate at much higher frequencies than single-locus expectations. Equilibria exist, and they can involve fixation of either autosomal or X-linked alleles. The exact equilibrium depends on whether synthetic alleles are dominant or recessive and whether fitness effects are seen in males, females, or both sexes. When single-locus fitness effects and synthetic incompatibilities are both present, population dynamics depend on the dominance of alleles and historical contingency (i.e., whether X-linked or autosomal mutations occur first). Recessive synthetic lethality can result in high-frequency X-linked alleles, and dominant synthetic lethality can result in high-frequency autosomal alleles. Many X-autosome incompatibilities in natural populations may be cryptic, appearing to be single-locus effects because one locus is fixed. We also discuss the implications of these findings with respect to standing genetic variation and the origins of Haldane's rule.

  12. Improving the iMM904 S. cerevisiae metabolic model using essentiality and synthetic lethality data

    Directory of Open Access Journals (Sweden)

    Maranas Costas D


    Full Text Available Abstract Background Saccharomyces cerevisiae is the first eukaryotic organism for which a multi-compartment genome-scale metabolic model was constructed. Since then a sequence of improved metabolic reconstructions for yeast has been introduced. These metabolic models have been extensively used to elucidate the organizational principles of yeast metabolism and drive yeast strain engineering strategies for targeted overproductions. They have also served as a starting point and a benchmark for the reconstruction of genome-scale metabolic models for other eukaryotic organisms. In spite of the successive improvements in the details of the described metabolic processes, even the recent yeast model (i.e., iMM904 remains significantly less predictive than the latest E. coli model (i.e., iAF1260. This is manifested by its significantly lower specificity in predicting the outcome of grow/no grow experiments in comparison to the E. coli model. Results In this paper we make use of the automated GrowMatch procedure for restoring consistency with single gene deletion experiments in yeast and extend the procedure to make use of synthetic lethality data using the genome-scale model iMM904 as a basis. We identified and vetted using literature sources 120 distinct model modifications including various regulatory constraints for minimal and YP media. The incorporation of the suggested modifications led to a substantial increase in the fraction of correctly predicted lethal knockouts (i.e., specificity from 38.84% (87 out of 224 to 53.57% (120 out of 224 for the minimal medium and from 24.73% (45 out of 182 to 40.11% (73 out of 182 for the YP medium. Synthetic lethality predictions improved from 12.03% (16 out of 133 to 23.31% (31 out of 133 for the minimal medium and from 6.96% (8 out of 115 to 13.04% (15 out of 115 for the YP medium. Conclusions Overall, this study provides a roadmap for the computationally driven correction of multi-compartment genome

  13. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. (United States)

    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


    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.

  14. Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma (United States)

    Yang, Yibin; Shaffer, Arthur L.; Emre, N.C. Tolga; Ceribelli, Michele; Zhang, Meili; Wright, George; Xiao, Wenming; Powell, John; Platig, John; Kohlhammer, Holger; Young, Ryan M.; Zhao, Hong; Yang, Yandan; Xu, Weihong; Buggy, Joseph J.; Balasubramanian, Sriram; Mathews, Lesley A.; Shinn, Paul; Guha, Rajarshi; Ferrer, Marc; Thomas, Craig; Waldmann, Thomas A.; Staudt, Louis M.


    Summary Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B-cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and also amplify pro-survival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor (BCR) signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies. PMID:22698399

  15. Synthetic lethal interaction between the tumour suppressor STAG2 and its paralog STAG1. (United States)

    Benedetti, Lorena; Cereda, Matteo; Monteverde, LeeAnn; Desai, Nikita; Ciccarelli, Francesca D


    Cohesin is a multi-protein complex that tethers sister chromatids during mitosis and mediates DNA repair, genome compartmentalisation and regulation of gene expression. Cohesin subunits frequently acquire cancer loss-of-function alterations and act as tumour suppressors in several tumour types. This has led to increased interest in cohesin as potential target in anti-cancer therapy. Here we show that the loss-of-function of STAG2, a core component of cohesin and an emerging tumour suppressor, leads to synthetic dependency of mutated cancer cells on its paralog STAG1. STAG1 and STAG2 share high sequence identity, encode mutually exclusive cohesin subunits and retain partially overlapping functions. We inhibited STAG1 and STAG2 in several cancer cell lines where the two genes have variable mutation and copy number status. In all cases, we observed that the simultaneous blocking of STAG1 and STAG2 significantly reduces cell proliferation. We further confirmed the synthetic lethal interaction developing a vector-free CRISPR system to induce STAG1/STAG2 double gene knockout. We provide strong evidence that STAG1 is a promising therapeutic target in cancers with inactivating alterations of STAG2.

  16. A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments (United States)

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


    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

  17. Roles of PARP inhibitor in synthetic lethality and as a sensitizer in cancer therapy

    International Nuclear Information System (INIS)

    Hirai, Takahisa; Masutani, Mitsuko; Sasai, Keisuke


    In a search for novel chemotherapeutic targets for cancer, recent interest has focused on DNA repair pathways. Poly (ADP-ribose) polymerase (PARP)-1 is an important protein for base excision repair and inhibitors of this pathway show anti-cancer effects when used as a mono-therapy for BRCA-deficient cancers in clinical trials. The results of such studies proved the concept of ''synthetic lethality'' by targeting DNA repair pathways. Considering the action of the PARP inhibitor (PARPi) in DNA repair pathways, PARPi is also predicted to act as a sensitizer for DNA damaging agents, such as certain chemotherapeutic drugs and radiation. A number of clinical trials using PARPi in combination with existing therapies are underway. We investigated the use of PARPi as a radiosensitizer for high LET (linear energy transfer) radiation. PARPi showed the radiosensitization effect of carbon-ion radiation, and the radiosensitization effect of PARPi was attributed to a delay in the DNA damage response and double strand break processing. Via its effects on DNA repair, the PARP inhibitor might be applicable as a radiosensitizer for a wide range of therapeutic LET radiation. This study suggests that development of research into DNA repair pathways could yield still further targets for cancer therapy. (author)

  18. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. (United States)

    Asim, Mohammad; Tarish, Firas; Zecchini, Heather I; Sanjiv, Kumar; Gelali, Eleni; Massie, Charles E; Baridi, Ajoeb; Warren, Anne Y; Zhao, Wanfeng; Ogris, Christoph; McDuffus, Leigh-Anne; Mascalchi, Patrice; Shaw, Greg; Dev, Harveer; Wadhwa, Karan; Wijnhoven, Paul; Forment, Josep V; Lyons, Scott R; Lynch, Andy G; O'Neill, Cormac; Zecchini, Vincent R; Rennie, Paul S; Baniahmad, Aria; Tavaré, Simon; Mills, Ian G; Galanty, Yaron; Crosetto, Nicola; Schultz, Niklas; Neal, David; Helleday, Thomas


    Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo. Our data suggest that ADT can functionally impair HR prior to the development of castration resistance and that, this potentially could be exploited therapeutically using PARP inhibitors in combination with androgen-deprivation therapy upfront in advanced or high-risk prostate cancer.Tumours with homologous recombination (HR) defects become sensitive to PARPi. Here, the authors show that androgen receptor (AR) regulates HR and AR inhibition activates the PARP pathway in vivo, thus inhibition of both AR and PARP is required for effective treatment of high risk prostate cancer.

  19. Targeting Synthetic Lethal Interactions between Myc and the eIF4F Complex Impedes Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Chen-Ju Lin


    Full Text Available The energetically demanding process of translation is linked to multiple signaling events through mTOR-mediated regulation of eukaryotic initiation factor (eIF4F complex assembly. Disrupting mTOR constraints on eIF4F activity can be oncogenic and alter chemotherapy response, making eIF4F an attractive antineoplastic target. Here, we combine a newly developed inducible RNAi platform and pharmacological targeting of eIF4F activity to define a critical role for endogenous eIF4F in Myc-dependent tumor initiation. We find elevated Myc levels are associated with deregulated eIF4F activity in the prelymphomatous stage of the Eμ-Myc lymphoma model. Inhibition of eIF4F is synthetic lethal with elevated Myc in premalignant pre-B/B cells resulting in reduced numbers of cycling pre-B/B cells and delayed tumor onset. At the organismal level, eIF4F suppression affected a subset of normal regenerating cells, but this was well tolerated and rapidly and completely reversible. Therefore, eIF4F is a key Myc client that represents a tumor-specific vulnerability.

  20. Systematic screening of isogenic cancer cells identifies DUSP6 as context-specific synthetic lethal target in melanoma

    DEFF Research Database (Denmark)

    Wittig-Blaich, Stephanie; Wittig, Rainer; Schmidt, Steffen


    Next-generation sequencing has dramatically increased genome-wide profiling options and conceptually initiates the possibility for personalized cancer therapy. State-of-the-art sequencing studies yield large candidate gene sets comprising dozens or hundreds of mutated genes. However, few technolo...... to identify new drug targets via the identification of the tumor suppressor DUSP6 as potential synthetic lethal target in melanoma cell lines with BRAF V600E mutations and high DUSP6 expression....

  1. ATM inhibition induces synthetic lethality and enhances sensitivity of PTEN-deficient breast cancer cells to cisplatin. (United States)

    Li, Ke; Yan, Huaying; Guo, Wenhao; Tang, Mei; Zhao, Xinyu; Tong, Aiping; Peng, Yong; Li, Qintong; Yuan, Zhu


    PTEN deficiency often causes defects in DNA damage repair. Currently, effective therapies for breast cancer are lacking. ATM is an attractive target for cancer treatment. Previous studies suggested a synthetic lethality between PTEN and PARP. However, the synthetically lethal interaction between PTEN and ATM in breast cancer has not been reported. Moreover, the mechanism remains elusive. Here, using KU-60019, an ATM kinase inhibitor, we investigated ATM inhibition as a synthetically lethal strategy to target breast cancer cells with PTEN defects. We found that KU-60019 preferentially sensitizes PTEN-deficient MDA-MB-468 breast cancer cells to cisplatin, though it also slightly enhances sensitivity of PTEN wild-type breast cancer cells. The increased cytotoxic sensitivity is associated with apoptosis, as evidenced by flow cytometry and PARP cleavage. Additionally, the increase of DNA damage accumulation due to the decreased capability of DNA repair, as indicated by γ-H2AX and Rad51 foci, also contributed to this selective cytotoxicity. Mechanistically, compared with PTEN wild-type MDA-MB-231 cells, PTEN-deficient MDA-MB-468 cells have lower level of Rad51, higher ATM kinase activity, and display the elevated level of DNA damage. Moreover, these differences could be further enlarged by cisplatin. Our findings suggest that ATM is a promising target for PTEN-defective breast cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. A Synthetic Lethal Screen Identifies a Role for Lin-44/Wnt in C. elegans Embryogenesis. (United States)

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


    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. 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. 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.

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

    DEFF Research Database (Denmark)

    Aziz, Ramy K.; Monk, Jonathan M.; Lewis, R. M.


    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...... 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...

  4. Synthetic Lethal Screen Identifies NF-κB as a Target for Combination Therapy with Topotecan for patients with Neuroblastoma

    International Nuclear Information System (INIS)

    Tsang, Patricia S; Cheuk, Adam T; Chen, Qing-Rong; Song, Young K; Badgett, Thomas C; Wei, Jun S; Khan, Javed


    Despite aggressive multimodal treatments the overall survival of patients with high-risk neuroblastoma remains poor. The aim of this study was to identify novel combination chemotherapy to improve survival rate in patients with high-risk neuroblastoma. We took a synthetic lethal approach using a siRNA library targeting 418 apoptosis-related genes and identified genes and pathways whose inhibition synergized with topotecan. Microarray analyses of cells treated with topotecan were performed to identify if the same genes or pathways were altered by the drug. An inhibitor of this pathway was used in combination with topotecan to confirm synergism by in vitro and in vivo studies. We found that there were nine genes whose suppression synergized with topotecan to enhance cell death, and the NF-κB signaling pathway was significantly enriched. Microarray analysis of cells treated with topotecan revealed a significant enrichment of NF-κB target genes among the differentially altered genes, suggesting that NF-κB pathway was activated in the treated cells. Combination of topotecan and known NF-κB inhibitors (NSC 676914 or bortezomib) significantly reduced cell growth and induced caspase 3 activity in vitro. Furthermore, in a neuroblastoma xenograft mouse model, combined treatment of topotecan and bortezomib significantly delayed tumor formation compared to single-drug treatments. Synthetic lethal screening provides a rational approach for selecting drugs for use in combination therapy and warrants clinical evaluation of the efficacy of the combination of topotecan and bortezomib or other NF-κB inhibitors in patients with high risk neuroblastoma

  5. Synthetic Lethal Screen Identifies NF-κB as a Target for Combination Therapy with Topotecan for patients with Neuroblastoma

    Directory of Open Access Journals (Sweden)

    Tsang Patricia S


    Full Text Available Abstract Background Despite aggressive multimodal treatments the overall survival of patients with high-risk neuroblastoma remains poor. The aim of this study was to identify novel combination chemotherapy to improve survival rate in patients with high-risk neuroblastoma. Methods We took a synthetic lethal approach using a siRNA library targeting 418 apoptosis-related genes and identified genes and pathways whose inhibition synergized with topotecan. Microarray analyses of cells treated with topotecan were performed to identify if the same genes or pathways were altered by the drug. An inhibitor of this pathway was used in combination with topotecan to confirm synergism by in vitro and in vivo studies. Results We found that there were nine genes whose suppression synergized with topotecan to enhance cell death, and the NF-κB signaling pathway was significantly enriched. Microarray analysis of cells treated with topotecan revealed a significant enrichment of NF-κB target genes among the differentially altered genes, suggesting that NF-κB pathway was activated in the treated cells. Combination of topotecan and known NF-κB inhibitors (NSC 676914 or bortezomib significantly reduced cell growth and induced caspase 3 activity in vitro. Furthermore, in a neuroblastoma xenograft mouse model, combined treatment of topotecan and bortezomib significantly delayed tumor formation compared to single-drug treatments. Conclusions Synthetic lethal screening provides a rational approach for selecting drugs for use in combination therapy and warrants clinical evaluation of the efficacy of the combination of topotecan and bortezomib or other NF-κB inhibitors in patients with high risk neuroblastoma.

  6. CSNK1E/CTNNB1 Are Synthetic Lethal To TP53 in Colorectal Cancer and Are Markers for Prognosis

    Directory of Open Access Journals (Sweden)

    Khong-Loon Tiong


    Full Text Available Two genes are called synthetic lethal (SL if their simultaneous mutations lead to cell death, but each individual mutation does not. Targeting SL partners of mutated cancer genes can kill cancer cells specifically, but leave normal cells intact. We present an integrated approach to uncovering SL pairs in colorectal cancer (CRC. Screening verified SL pairs using microarray gene expression data of cancerous and normal tissues, we first identified potential functionally relevant (simultaneously differentially expressed gene pairs. From the top-ranked pairs, ~20 genes were chosen for immunohistochemistry (IHC staining in 171 CRC patients. To find novel SL pairs, all 169 combined pairs from the individual IHC were synergistically correlated to five clinicopathological features, e.g. overall survival. Of the 11 predicted SL pairs, MSH2-POLB and CSNK1E-MYC were consistent with literature, and we validated the top two pairs, CSNK1E-TP53 and CTNNB1-TP53 using RNAi knockdown and small molecule inhibitors of CSNK1E in isogenic HCT-116 and RKO cells. Furthermore, synthetic lethality of CSNK1E and TP53 was verified in mouse model. Importantly, multivariate analysis revealed that CSNK1E-P53, CTNNB1-P53, MSH2-RB1, and BRCA1-WNT5A were independent prognosis markers from stage, with CSNK1E-P53 applicable to early-stage and the remaining three throughout all stages. Our findings suggest that CSNK1E is a promising target for TP53-mutant CRC patients which constitute ~40% to 50% of patients, while to date safety regarding inhibition of TP53 is controversial. Thus the integrated approach is useful in finding novel SL pairs for cancer therapeutics, and it is readily accessible and applicable to other cancers.

  7. MHO1, an evolutionarily conserved gene, is synthetic lethal with PLC1; Mho1p has a role in invasive growth.

    Directory of Open Access Journals (Sweden)

    Ivan D Schlatter

    Full Text Available The novel protein Memo (Mediator of ErbB2 driven cell motility was identified in a screen for ErbB2 interacting proteins and found to have an essential function in cell motility. Memo is evolutionarily conserved with homologs found in all branches of life; the human and yeast proteins have a similarity of >50%. In the present study we used the model organism S. cerevisiae to characterize the Memo-homologue Mho1 (Yjr008wp and to investigate its function in yeast. In a synthetic lethal screen we found MHO1 as a novel synthetic lethal partner of PLC1, which encodes the single phospholipase C in yeast. Double-deleted cells lacking MHO1 and PLC1, proliferate for up to ten generations. Introduction of human Memo into the memoΔplc1Δ strain rescued the synthetic lethal phenotype suggesting that yeast and human proteins have similar functions. Mho1 is present in the cytoplasm and the nucleus of yeast cells; the same distribution of Memo was found in mammalian cells. None of the Memo homologues have a characteristic nuclear localization sequence, however, a conserved nuclear export sequence is found in all. In mammalian cells, blocking nuclear export with Leptomycin B led to nuclear Memo accumulation, suggesting that it is actively exported from the nucleus. In yeast MHO1 expression is induced by stress conditions. Since invasive growth in S. cerevisiea is also stress-induced, we tested Mho1's role in this response. MHO1 deletion had no effect on invasion induced by nutrient deprivation, however, Mho1 overexpression blocked the invasive ability of yeast cells, suggesting that Mho1 might be acting in a dominant negative manner. Taken together, our results show that MHO1 is a novel synthetic lethal interactor with PLC1, and that both gene products are required for proliferation. Moreover, a role for Memo in cell motility/invasion appears to be conserved across species.

  8. Synthetic lethal genetic interactions that decrease somatic cell proliferation in Caenorhabditis elegans identify the alternative RFC CTF18 as a candidate cancer drug target. (United States)

    McLellan, Jessica; O'Neil, Nigel; Tarailo, Sanja; Stoepel, Jan; Bryan, Jennifer; Rose, Ann; Hieter, Philip


    Somatic mutations causing chromosome instability (CIN) in tumors can be exploited for selective killing of cancer cells by knockdown of second-site genes causing synthetic lethality. We tested and statistically validated synthetic lethal (SL) interactions between mutations in six Saccharomyces cerevisiae CIN genes orthologous to genes mutated in colon tumors and five additional CIN genes. To identify which SL interactions are conserved in higher organisms and represent potential chemotherapeutic targets, we developed an assay system in Caenorhabditis elegans to test genetic interactions causing synthetic proliferation defects in somatic cells. We made use of postembryonic RNA interference and the vulval cell lineage of C. elegans as a readout for somatic cell proliferation defects. We identified SL interactions between members of the cohesin complex and CTF4, RAD27, and components of the alternative RFC(CTF18) complex. The genetic interactions tested are highly conserved between S. cerevisiae and C. elegans and suggest that the alternative RFC components DCC1, CTF8, and CTF18 are ideal therapeutic targets because of their mild phenotype when knocked down singly in C. elegans. Furthermore, the C. elegans assay system will contribute to our knowledge of genetic interactions in a multicellular animal and is a powerful approach to identify new cancer therapeutic targets.

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

    Directory of Open Access Journals (Sweden)

    Ramy Karam Aziz


    Full Text Available 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.

  10. Synthetic Genetic Targeting of Genome Instability in Cancer

    International Nuclear Information System (INIS)

    Sajesh, Babu V.; Guppy, Brent J.; McManus, Kirk J.


    Cancer is a leading cause of death throughout the World. A limitation of many current chemotherapeutic approaches is that their cytotoxic effects are not restricted to cancer cells, and adverse side effects can occur within normal tissues. Consequently, novel strategies are urgently needed to better target cancer cells. As we approach the era of personalized medicine, targeting the specific molecular defect(s) within a given patient’s tumor will become a more effective treatment strategy than traditional approaches that often target a given cancer type or sub-type. Synthetic genetic interactions are now being examined for their therapeutic potential and are designed to target the specific genetic and epigenetic phenomena associated with tumor formation, and thus are predicted to be highly selective. In general, two complementary approaches have been employed, including synthetic lethality and synthetic dosage lethality, to target aberrant expression and/or function associated with tumor suppressor genes and oncogenes, respectively. Here we discuss the concepts of synthetic lethality and synthetic dosage lethality, and explain three general experimental approaches designed to identify novel genetic interactors. We present examples and discuss the merits and caveats of each approach. Finally, we provide insight into the subsequent pre-clinical work required to validate novel candidate drug targets

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

    Directory of Open Access Journals (Sweden)

    Harsh B Pathak

    Full Text Available 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

  12. Synthetic

    Directory of Open Access Journals (Sweden)

    Anna Maria Manferdini


    Full Text Available Traditionally materials have been associated with a series of physical properties that can be used as inputs to production and manufacturing. Recently we witnessed an interest in materials considered not only as ‘true matter’, but also as new breeds where geometry, texture, tooling and finish are able to provoke new sensations when they are applied to a substance. These artificial materials can be described as synthetic because they are the outcome of various qualities that are not necessarily true to the original matter, but they are the combination of two or more parts, whether by design or by natural processes. The aim of this paper is to investigate the potential of architectural surfaces to produce effects through the invention of new breeds of artificial matter, using micro-scale details derived from Nature as an inspiration.

  13. Radiation dosage

    International Nuclear Information System (INIS)

    Finston, Roland


    Radiation dosage at Bikini Atoll is the result of current soil contamination, a relic of the nuclear weapons testing program of some 30 years ago. The principal contaminants today and some of their physical properties are listed: cesium-137, strontium-90, plutonium -239, 240 and americium-241. Cobalt-60 contributes less than 1 to the dose and is not considered significant. A resident of the atoll would accumulate radiation dose (rem) in two ways -- by exposure to radiation emanating from the ground and vegetation, and by exposure to radiation released in the spontaneous decay of radionuclides that have entered his body during the ingestion of locally grown foods. The latter process would account for some 90% of the dose; cesium-137 would be responsible for 0 90% of it. Since BARC's method of estimating dosage differs in some respects from that employed by the Lawrence Livermore National Laboratory (LLNL), (Ref.1, LLNL 1982) we are presenting our method in detail. The differences have two sources. First, the numbers used by BARC for the daily ingestion of radionuclides via the diet are higher than LLNL's. Second, BARC's calculation of dose from radionuclide intake utilizes the ICRP system. The net result is that BARC doses are consistently higher than LLNL doses, and in this respect are more conservative

  14. Gene interactions in the DNA damage-response pathway identified by genome-wide RNA-interference analysis of synthetic lethality

    NARCIS (Netherlands)

    van Haaften, Gijs; Vastenhouw, Nadine L; Nollen, Ellen A A; Plasterk, Ronald H A; Tijsterman, Marcel


    Here, we describe a systematic search for synthetic gene interactions in a multicellular organism, the nematode Caenorhabditis elegans. We established a high-throughput method to determine synthetic gene interactions by genome-wide RNA interference and identified genes that are required to protect

  15. Lethal Epistaxis. (United States)

    Byard, Roger W


    Epistaxis or nosebleed refers to bleeding from the nostrils, nasal cavity, or nasopharynx. Occasional cases may present with torrential lethal hemorrhage. Three cases are reported to demonstrate particular features: Case 1: A 51-year-old woman with lethal epistaxis with no obvious bleeding source; Case 2: A 77-year-old man with treated nasopharyngeal carcinoma who died from epistaxis arising from a markedly neovascularized tumor bed; Case 3: A 2-year-old boy with hemophilia B who died from epistaxis with airway obstruction in addition to gastrointestinal bleeding. Epistaxis may be associated with trauma, tumors, vascular malformations, bleeding diatheses, infections, pregnancy, endometriosis, and a variety of different drugs. Careful dissection of the nasal cavity is required to locate the site of hemorrhage and to identify any predisposing conditions. This may be guided by postmortem computerized tomographic angiography (PCTA). Despite careful dissection, however, a source of bleeding may never be identified. © 2016 American Academy of Forensic Sciences.

  16. Protection Against Lethal Sendai Virus Infection by in vivo Priming of Virus-Specific Cytotoxic T Lymphocytes with a Free Synthetic Peptide (United States)

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


    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.

  17. The pkaB Gene Encoding the Secondary Protein Kinase A Catalytic Subunit Has a Synthetic Lethal Interaction with pkaA and Plays Overlapping and Opposite Roles in Aspergillus nidulans (United States)

    Ni, Min; Rierson, Sara; Seo, Jeong-Ah; Yu, Jae-Hyuk


    Filamentous fungal genomes contain two distantly related cyclic AMP-dependent protein kinase A catalytic subunits (PKAs), but only one PKA is found to play a principal role. In Aspergillus nidulans, PkaA is the primary PKA that positively functions in vegetative growth and spore germination but negatively controls asexual sporulation and production of the mycotoxin sterigmatocystin. In this report, we present the identification and characterization of pkaB, encoding the secondary PKA in A. nidulans. Although deletion of pkaB alone does not cause any apparent phenotypic changes, the absence of both pkaB and pkaA is lethal, indicating that PkaB and PkaA are essential for viability of A. nidulans. Overexpression of pkaB enhances hyphal proliferation and rescues the growth defects caused by ΔpkaA, indicating that PkaB plays a role in vegetative growth signaling. However, unlike ΔpkaA, deletion of pkaB does not suppress the fluffy-autolytic phenotype resulting from ΔflbA. While upregulation of pkaB rescues the defects of spore germination resulting from ΔpkaA in the presence of glucose, overexpression of pkaB delays spore germination. Furthermore, upregulation of pkaB completely abolishes spore germination on medium lacking a carbon source. In addition, upregulation of pkaB enhances the level of submerged sporulation caused by ΔpkaA and reduces hyphal tolerance to oxidative stress. In conclusion, PkaB is the secondary PKA that has a synthetic lethal interaction with PkaA, and it plays an overlapping role in vegetative growth and spore germination in the presence of glucose but an opposite role in regulating asexual sporulation, germination in the absence of a carbon source, and oxidative stress responses in A. nidulans. PMID:16087751

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

    Energy Technology Data Exchange (ETDEWEB)

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


    olaparib by contextual 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.

  19. Protease Addiction and Synthetic Lethality in Cancer

    International Nuclear Information System (INIS)

    Freije, José M. P.; Fraile, Julia M.; López-Otín, Carlos


    The “oncogene addiction” concept refers to the dependence of cancer cells on the function of the oncogenes responsible for their transformed phenotype, while the term “non-oncogene addiction” has been introduced to define the exacerbated necessity of the normal function of non-mutated genes. In this Perspective, we focus on the importance of proteolytic enzymes to maintain the viability of cancer cells and hypothesize that most, if not all, tumors present “addiction” to a number of proteolytic activities, which in turn may represent valuable targets of anti-cancer therapies, even without being mutated or over-expressed by the malignant cells.

  20. [Understanding dosage calculations]. (United States)

    Benlahouès, Daniel


    The calculation of dosages in paediatrics is the concern of the whole medical and paramedical team. This activity must generate a minimum of risks in order to prevent care-related adverse events. In this context, the calculation of dosages is a practice which must be understood by everyone. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. Drosophila simulans Lethal hybrid rescue mutation (Lhr) rescues ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 86; Issue 3. Drosophila simulans Lethal hybrid rescue mutation (Lhr) rescues inviable hybrids by restoring X chromosomal dosage compensation and causes fluctuating asymmetry of development. R. N. Chatterjee P. Chatterjee A. Pal M. Pal-Bhadra. Research Article Volume 86 ...

  2. Synthetic Genetic Arrays: Automation of Yeast Genetics. (United States)

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


    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. © 2016 Cold Spring Harbor Laboratory Press.

  3. Endotoxin dosage in sepsis

    Directory of Open Access Journals (Sweden)

    Vincenzo Rondinelli


    Full Text Available Introduction. Endotoxin, a component of the cell wall of Gram-negative bacteria is a major contributor to the pathogenesis of septic shock and multiple organ failure (MOF. Its entry into the bloodstream stimulates monocytes/macrophages which once activated produce and release cytokines, nitric oxide and other mediators that induce systemic inflammation, endothelial damage, organ dysfunction, hypotension (shock and MOF.The aim of this study is to evaluate the usefulness of a quantitative test for the dosage of endotoxin to determine the risk of severe Gram-negative sepsis. Materials and methods. In the period January 2009 - June 2011 we performed 897 tests for 765 patients, mostly coming from the emergency room and intensive care, of which 328 (43% women (mean age 53 and 437 (57% male (mean age 49. Fifty-nine patients, no statistically significant difference in sex, were monitored by an average of two determinations of EA.All patients had procalcitonin values significantly altered.The kit used was EAA (Endotoxin Activity Assay Estor Company, Milan, which has three ranges of endotoxin activity (EA: low risk of sepsis if <0.40 units, medium if between 0.40 and 0.59; high if 0.60. Results. 78 out of 765 patients (10% had a low risk, 447 (58% a medium risk and 240 (32% a high risk.The dosage of EA, combined with that of procalcitonin, has allowed a more targeted antibiotic therapy. Six patients in serious clinical conditions were treated by direct hemoperfusion with Toraymyxin, a device comprising a housing containing a fiber polypropylene and polystyrene with surface-bound polymyxin B, an antibiotic that removes bacterial endotoxins from the blood. Conclusions.The test is useful in risk stratification as well as Gram negative sepsis, to set and monitor targeted therapies, also based on the neutralization of endotoxin.

  4. Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer (United States)

    Duffy, Supipi; Fam, Hok Khim; Wang, Yi Kan; Styles, Erin B.; Kim, Jung-Hyun; Ang, J. Sidney; Singh, Tejomayee; Larionov, Vladimir; Shah, Sohrab P.; Andrews, Brenda; Boerkoel, Cornelius F.; Hieter, Philip


    Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors. PMID:27551064

  5. X chromosome dosage compensation via enhanced transcriptional elongation in Drosophila. (United States)

    Larschan, Erica; Bishop, Eric P; Kharchenko, Peter V; Core, Leighton J; Lis, John T; Park, Peter J; Kuroda, Mitzi I


    The evolution of sex chromosomes has resulted in numerous species in which females inherit two X chromosomes but males have a single X, thus requiring dosage compensation. MSL (Male-specific lethal) complex increases transcription on the single X chromosome of Drosophila males to equalize expression of X-linked genes between the sexes. The biochemical mechanisms used for dosage compensation must function over a wide dynamic range of transcription levels and differential expression patterns. It has been proposed that the MSL complex regulates transcriptional elongation to control dosage compensation, a model subsequently supported by mapping of the MSL complex and MSL-dependent histone 4 lysine 16 acetylation to the bodies of X-linked genes in males, with a bias towards 3' ends. However, experimental analysis of MSL function at the mechanistic level has been challenging owing to the small magnitude of the chromosome-wide effect and the lack of an in vitro system for biochemical analysis. Here we use global run-on sequencing (GRO-seq) to examine the specific effect of the MSL complex on RNA Polymerase II (RNAP II) on a genome-wide level. Results indicate that the MSL complex enhances transcription by facilitating the progression of RNAP II across the bodies of active X-linked genes. Improving transcriptional output downstream of typical gene-specific controls may explain how dosage compensation can be imposed on the diverse set of genes along an entire chromosome.

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

    Directory of Open Access Journals (Sweden)

    Ollivier Emmanuelle


    Full Text Available Abstract 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.

  7. Histopathological effects of lethal and sub-lethal concentrations of ...

    African Journals Online (AJOL)

    The histopathological effects of lethal and sub-lethal concentrations of glyphosate on African catfish Clarias gariepinus were investigated. C. gariepinus juveniles were assessed in a static renewal bioassay for 96 hours (acute toxicity) and 28 days (chronic toxicity) using varying concentrations (0.0 mg/l 20.0 mg/l, 30.0 mg/l, ...

  8. Suicide Lethality: A Concept Analysis. (United States)

    DeBastiani, Summer; De Santis, Joseph P


    Suicide is a significant health problem internationally. Those who complete suicide may have different behaviors and risk factors than those who attempt a non-fatal suicide. The purpose of this article is to analyze the concept of suicide lethality and propose a clear definition of the concept through the identification of antecedents, attributes, and consequences. A literature search for articles published in the English language between 1970 and 2016 was conducted using MEDLINE, the Cochrane Library, Pubmed, Psychlit, Ovid, PsycINFO, and Proquest. The bibliographies of all included studies were also reviewed to identify additional relevant citations. A concept analysis was conducted on the literature findings using six stages of Walker and Avant's method. The concept analysis differentiated between suicide, lethality, suicidal behavior, and suicide lethality. Presence of a suicide plan or a written suicide note was not found to be associated with the majority of completed suicides included in the definition of suicide lethality. There are a few scales that measure the lethality of a suicide attempt, but none that attempt to measure the concept of suicide lethality as described in this analysis. Clarifying the concept of suicide lethality encourages awareness of the possibility of different suicidal behaviors associated with different suicide outcomes and will inform the development of future nursing interventions. A clearer definition of the concept of suicide lethality will guide clinical practice, research, and policy development aimed at suicide prevention.

  9. Synthetic Lethality as a Targeted Approach to Advanced Prostate Cancer (United States)


    6. Varma DR, Sareen KN, Roy AK, & Gural ML. Oral contraceptive . Part IV. Hormonal and antihormonal effects of rottlerin. Indian J Physiol...Pharmacol. 3:246-54 (1959). 7. Varma DR, Sareen KN, Roy AK, & Gural ML. Oral contraceptive . Part III. Further observations on the antifertility effect...Prostate Cancer PRINCIPAL INVESTIGATOR: Douglas V. Faller, Ph.D., M.D. CONTRACTING

  10. Synthetic Lethality as a Targeted Approach to Advanced Prostate Cancer (United States)


    Next, lithium acetylide addition to 3 provides 4, which was subsequently reduced to the E-olefin 5 in excellent yield. Manganese dioxide oxidation Differential secretome analysis of cancer-associated fibroblasts and bone marrow-derived precursors to identify microenvironmental regulators of...therapy for patients with metastatic soft tissue or bone sarcoma who have stable disease or better after four or more cycles of chemotherapy. The

  11. Genetic basis for dosage sensitivity in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Isabelle M Henry


    Full Text Available Aneuploidy, the relative excess or deficiency of specific chromosome types, results in gene dosage imbalance. Plants can produce viable and fertile aneuploid individuals, while most animal aneuploids are inviable or developmentally abnormal. The swarms of aneuploid progeny produced by Arabidopsis triploids constitute an excellent model to investigate the mechanisms governing dosage sensitivity and aneuploid syndromes. Indeed, genotype alters the frequency of aneuploid types within these swarms. Recombinant inbred lines that were derived from a triploid hybrid segregated into diploid and tetraploid individuals. In these recombinant inbred lines, a single locus, which we call SENSITIVE TO DOSAGE IMBALANCE (SDI, exhibited segregation distortion in the tetraploid subpopulation only. Recent progress in quantitative genotyping now allows molecular karyotyping and genetic analysis of aneuploid populations. In this study, we investigated the causes of the ploidy-specific distortion at SDI. Allele frequency was distorted in the aneuploid swarms produced by the triploid hybrid. We developed a simple quantitative measure for aneuploidy lethality and using this measure demonstrated that distortion was greatest in the aneuploids facing the strongest viability selection. When triploids were crossed to euploids, the progeny, which lack severe aneuploids, exhibited no distortion at SDI. Genetic characterization of SDI in the aneuploid swarm identified a mechanism governing aneuploid survival, perhaps by buffering the effects of dosage imbalance. As such, SDI could increase the likelihood of retaining genomic rearrangements such as segmental duplications. Additionally, in species where triploids are fertile, aneuploid survival would facilitate gene flow between diploid and tetraploid populations via a triploid bridge and prevent polyploid speciation. Our results demonstrate that positional cloning of loci affecting traits in populations containing ploidy and

  12. Synthetic Plant Defense Elicitors

    Directory of Open Access Journals (Sweden)

    Yasemin eBektas


    Full Text Available 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 the 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.

  13. Synthetic Cannabinoids

    Directory of Open Access Journals (Sweden)

    Aslihan Okan Ibiloglu


    Full Text Available Synthetic cannabinoids which is a subgroup of cannabinoids are commonly used for recreational drug use throughout the whole world. Although both marijuana and synthetic cannabinoids stimulate the same receptors, cannabinoid receptor 1 (CB1 and cannabinoid receptor 2 (CB2, studies have shown that synthetic cannabinoids are much more potent than marijuana. The longer use of synthetic cannabinoids can cause severe physical and psychological symptoms that might even result in death, similar to many known illicit drugs. Main treatment options mostly involve symptom management and supportive care. The aim of this article is to discuss clinical and pharmacological properties of the increasingly used synthetic cannabinoids. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2017; 9(3.000: 317-328


    African Journals Online (AJOL)


    East African Medical Journal Vol. 80. No. 7 July 2003. MIDLINE LETHAL GRANULOMA COMPLICATING PREGNANCY: CASE REPORT. B.D.O. Saheeb, BDS, FWACS, FICS, FDS, RCS (Edin) Senior Lecturer/Consultant, and M.A. Ojo, BDS, MMed Sc, Dip Maxfac Rad, Associate Professor/Consultant. Department of oral ...

  15. [The "lethal white foal" syndrome]. (United States)

    Blendinger, C; Müller, G; Bostedt, H


    The lethal white foal syndrome (congenital intestinal aganglionosis) was diagnosed by history, clinical signs and pathological findings in a female foal, born in March 1992, that was an offspring of two overo-spotted paint horses. The syndrome is a congenital innervation defect of the gastrointestinal tract. A literature review of this condition, relatively unknown in Germany, is given.

  16. Synthetic oils (United States)

    Hatton, R. E.


    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.

  17. Satellite Repeats Identify X Chromatin for Dosage Compensation in Drosophila melanogaster Males. (United States)

    Joshi, Sonal S; Meller, Victoria H


    A common feature of sex chromosomes is coordinated regulation of X-linked genes in one sex. Drosophila melanogaster males have one X chromosome, whereas females have two. The resulting imbalance in gene dosage is corrected by increased expression from the single X chromosome of males, a process known as dosage compensation. In flies, compensation involves recruitment of the male-specific lethal (MSL) complex to X-linked genes and modification of chromatin to increase expression. The extraordinary selectivity of the MSL complex for the X chromosome has never been explained. We previously demonstrated that the small interfering RNA (siRNA) pathway and siRNA from a family of X-linked satellite repeats (1.688 X repeats) promote X recognition. Now, we test the ability of 1.688 X DNA to attract compensation to genes nearby and report that autosomal integration of 1.688 X repeats increases MSL recruitment and gene expression in surrounding regions. Placement of 1.688 X repeats opposite a lethal autosomal deletion achieves partial rescue of males, demonstrating functional compensation of autosomal chromatin. Females block formation of the MSL complex and are not rescued. The 1.688 X repeats are therefore cis-acting elements that guide dosage compensation. Furthermore, 1.688 X siRNA enhances rescue of males with a lethal deletion but only when repeat DNA is present on the intact homolog. We propose that the siRNA pathway promotes X recognition by enhancing the ability of 1.688 X DNA to attract compensation in cis. The dense and near-exclusive distribution of 1.688 X sequences along the X chromosome suggests that they play a primary role in determining X identity during dosage compensation. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  18. Radioimmunological dosage of human prolactin

    International Nuclear Information System (INIS)

    Reuter, A; Kennes, F.; Gevaert, Y.; Franchimont, P.


    The radioimmunological dosage of human prolactin using the hormone as tracer and reference and an anti-prolactin antiserum is described. The labelling of human prolactin is carried out in the presence of a small quanitity of chloraminet (10 ug). The purification of the labelled hormone is carried out by gel filtration on sephadex G-75 by polyacrylamide gel electrophoresis. The optimal incubation conditions were found using a first incubation of 40-48 hours at room temperature followed by one of 4 to 6 hours with cellulosebound second antibody. The interference of serum proteins is small. There is no cross-reaction with follicle stimulating hormone (FSH), luteinizing hormone (LH), tyroid stimulating hormone (FSH), human chorionic gonadotrophin (HCG), human placental lactogen (HPL) and human growth hormone (HGH). However, cross-reaction with ovine, bovine and rat prolactin is found. These cross-reactions are complete with endogenous human prolactin and hormone of different origin. Serum prolactin was determined in normal subjects and subjects treated with TRH and bromoergocryptine. (G.C.)

  19. Dosage form design and development. (United States)

    Allen, Loyd V


    Drugs must be properly formulated for administration to patients, regardless of age. Pediatric patients provide some additional challenges to the formulator in terms of compliance and therapeutic efficacy. Due to the lack of sufficient drug products for the pediatric population, the pharmaceutical industry and compounding pharmacies must develop and provide appropriate medications designed for children. The purpose of this article was to review the physical, chemical, and biological characteristics of drug substances and pharmaceutical ingredients to be used in preparing a drug product. In addition, stability, appearance, palatability, flavoring, sweetening, coloring, preservation, packaging, and storage are discussed. Information for the current article was gathered from a literature review; from presentations at professional and technical meetings; and from lectures, books, and publications of the author, as well as from his professional experience. Professional society meetings and standards-setting bodies were also used as a resource. The proper design and formulation of a dosage form requires consideration of the physical, chemical, and biological characteristics of all of the drug substances and pharmaceutical ingredients (excipients) to be used in fabricating the product. The drug and pharmaceutical materials utilized must be compatible and produce a drug product that is stable, efficacious, palatable, easy to administer, and well tolerated. Preformulation factors include physical properties such as particle size, crystalline structure, melting point, solubility, partition coefficient, dissolution, membrane permeability, dissociation constants, and drug stability. Successful development of a formulation includes multiple considerations involving the drug, excipients, compliance, storage, packaging, and stability, as well as patient considerations of taste, appearance, and palatability.

  20. Pentamidine Dosage: A Base/Salt Confusion

    NARCIS (Netherlands)

    Dorlo, Thomas P. C.; Kager, Piet A.


    Pentamidine has a long history in the treatment of human African trypanosomiasis (HAT) and leishmaniasis. Early guidelines on the dosage of pentamidine were based on the base-moiety of the two different formulations available. Confusion on the dosage of pentamidine arose from a different labelling

  1. [Pharmaceutical advice concerning different pharmaceutical dosage forms]. (United States)

    Szakonyi, Gergely; Zelkó, Romána


    The present paper summarizes the commonly applied types of drug uptake and the pharmacists' advice concerning a certain dosage form. The manuscript also deals with the modified release dosage forms and their abbreviations in the name of the marketing authorized products.

  2. A brief history of dosage compensation

    Indian Academy of Sciences (India)

    In 1914, H. J. Muller postulated the origin of the Y chromosome as having resulted from restricted recombination between homologous sex chromosomes in the male and the accumulation of deleterious mutations. This evolutionary process leads to dosage compensation. This article lays out a brief history of dosage ...

  3. A brief history of dosage compensation

    Indian Academy of Sciences (India)

    to dosage compensation and their citation numbers would therefore not be relevant. Also supportive of the lack of interest in dosage compensa- tion at the time is the fact ..... Received 4 October 2013, in revised form 28 November 2013; accepted 3 December 2013. Published on the Web: 11 July 2014. Journal of Genetics ...

  4. Synthetic environments (United States)

    Lukes, George E.; Cain, Joel M.


    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. Synthetic Rutile

    International Nuclear Information System (INIS)

    Burastero, J.


    This work is about the laboratory scale investigation of the conditions in the rutile synthetic production from one me nita in Aguas Dulces reservoir. The iron mineral is chlorinated and volatilized selectively leaving a residue enriched in titanium dioxide which can be used as a substitute of rutile mineral

  6. Electroshock weapons can be lethal! (United States)

    Lundquist, Marjorie


    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 study of consistent properties of the vasopressin nasal dosage form


    Al Nukarii Abdulkarim; A. L. Drozdov; A. P. Lysyanskaya


    Evaluation of consistent properties is an important and integral part of investigations on the creation of semisolid nasal pharmacotherapeutic agents. The aim of this work is the study of consistent properties of developed nasal semisolid dosage form with synthetic analogue of vasopressin – arginine-vasopressin for the treatment of cognitive consequences of cerebral-vascular pathology. Materials and methods. The study of structural-mechanical characteristics of nasal ointment with 0.0...

  8. Pentamidine dosage: a base/salt confusion.

    Directory of Open Access Journals (Sweden)

    Thomas P C Dorlo

    Full Text Available Pentamidine has a long history in the treatment of human African trypanosomiasis (HAT and leishmaniasis. Early guidelines on the dosage of pentamidine were based on the base-moiety of the two different formulations available. Confusion on the dosage of pentamidine arose from a different labelling of the two available products, either based on the salt or base moiety available in the preparation. We provide an overview of the various guidelines concerning HAT and leishmaniasis over the past decades and show the confusion in the calculation of the dosage of pentamidine in these guidelines and the subsequent published reports on clinical trials and reviews. At present, only pentamidine isethionate is available, but the advised dosage for HAT and leishmaniasis is (historically based on the amount of pentamidine base. In the treatment of leishmaniasis this is probably resulting in a subtherapeutic treatment. There is thus a need for a new, more transparent and concise guideline concerning the dosage of pentamidine, at least in the treatment of HAT and leishmaniasis.

  9. Effect of lethal and sub-lethal concentrations of tobacco (Nicotiana ...

    African Journals Online (AJOL)

    Lethal and sub-lethal bioassays on Clarias gariepinus were conducted to evaluate the toxicity of tobacco (Nicotiana tobaccum) leaf dust on weight gain and haematological indices of Clarias gariepinus (mean weight 10.5±0.70g) in glass aquaria with aeration system. The concentrations used during the lethal exposure are: ...

  10. Dosage-dependent role of Rac1 in podocyte injury (United States)

    Wan, Xiaoyang; Lee, Mi-Sun


    Activation of small GTPase Rac1 in podocytes is associated with rodent models of kidney injury and familial nephrotic syndrome. Induced Rac1 activation in podocytes in transgenic mice results in rapid transient proteinuria and foot process effacement, but not glomerular sclerosis. Thus it remains an open question whether abnormal activation of Rac1 in podocytes is sufficient to cause permanent podocyte damage. Using a number of transgenic zebrafish models, we showed that moderate elevation of Rac1 activity in podocytes did not impair the glomerular filtration barrier but aggravated metronidazole-induced podocyte injury, while inhibition of Rac1 activity ameliorated metronidazole-induced podocyte injury. Furthermore, a further increase in Rac1 activity in podocytes was sufficient to cause proteinuria and foot process effacement, which resulted in edema and lethality in juvenile zebrafish. We also found that activation of Rac1 in podocytes significantly downregulated the expression of nephrin and podocin, suggesting an adverse effect of Rac1 on slit diaphragm protein expression. Taken together, our data have demonstrated a causal link between excessive Rac1 activity and podocyte injury in a dosage-dependent manner, and transgenic zebrafish of variable Rac1 activities in podocytes may serve as useful animal models for the study of Rac1-related podocytopathy. PMID:26792065

  11. accessions resistants to lethal yellowing disease

    African Journals Online (AJOL)



    Feb 19, 2007 ... One of the problems faced in coconut cultivation is the lethal yellowing disease. Experimental trials, conducted in endemic region, showed that the Vanuatu Tall and Sri-Lanka Green Dwarf genotypes were tolerant while the West African Tall appeared susceptible to the lethal yellowing disease. Genetic.

  12. Synthetic Cannabinoids. (United States)

    Mills, Brooke; Yepes, Andres; Nugent, Kenneth


    Synthetic cannabinoids (SCBs), also known under the brand names of "Spice," "K2," "herbal incense," "Cloud 9," "Mojo" and many others, are becoming a large public health concern due not only to their increasing use but also to their unpredictable toxicity and abuse potential. There are many types of SCBs, each having a unique binding affinity for cannabinoid receptors. Although both Δ-tetrahydrocannabinol (THC) and SCBs stimulate the same receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), studies have shown that SCBs are associated with higher rates of toxicity and hospital admissions than is natural cannabis. This is likely due to SCBs being direct agonists of the cannabinoid receptors, whereas THC is a partial agonist. Furthermore, the different chemical structures of SCBs found in Spice or K2 may interact in unpredictable ways to elicit previously unknown, and the commercial products may have unknown contaminants. The largest group of users is men in their 20s who participate in polydrug use. The most common reported toxicities with SCB use based on studies using Texas Poison Control records are tachycardia, agitation and irritability, drowsiness, hallucinations, delusions, hypertension, nausea, confusion, dizziness, vertigo and chest pain. Acute kidney injury has also been strongly associated with SCB use. Treatment mostly involves symptom management and supportive care. More research is needed to identify which contaminants are typically found in synthetic marijuana and to understand the interactions between different SBCs to better predict adverse health outcomes.

  13. Prescribing Errors Involving Medication Dosage Forms (United States)

    Lesar, Timothy S


    CONTEXT Prescribing errors involving medication dose formulations have been reported to occur frequently in hospitals. No systematic evaluations of the characteristics of errors related to medication dosage formulation have been performed. OBJECTIVE To quantify the characteristics, frequency, and potential adverse patient effects of prescribing errors involving medication dosage forms . DESIGN Evaluation of all detected medication prescribing errors involving or related to medication dosage forms in a 631-bed tertiary care teaching hospital. MAIN OUTCOME MEASURES Type, frequency, and potential for adverse effects of prescribing errors involving or related to medication dosage forms. RESULTS A total of 1,115 clinically significant prescribing errors involving medication dosage forms were detected during the 60-month study period. The annual number of detected errors increased throughout the study period. Detailed analysis of the 402 errors detected during the last 16 months of the study demonstrated the most common errors to be: failure to specify controlled release formulation (total of 280 cases; 69.7%) both when prescribing using the brand name (148 cases; 36.8%) and when prescribing using the generic name (132 cases; 32.8%); and prescribing controlled delivery formulations to be administered per tube (48 cases; 11.9%). The potential for adverse patient outcome was rated as potentially “fatal or severe” in 3 cases (0.7%), and “serious” in 49 cases (12.2%). Errors most commonly involved cardiovascular agents (208 cases; 51.7%). CONCLUSIONS Hospitalized patients are at risk for adverse outcomes due to prescribing errors related to inappropriate use of medication dosage forms. This information should be considered in the development of strategies to prevent adverse patient outcomes resulting from such errors. PMID:12213138

  14. Lethality of patients with rheumatoid arthritis depending on adalimumab administration: imitation modeling

    Directory of Open Access Journals (Sweden)

    D V Goryachev


    Full Text Available Lethality of pts with rheumatoid arthritis (RA exceeds mortality values in general population. Possibility of disease modifying anti-rheumatic drugs (DMARD influence on RA pts lethality has been widely discussed lately in scientific works. Objective. To determine possible lethality diminishment in Russian population of RA pts with one of biological drugs TNFα antagonist adalimumab. Material and methods. Model construction is based on the fact of lethality dependence on pt functional state assessed by HAQ. Model simulating progression of functional disability in pts with RA visiting medical institutions of Russia was made (RAISER study. 3 model variants for imitation of consecutive change of DMARDs including adalimumab were done. First consecution assessed DMARD change in the next chain: adalimumab-methotrexate-sulfasalazine-leflunomide-azathioprine-cyclosporine-palliative therapy. Second consecution: adalimumab administration after failure of first 3 DMARDs. Third consecution considered only change of synthetic DMARDs without adalimumab inclusion. Model imitated participation of 3000 pts in every consecution. Prognosis horizon was 12 years. Age of pts and initial HAQ distribution were get from results of epidemiological RAISER study. Calculation was done on the base of elevation of standardized lethality level (SLL in population of RA pts in average from 135% to 300%. SLL values from 80 to 320% were used depending on functional disability degree with converting to Russian values of age-specific lethality coefficient for 1999. Results. Lethality in treatment consecutions including adalimumab was significantly lower. To the end of 12th year in group not using adalimumab, using it at once and using it after 376 DMARDs respectively 65,1%, 71,6% and 71,1% of pts were still alive. Conclusion. Significant decrease of lethality with adalimumab inclusion in consecution of DMARD change during treatment of RA pts was demonstrated with imitation modeling

  15. Synthetic Botany. (United States)

    Boehm, Christian R; Pollak, Bernardo; Purswani, Nuri; Patron, Nicola; Haseloff, Jim


    Plants are attractive platforms for synthetic biology and metabolic engineering. Plants' modular and plastic body plans, capacity for photosynthesis, extensive secondary metabolism, and agronomic systems for large-scale production make them ideal targets for genetic reprogramming. However, efforts in this area have been constrained by slow growth, long life cycles, the requirement for specialized facilities, a paucity of efficient tools for genetic manipulation, and the complexity of multicellularity. There is a need for better experimental and theoretical frameworks to understand the way genetic networks, cellular populations, and tissue-wide physical processes interact at different scales. We highlight new approaches to the DNA-based manipulation of plants and the use of advanced quantitative imaging techniques in simple plant models such as Marchantia polymorpha. These offer the prospects of improved understanding of plant dynamics and new approaches to rational engineering of plant traits. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  16. Synthetic Brainbows

    KAUST Repository

    Wan, Y.


    Brainbow is a genetic engineering technique that randomly colorizes cells. Biological samples processed with this technique and imaged with confocal microscopy have distinctive colors for individual cells. Complex cellular structures can then be easily visualized. However, the complexity of the Brainbow technique limits its applications. In practice, most confocal microscopy scans use different florescence staining with typically at most three distinct cellular structures. These structures are often packed and obscure each other in rendered images making analysis difficult. In this paper, we leverage a process known as GPU framebuffer feedback loops to synthesize Brainbow-like images. In addition, we incorporate ID shuffing and Monte-Carlo sampling into our technique, so that it can be applied to single-channel confocal microscopy data. The synthesized Brainbow images are presented to domain experts with positive feedback. A user survey demonstrates that our synthetic Brainbow technique improves visualizations of volume data with complex structures for biologists.

  17. A brief history of dosage compensation

    Indian Academy of Sciences (India)

    know that the random X inactivation system of placental mammals likely evolved from the nonrandom paternal X in- activation dosage compensation system characteristic of marsupials (Brown and Chandra 1973) and that the XIST gene evolved from a marsupial protein coding gene (Duret et al. 2006). It seems likely that ...

  18. Spectrophotometric Determination of Trimipramine in Tablet Dosage ...

    African Journals Online (AJOL)

    Purpose: To develop and validate simple, rapid and sensitive spectrophotometric procedures for determination of trimipramine in tablet dosage form. Methods: The methods were based on the interaction of trimipramine as n-electron donor with the σ- acceptor, iodine and various π-acceptors, namely: chloranil (CH), ...

  19. Spectrophotometric Determination of Trimipramine in Tablet Dosage ...

    African Journals Online (AJOL)

    Purpose: To develop and validate simple, rapid and sensitive spectrophotometric procedures for determination of trimipramine in tablet dosage form. Methods: The methods were based on the interaction of trimipramine as n-electron donor with the ο-acceptor, iodine and various π-acceptors, namely: chloranil (CH), ...

  20. Intelligent system for improving dosage control

    Directory of Open Access Journals (Sweden)

    Fabio Cosme Rodrigues dos Santos


    Full Text Available Coagulation is one of the most important processes in a drinking-water treatment plant, and it is applied to destabilize impurities in water for the subsequent flocculation stage. Several techniques are currently used in the water industry to determine the best dosage of the coagulant, such as the jar-test method, zeta potential measurements, artificial intelligence methods, comprising neural networks, fuzzy and expert systems, and the combination of the above-mentioned techniques to help operators and engineers in the water treatment process. Current paper presents an artificial neural network approach to evaluate optimum coagulant dosage for various scenarios in raw water quality, using parameters such as raw water color, raw water turbidity, clarified and filtered water turbidity and a calculated Dose Rate to provide the best performance in the filtration process. Another feature in current approach is the use of a backpropagation neural network method to estimate the best coagulant dosage simultaneously at two points of the water treatment plant. Simulation results were compared to the current dosage rate and showed that the proposed system may reduce costs of raw material in water treatment plant.

  1. Factors influencing circadian rhythms in acetaminophen lethality. (United States)

    Schnell, R C; Bozigian, H P; Davies, M H; Merrick, B A; Park, K S; McMillan, D A


    Experiments were conducted to examine the effects of changes in lighting schedules and food consumption on circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice. Under a normal lighting schedule (light: 06.00-18.00 h), male mice exhibited a circadian rhythm in acetaminophen lethality (peak: 18.00 h; nadir: 06.00, 10.00 h) and an inverse rhythm in hepatic glutathione concentrations (peak: 06.00, 10.00 h; nadir: 18.00 h). Under a reversed lighting schedule (light: 18.00-06.00 h) the glutathione rhythm was reversed and the rhythm in acetaminophen lethality was altered showing greater sensitivity to the drug. Under continuous light, there was a shift in the acetaminophen lethality and the hepatic glutathione rhythms. Under continuous dark, both rhythms were abolished. Under a normal lighting regimen, hepatic glutathione levels were closely correlated with food consumption; i.e., both were increased during the dark phase and decreased during the light phase. Fasting the mice for 12 h abolished the rhythms in acetaminophen lethality and hepatic glutathione levels; moreover, the lethality was increased and the hepatic glutathione levels were decreased. These experiments show that both lighting schedules and feeding can alter the circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice.

  2. Gene dosage effects of the imprinted delta-like homologue 1 (dlk1/pref1 in development: implications for the evolution of imprinting.

    Directory of Open Access Journals (Sweden)

    Simao Teixeira da Rocha


    Full Text Available Genomic imprinting is a normal process that causes genes to be expressed according to parental origin. The selective advantage conferred by imprinting is not understood but is hypothesised to act on dosage-critical genes. Here, we report a unique model in which the consequences of a single, double, and triple dosage of the imprinted Dlk1/Pref1, normally repressed on the maternally inherited chromosome, can be assessed in the growing embryo. BAC-transgenic mice were generated that over-express Dlk1 from endogenous regulators at all sites of embryonic activity. Triple dosage causes lethality associated with major organ abnormalities. Embryos expressing a double dose of Dlk1, recapitulating loss of imprinting, are growth enhanced but fail to thrive in early life, despite the early growth advantage. Thus, any benefit conferred by increased embryonic size is offset by postnatal lethality. We propose a negative correlation between gene dosage and survival that fixes an upper limit on growth promotion by Dlk1, and we hypothesize that trade-off between growth and lethality might have driven imprinting at this locus.

  3. Estimated Maximal Safe Dosages of Tumescent Lidocaine (United States)

    Jeske, Daniel R.


    BACKGROUND: Tumescent lidocaine anesthesia consists of subcutaneous injection of relatively large volumes (up to 4 L or more) of dilute lidocaine (≤1 g/L) and epinephrine (≤1 mg/L). Although tumescent lidocaine anesthesia is used for an increasing variety of surgical procedures, the maximum safe dosage is unknown. Our primary aim in this study was to measure serum lidocaine concentrations after subcutaneous administration of tumescent lidocaine with and without liposuction. Our hypotheses were that even with large doses (i.e., >30 mg/kg), serum lidocaine concentrations would be below levels associated with mild toxicity and that the concentration-time profile would be lower after liposuction than without liposuction. METHODS: Volunteers participated in 1 to 2 infiltration studies without liposuction and then one study with tumescent liposuction totally by local anesthesia. Serum lidocaine concentrations were measured at 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 24 hours after each tumescent lidocaine infiltration. Area under the curve (AUC∞) of the serum lidocaine concentration-time profiles and peak serum lidocaine concentrations (Cmax) were determined with and without liposuction. For any given milligram per kilogram dosage, the probability that Cmax >6 μg/mL, the threshold for mild lidocaine toxicity was estimated using tolerance interval analysis. RESULTS: In 41 tumescent infiltration procedures among 14 volunteer subjects, tumescent lidocaine dosages ranged from 19.2 to 52 mg/kg. Measured serum lidocaine concentrations were all lidocaine toxicity without liposuction at a dose of 28 mg/kg and with liposuction at a dose of 45 mg/kg was ≤1 per 2000. CONCLUSIONS: Preliminary estimates for maximum safe dosages of tumescent lidocaine are 28 mg/kg without liposuction and 45 mg/kg with liposuction. As a result of delayed systemic absorption, these dosages yield serum lidocaine concentrations below levels associated with mild toxicity and are a nonsignificant

  4. Dosage compensation in Drosophila melanogaster, a model for control in other insect species

    International Nuclear Information System (INIS)

    Hilfiker, A.; Hilfiker-Kleiner, D.; Lucchesi, J.C.


    In the animal kingdom, many species with euchromatic heteromorphic sex chromosomes have developed mechanisms for the equalization of gene products in the homo- and the heterogametic sex. This mechanism, called dosage compensation, is achieved in Drosophila by the doubling of the transcriptional activity of X-linked genes in the male, in comparison to the female. Any failure in achieving dosage compensation causes lethality: hapto-X male individuals that fail to hyperactivate their single X-chromosome as well as diplo-X female individuals that hyperactivate their X-chromosomes die. Five genes that are involved in the regulation of this process have been identified. in males, a group of four genes, the so called male-specific lethals (mle, msl-1, msl-2, msl-3), must be active in order for hypertranscription to occur, whereas in females the Sxl gene, the master key gene of sex determination, has to be active to prevent the msl genes from becoming active. However, XX individuals with mutations in Sxl cannot be rescued by mutations in the msl genes indicating that at least one member of this group is yet to be uncovered. Furthermore, the msl gene that is regulated in a sex-specific manner has not yet been identified. Given that msl-1 is transcribed in both sexes but its protein product is nearly absent in females, we have investigated whether this gene is the target of sex-specific regulation. We have also carried out extensive genetic screens for the purpose of identifying additional members of the msl group. These investigations are necessary prerequisites to the development of genetic sexing techniques based on the constitutive expression of msl genes in females causing female-specific lethality. (author)

  5. Command and Control for Distributed Lethality (United States)


    communications over vast distances, and the need for near-real-time coordination means that stakeholders for the distributed lethality concept can encompass a...and methods of effective communication systems. 14. SUBJECT TERMS command and control (C2) distributed lethality system of systems (SOS) model...refinement through simulations of the C2 structure and further research into technologies and methods of effective communication systems. vi THIS PAGE

  6. Experiences in therapy for lethal midline granuloma

    Energy Technology Data Exchange (ETDEWEB)

    Tosaka, K.; Ishikawa, T. (Kumamoto Univ. (Japan). School of Medicine)


    Four cases of the lethal midline granuloma or malignant granuloma of the nose were treated by irradiation and chemotherapy, which are generally prescribed for malignant lymphomas. Clinical, histological and laboratory examination indicated that they were the lethal midline granuloma and clearly differentiated from Wegener's granulomatosis or malignant lymphoma. All of the cases exhibited primary remission. The four cases were observed up to 38, 22, 14, and 10 months since the beginning of the therapy, showing no local or general recurrence.

  7. Glucocorticoids in nephrology II: indications and dosage

    Directory of Open Access Journals (Sweden)

    Jernej Pajek


    Full Text Available Present article describes glucocorticoid prescriptions in nephrology and renal transplantation, the dosages in induction and maintenance treatment phases and discontinuation. Key evidence and landmark trials are referenced, to establish the basis for modern glucocorticoid application in specific kidney disease indications. The glucocorticoid regimens in IgA glomerulonephritis, major primary glomerular diseases with nephrotic syndrome, vasculitides and tubulointerstitial nephritis are described. Various schemes for glucocorticoid dosage in lupus nephritis are given. The evolution of glucocorticoid usage in kidney transplantation is delineated and the modern role of these drugs in renal transplantation is defined. There are attempts to replace glucocorticoids with adrenocorticotrophic hormone in some glomerular diseases. Despite being relatively old drugs and having numerous side effects, glucocorticoids still function as major therapeutic agents for specific immunosuppressive treatment in nephrology.

  8. Lubricants in Pharmaceutical Solid Dosage Forms


    Jinjiang Li; Yongmei Wu


    Lubrication plays a key role in successful manufacturing of pharmaceutical solid dosage forms; lubricants are essential ingredients in robust formulations to achieve this. Although many failures in pharmaceutical manufacturing operations are caused by issues related to lubrication, in general, lubricants do not gain adequate attention in the development of pharmaceutical formulations. In this paper, the fundamental background on lubrication is introduced, in which the relationships between lu...

  9. Radiation Dosages Produced by Telephone Cellular

    International Nuclear Information System (INIS)

    Ali, A.


    This research includes the problem of protection against the none-ionized electromagnetic field radiation. In this respect, we highlight one of the advanced methods d igital simulation of the electric field , which is called the Finite Difference Time Domain method (FDTD). This method aims at solving the problem of measuring the radiation dosages produced by the cellular (phone). Therefore, we have got numerical mathematical results to be presented as proofs and examples. (author)

  10. Place du dosage des immunoglobulines e totales en pratique ...

    African Journals Online (AJOL)

    Mots clés: Immunoglobulines E, allergie, Togo. English Abstract. Place of total immunoglobulin E dosage in common practice in Togo. Objective: to determine the place of total immunoglobulin E (IgE) dosage in common practice in Togo. Material and methods: 650 total IgE dosages performed during 4 years (2008 to 2011) ...

  11. Lethality Index 2008-2014: Less shootings, same lethality, more opacity

    Directory of Open Access Journals (Sweden)

    Carlos Silva Forné


    Full Text Available This article evaluates the use of lethal force by Mexican federal security forces during shootings with presumed members of organized crime from 2008-2014. The authors use official data and press reports on deaths and wounded in shootings to construct indicators such as the number of dead civilians over the number of dead officials from the federal security forces and the number of dead civilians over the number of wounded civilians. In a context where certain factors that contribute to an excessive use of force become more common, the results of the study show a growing use of lethal force. This raises questions over the possible excessive use of lethal force as a normal or systematic practice. The study also shows a growing context of opacity in the information available to evaluate the use of lethal force and the general lack of a legal framework to regulate the use of lethal force in Mexico.

  12. The characteristics of novel dosage forms

    Directory of Open Access Journals (Sweden)

    Milić-Aškrabić Jela


    Full Text Available The objective of pharmaceutical-technological development is to find a procedure of transforming an active substance (a drug into a drug dosage form which is not only acceptable for application, but also enables the active substance to be released following administration, pursuant to therapy objectives. The aim is that the concentration of the active substance in the action location rapidly reaches a therapeutic level and maintains an approximately constant level in the course of a particular time, according to the established therapeutic goal. The primary objective is to present the active ingredient (drug in the form and concentration/quantity that enables the corresponding therapeutic response, i.e. to control the site and rate of medicinal substance release from the drug, as well as the rate at which it reaches the membranes and surfaces to which it is absorbed, while applying a common method of administration. The procedures used to achieve this goal are becoming highly complex and demanding and are aiming at sophisticated drug delivery systems and functional packaging material. Development from the existing drug molecule, through the conventional drug dosage form, to a new system of drug "delivery" (novel delivery system, can improve the drug (active substance characteristics significantly in view of compliance (acceptability by the patient, safety and efficiency. The paper presents an overview of the most important examples of pharmaceutical forms with controlled release and advanced drug "carriers".

  13. [Redistribution of gastrointestinal ammonia into blood in alcohol coma rat: the role in lethal outcome]. (United States)

    Ivnitskiĭ, Iu Iu; Shefer, T V; Reĭniuk, V L


    At 3 h after the intragastral administration of ethanol (446 mmol/kg) the blood ammonia concentration in v. portae increased 1.4 times, in v. cava inf. caudally of vv. renales inflow - 2.2 times, cranially of vv. hepaticae - 2.5 times, and in blood obtained by decapitation - by 65%7. The rate of ammonia accumulation in 'avage medium injected intraperitoneally was triple as that in intact rats. The exposure to atmospheric ammoniac (0.84-1.07 mg/l) for 3 h resuited in increasing blood ammonia concentration 2.4 times compared with the isolated ethanol action. The ammonia inhalation promoted the lethal action of ethanol with a dose alteration factor of 0.81 and suppressed gas-exchange. The promotion of the ethanol lethal action by the non-lethal ammonium acetate dosage has been observed. These data suggest that in rat, the coma-inducing ethanol ingestion promotes the translocation of intestinal ammonia into the common bloodstream, which has a detrimental effect on the outcome of alcohol coma.

  14. Guidebook for non-lethal experimentation

    NARCIS (Netherlands)

    Paulissen, J.J.M.; Rahimi, R.


    In the 2009-2011 timeframe, NATO conducts a capability based assessment of Non-Lethal Weapon (NLW) systems. The work, performed by the RTO study team SAS-078, involves the development of NLW requirement descriptions, which are put against a set of NLW systems. Gaps are likely to occur, indicating

  15. Genetics Home Reference: Amish lethal microcephaly (United States)

    ... 1 in 500 newborns in the Old Order Amish population of Pennsylvania. It has not been found outside this population. Related Information What information about a genetic condition can statistics provide? Why are some genetic ... gene cause Amish lethal microcephaly . The SLC25A19 gene provides instructions for ...

  16. A new lethal sclerosing bone dysplasia

    International Nuclear Information System (INIS)

    Kingston, H.M.; Freeman, J.S.; Hall, C.M.


    A neonate is described with a lethal sclerosing bone dysplasia associated with prenatal fractures and craniofacial abnormalities including microcephaly, exophthalmos, hypoplastic nose and mid-face, small jaw and nodular hyperplasia of the gums. Parental consanguinity suggests that an autosomal recessive mutation is the likely aetiology. (orig.)

  17. [Oral films as perspective dosage form]. (United States)

    Walicová, Veronika; Gajdziok, Jan

    Oral films, namely buccal mucoadhesive films and orodispersible films represent innovative formulations for administration of a wide range of drugs. Oral films show many advantageous properties and are intended for systemic drug delivery or for local treatment of the oral mucosa. In both cases, the film represents a thin layer, which could be intended to adhere to the oral mucosa by means of mucoadhesion; or to rapid dissolution and subsequent swallowing without the need of liquid intake, in the case of orodispersible films. Main constitutive excipients are film-forming polymers, which must in the case of mucoadhesive forms remain on the mucosa within the required time interval. Oral films are currently available on the pharmaceutical market and could compete with conventional oral dosage forms in the future. oral cavity oral films buccal mucoadhesive films orodispersible films film-forming polymers.

  18. Plant synthetic biology. (United States)

    Liu, Wusheng; Stewart, C Neal


    Plant synthetic biology is an emerging field that combines engineering principles with plant biology toward the design and production of new devices. This emerging field should play an important role in future agriculture for traditional crop improvement, but also in enabling novel bioproduction in plants. In this review we discuss the design cycles of synthetic biology as well as key engineering principles, genetic parts, and computational tools that can be utilized in plant synthetic biology. Some pioneering examples are offered as a demonstration of how synthetic biology can be used to modify plants for specific purposes. These include synthetic sensors, synthetic metabolic pathways, and synthetic genomes. We also speculate about the future of synthetic biology of plants. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Lethal and sub-lethal effects of copper to the african catfish ( clarias ...

    African Journals Online (AJOL)

    Lethal and sub-lethal effects of copper on Clarias gariepinus were studied using a 96-hour static bioassay. Copper (as copper chloride, CuCl2 . H2O) was used to prepare the stock solution from which five standard concentrations 0.0, 1.8, 3.2, 5.6, and 10.0 mg/L were prepared (coded A – E). 15 juvenile C. gariepinus fish ...

  20. X Chromosome and Autosome Dosage Responses in Drosophila melanogaster Heads (United States)

    Chen, Zhen-Xia; Oliver, Brian


    X chromosome dosage compensation is required for male viability in Drosophila. Dosage compensation relative to autosomes is two-fold, but this is likely to be due to a combination of homeostatic gene-by-gene regulation and chromosome-wide regulation. We have baseline values for gene-by-gene dosage compensation on autosomes, but not for the X chromosome. Given the evolutionary history of sex chromosomes, these baseline values could differ. We used a series of deficiencies on the X and autosomes, along with mutations in the sex-determination gene transformer-2, to carefully measure the sex-independent X-chromosome response to gene dosage in adult heads by RNA sequencing. We observed modest and indistinguishable dosage compensation for both X chromosome and autosome genes, suggesting that the X chromosome is neither inherently more robust nor sensitive to dosage change. PMID:25850426

  1. Synthetic antifreeze peptide



    A synthetic antifreeze peptide and a synthetic gene coding for the antifreeze peptide have been produced. The antifreeze peptide has a greater number of repeating amino acid sequences than is present in the native antifreeze peptides from winter flounder upon which the synthetic antifreeze peptide was modeled. Each repeating amino acid sequence has two polar amino acid residues which are spaced a controlled distance apart so that the antifreeze peptide may inhibit ice formation. The synthetic...

  2. Applications of Polymers as Pharmaceutical Excipients in Solid Oral Dosage Forms. (United States)

    Debotton, Nir; Dahan, Arik


    Over the last few decades, polymers have been extensively used as pharmaceutical excipients in drug delivery systems. Pharmaceutical polymers evolved from being simply used as gelatin shells comprising capsule to offering great formulation advantages including enabling controlled/slow release and specific targeting of drugs to the site(s) of action (the "magic bullets" concept), hence hold a significant clinical promise. Oral administration of solid dosage forms (e.g., tablets and capsules) is the most common and convenient route of drug administration. When formulating challenging molecules into solid oral dosage forms, polymeric pharmaceutical excipients permit masking undesired physicochemical properties of drugs and consequently, altering their pharmacokinetic profiles to improve the therapeutic effect. As a result, the number of synthetic and natural polymers available commercially as pharmaceutical excipients has increased dramatically, offering potential solutions to various difficulties. For instance, the different polymers may allow increased solubility, swellability, viscosity, biodegradability, advanced coatings, pH dependency, mucodhesion, and inhibition of crystallization. The aim of this article is to provide a wide angle prospect of the different uses of pharmaceutical polymers in solid oral dosage forms. The various types of polymeric excipients are presented, and their distinctive role in oral drug delivery is emphasized. The comprehensive know-how provided in this article may allow scientists to use these polymeric excipients rationally, to fully exploit their different features and potential influence on drug delivery, with the overall aim of making better drug products. © 2016 Wiley Periodicals, Inc.

  3. A screen for F1 hybrid male rescue reveals no major-effect hybrid lethality loci in the Drosophila melanogaster autosomal genome. (United States)

    Cuykendall, Tawny N; Satyaki, P; Ji, Shuqing; Clay, Derek M; Edelman, Nathaniel B; Kimchy, Alexandra; Li, Ling-Hei; Nuzzo, Erin A; Parekh, Neil; Park, Suna; Barbash, Daniel A


    Hybrid sons between Drosophila melanogaster females and D. simulans males die as 3rd instar larvae. Two genes, D. melanogaster Hybrid male rescue (Hmr) on the X chromosome, and D. simulans Lethal hybrid rescue (Lhr) on chromosome II, interact to cause this lethality. Loss-of-function mutations in either gene suppress lethality, but several pieces of evidence suggest that additional factors are required for hybrid lethality. Here we screen the D. melanogaster autosomal genome by using the Bloomington Stock Center Deficiency kit to search for additional regions that can rescue hybrid male lethality. Our screen is designed to identify putative hybrid incompatibility (HI) genes similar to Hmr and Lhr which, when removed, are dominant suppressors of lethality. After screening 89% of the autosomal genome, we found no regions that rescue males to the adult stage. We did, however, identify several regions that rescue up to 13% of males to the pharate adult stage. This weak rescue suggests the presence of multiple minor-effect HI loci, but we were unable to map these loci to high resolution, presumably because weak rescue can be masked by genetic background effects. We attempted to test one candidate, the dosage compensation gene male specific lethal-3 (msl-3), by using RNA interference with short hairpin microRNA constructs targeted specifically against D. simulans msl-3 but failed to achieve knockdown, in part due to off-target effects. We conclude that the D. melanogaster autosomal genome likely does not contain additional major-effect HI loci. We also show that Hmr is insufficient to fully account for the lethality associated with the D. melanogaster X chromosome, suggesting that additional X-linked genes contribute to hybrid lethality. Copyright © 2014 Cuykendall et al.

  4. TIP peptide inhalation in experimental acute lung injury: effect of repetitive dosage and different synthetic variants. (United States)

    Hartmann, Erik K; Thomas, Rainer; Liu, Tanghua; Stefaniak, Joanna; Ziebart, Alexander; Duenges, Bastian; Eckle, Daniel; Markstaller, Klaus; David, Matthias


    Inhalation of TIP peptides that mimic the lectin-like domain of TNF-α is a novel approach to attenuate pulmonary oedema on the threshold to clinical application. A placebo-controlled porcine model of acute respiratory distress syndrome (ARDS) demonstrated a reduced thermodilution-derived extravascular lung water index (EVLWI) and improved gas exchange through TIP peptide inhalation within three hours. Based on these findings, the present study compares a single versus a repetitive inhalation of a TIP peptide (TIP-A) and two alternate peptide versions (TIP-A, TIP-B). Following animal care committee approval ARDS was induced by bronchoalveolar lavage followed by injurious ventilation in 21 anaesthetized pigs. A randomised-blinded three-group setting compared the single-dosed peptide variants TIP-A and TIP-B as well as single versus repetitive inhalation of TIP-A (n = 7 per group). Over two three-hour intervals parameters of gas exchange, transpulmonary thermodilution, calculated alveolar fluid clearance, and ventilation/perfusion-distribution were assessed. Post-mortem measurements included pulmonary wet/dry ratio and haemorrhage/congestion scoring. The repetitive TIP-A inhalation led to a significantly lower wet/dry ratio than a single dose and a small but significantly lower EVLWI. However, EVLWI changes over time and the derived alveolar fluid clearance did not differ significantly. The comparison of TIP-A and B showed no relevant differences. Gas exchange and ventilation/perfusion-distribution significantly improved in all groups without intergroup differences. No differences were found in haemorrhage/congestion scoring. In comparison to a single application the repetitive inhalation of a TIP peptide in three-hour intervals may lead to a small additional reduction the lung water content. Two alternate TIP peptide versions showed interchangeable characteristics.

  5. The study of consistent properties of the vasopressin nasal dosage form

    Directory of Open Access Journals (Sweden)

    Al Nukarii Abdulkarim


    Full Text Available Evaluation of consistent properties is an important and integral part of investigations on the creation of semisolid nasal pharmacotherapeutic agents. The aim of this work is the study of consistent properties of developed nasal semisolid dosage form with synthetic analogue of vasopressin – arginine-vasopressin for the treatment of cognitive consequences of cerebral-vascular pathology. Materials and methods. The study of structural-mechanical characteristics of nasal ointment with 0.000005% arginine-vasopressin on the vaseline-lanolin-paraffin base was carried out by a rotary viscosimeter «Reotest-2» with cylindrical arrangement. It was established that consistent properties of arginine-vasopressin semisolid dosage form and «mechanical stability» (2.56 describe composition as a thixotropic system which provides with restorability after applying tension and allow to predict stability of consistent properties during a long-term storage. Calculated factors of dynamical flowing of arginine- vasopressin dosage form on the vaseline-lanolin-paraffin base (Кd1=28.7%; Kd2=53.84% quantitatively confirm satisfactory spreading degree of the system during application on the mucous membranes or in manufacturing process. Conclusions. The studies of consistent properties of nasal ointment with synthetic analogue of vasopressin – arginine-vasopressin 0.000005% on lipophilic basis for treatment of cognitive effects of cerebrovascular disease have been conducted by rotary viscometer «Reotest 2». It has been established that consistent properties of studied soft nasal dosage form of arginine-vasopressin and «mechanical stability» value of the system (2.56 characterize it as a thixotropic, that assure recovery from mechanical stress, that allows to predict the stability of consistent properties of the composition during prolonged storage. The calculated values of coefficients of dynamic flow of intranasal dosage form of arginine-vasopressin on vaseline


    Sergeyev, O V; Barinsky, I F


    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.

  7. Detection of warfare agents in liquid foods using the brine shrimp lethality assay. (United States)

    Lumor, Stephen E; Diez-Gonzalez, Francisco; Labuza, Theodore P


    The brine shrimp lethality assay (BSLA) was used for rapid and non-specific detection of biological and chemical warfare agents at concentrations considerably below that which will cause harm to humans. Warfare agents detected include T-2 toxin, trimethylsilyl cyanide, and commercially available pesticides such as dichlorvos, diazinon, dursban, malathion, and parathion. The assay was performed by introducing 50 μL of milk or orange juice contaminated with each analyte into vials containing 10 freshly hatched brine shrimp nauplii in seawater. This was incubated at 28 °C for 24 h, after which mortality was determined. Mortality was converted to probits and the LC(50) was determined for each analyte by plotting probits of mortality against analyte concentration (log(10)). Our findings were the following: (1) the lethal effects of toxins dissolved in milk were observed, with T-2 toxin being the most lethal and malathion being the least, (2) except for parathion, the dosage (based on LC(50)) of analyte in a cup of milk (200 mL) consumed by a 6-y-old (20 kg) was less than the respective published rat LD(50) values, and (3) the BSLA was only suitable for detecting toxins dissolved in orange juice if incubation time was reduced to 6 h. Our results support the application of the BSLA for routine, rapid, and non-specific prescreening of liquid foods for possible sabotage by an employee or an intentional bioterrorist act. Practical Application: The findings of this study strongly indicate that the brine shrimp lethality assay can be adapted for nonspecific detection of warfare agents or toxins in food at any point during food production and distribution.

  8. Dosage sensitivity of RPL9 and concerted evolution of ribosomal protein genes in plants

    Directory of Open Access Journals (Sweden)

    Deborah eDevis


    Full Text Available The ribosome in higher eukaryotes is a large macromolecular complex composed of four rRNAs and eighty different ribosomal proteins. In plants, each ribosomal protein is encoded by multiple genes. Duplicate genes within a family are often necessary to provide a threshold dose of a ribosomal protein but in some instances appear to have non-redundant functions. Here, we addressed whether divergent members of the RPL9 gene family are dosage sensitive or whether these genes have non-overlapping functions. The RPL9 family in A. thaliana comprises two nearly identical members, RPL9B and RPL9C, and a more divergent member, RPL9D. Mutations in RPL9C and RPL9D genes leads to delayed growth early in development, and loss of both genes is embryo lethal, indicating that these are dosage-sensitive and redundant genes. Phylogenetic analysis of RPL9 as well as RPL4, RPL5, RPL27a, RPL36a and RPS6 family genes in the Brassicaceae indicated that multicopy ribosomal protein genes have been largely retained following whole genome duplication. However, these gene families also show instances of tandem duplication, small scale deletion and evidence of gene conversion. Furthermore, phylogenetic analysis of RPL9 genes in angiosperm species showed that genes within a species are more closely related to each other than to RPL9 genes in other species, suggesting ribosomal protein genes undergo convergent evolution. Our analysis indicates that ribosomal protein gene retention following whole genome duplication contributes to the number of genes in a family. However, small scale rearrangements influence copy number and likely drive concerted evolution of these dosage-sensitive genes.

  9. Lethal neonatal short-limbed dwarfism

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ok Hwa; Yim, Chung Ik; Bahk, Yong Whee [Catholic Medical College, Seoul (Korea, Republic of)


    We have detailed our experiences on 6 cases of neonatal lethal short-limbed dwarfism and reviewed the articles. They include, achondrogenesis, thanatophoric dysplasia, asphyxiating thoracic dysplasia, osteogenesis imperfect a congenita, and hypophosphatasia lethals. Five babies were born alive but died soon after birth and one was a stillbirth. The main cause of failure to thrive was respiratory insufficiency. Each case was having quite characteristic radiologic findings, even if the general appearances were similar to the achondroplasts clinically. Precise diagnosis is very important for genetic counselling of the parents and alarm to them the possibility of bone dysplasias to the next offsprings. For this purpose, the radiologists play major role for the correct diagnosis. We stress that when the baby is born with short-limbed dwarfism, whole body radiogram should be taken including lateral view and postmortem radiogram is also very precious.

  10. Lethal Interpersonal Violence in the Middle Pleistocene


    Sala, Nohemi; Arsuaga, Juan Luis; Pantoja-P?rez, Ana; Pablos, Adri?n; Mart?nez, Ignacio; Quam, Rolf M.; G?mez-Olivencia, Asier; Berm?dez de Castro, Jos? Mar?a; Carbonell, Eudald


    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 ...

  11. Lethal midline granuloma syndrome: a diagnostic dilemma

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Bruno Niemeyer de Freitas; Bahia, Paulo Roberto Valle [Radiology, Hospital Universitario Clementino Fraga Filho - Universidade Federal do Rio de Janeiro (HUCFF-UFRJ), Rio de Janeiro, RJ (Brazil); Oliveira, Ana Luiza Vianna Sobral de Magalhaes [Resident of Medical Practice, Hospital Federal da Lagoa, Rio de Janeiro, RJ (Brazil); Marchon Junior, Joao Luiz [Unit of Computed Tomography, Hospital Federal da Lagoa, Rio de Janeiro, RJ (Brazil)


    The rare lethal midline granuloma syndrome is difficult to diagnose because of the wide array of related diseases and lack of knowledge by the majority of physicians. In the present report, the authors describe the case of a patient with this disease, caused by squamous cell carcinoma, drawing attention to differential diagnoses and to clinical and radiological findings that may be useful to define the diagnosis. (author)

  12. Non-Lethal Weapons (NLW) Reference Book (United States)


    exist regarding the use of a Optical Distractors (e.g., Dazzling Lasers )? ANSWER: Strict laws, SECDEF guidance, and ROE exist to control the use of...National Guard Bureau (NGB) 1 Domestic Operations Kits (DOK) Joint Non-Lethal Warning Munitions (JNLWM) 2 Green Lasers 2...Chemical Weapons and on their Destruction. Paris, 13 January 1993. 16. UNCCW Protocol on Blinding Laser Weapons (Protocol IV to the 1980

  13. Lethal interpersonal violence in the Middle Pleistocene.

    Directory of Open Access Journals (Sweden)

    Nohemi Sala

    Full Text Available 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.

  14. Lethal interpersonal violence in the Middle Pleistocene. (United States)

    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


    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.

  15. Lubricants in Pharmaceutical Solid Dosage Forms

    Directory of Open Access Journals (Sweden)

    Jinjiang Li


    Full Text Available Lubrication plays a key role in successful manufacturing of pharmaceutical solid dosage forms; lubricants are essential ingredients in robust formulations to achieve this. Although many failures in pharmaceutical manufacturing operations are caused by issues related to lubrication, in general, lubricants do not gain adequate attention in the development of pharmaceutical formulations. In this paper, the fundamental background on lubrication is introduced, in which the relationships between lubrication and friction/adhesion forces are discussed. Then, the application of lubrication in the development of pharmaceutical products and manufacturing processes is discussed with an emphasis on magnesium stearate. In particular, the effect of its hydration state (anhydrate, monohydrate, dihydrate, and trihydrate and its powder characteristics on lubrication efficiency, as well as product and process performance is summarized. In addition, the impact of lubrication on the dynamics of compaction/compression processes and on the mechanical properties of compacts/tablets is presented. Furthermore, the online monitoring of magnesium stearate in a blending process is briefly mentioned. Finally, the chemical compatibility of active pharmaceutical ingredient (API with magnesium stearate and its reactive impurities is reviewed with examples from the literature illustrating the various reaction mechanisms involved.

  16. Reduced dosages of atrazine and narrow rows can provide ...

    African Journals Online (AJOL)



    Nov 8, 2010 ... of reduced herbicide dosages and narrow rows to achieve adequate weed control and optimise on yields in smallholder farming systems. Key words: Row spacing, reduced atrazine dosages, weed density, weed biomass, maize yield. INTRODUCTION. Inadequate weed control is one of the major causes of.

  17. A System for Dosage-Based Functional Genomics in Poplar. (United States)

    Henry, Isabelle M; Zinkgraf, Matthew S; Groover, Andrew T; Comai, Luca


    Altering gene dosage through variation in gene copy number is a powerful approach to addressing questions regarding gene regulation, quantitative trait loci, and heterosis, but one that is not easily applied to sexually transmitted species. Elite poplar (Populus spp) varieties are created through interspecific hybridization, followed by clonal propagation. Altered gene dosage relationships are believed to contribute to hybrid performance. Clonal propagation allows for replication and maintenance of meiotically unstable ploidy or structural variants and provides an alternative approach to investigating gene dosage effects not possible in sexually propagated species. Here, we built a genome-wide structural variation system for dosage-based functional genomics and breeding of poplar. We pollinated Populus deltoides with gamma-irradiated Populus nigra pollen to produce >500 F1 seedlings containing dosage lesions in the form of deletions and insertions of chromosomal segments (indel mutations). Using high-precision dosage analysis, we detected indel mutations in ∼55% of the progeny. These indels varied in length, position, and number per individual, cumulatively tiling >99% of the genome, with an average of 10 indels per gene. Combined with future phenotype and transcriptome data, this population will provide an excellent resource for creating and characterizing dosage-based variation in poplar, including the contribution of dosage to quantitative traits and heterosis. © 2015 American Society of Plant Biologists. All rights reserved.

  18. Microbial quality of some herbal solid dosage forms

    African Journals Online (AJOL)



    Mar 15, 2010 ... 20 herbal products as tablet, powder and capsule were prepared. .... Capsule. Blister. 2/2005. 1/2008. These herbal dosage forms were use as dispensed. prepared from plant material) and their raw materials. They concluded that in most .... presence of bacteria in herbal solid dosage forms constitutes a ...

  19. 21 CFR 520.88 - Amoxicillin oral dosage forms. (United States)


    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Amoxicillin oral dosage forms. 520.88 Section 520.88 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.88 Amoxicillin oral...

  20. 21 CFR 522.1222 - Ketamine hydrochloride injectable dosage forms. (United States)


    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Ketamine hydrochloride injectable dosage forms. 522.1222 Section 522.1222 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... ANIMAL DRUGS § 522.1222 Ketamine hydrochloride injectable dosage forms. ...

  1. [From synthetic biology to synthetic humankind]. (United States)

    Nouvel, Pascal


    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. Copyright © 2015 Académie des sciences. Published by Elsevier SAS. All rights reserved.

  2. Synthetic Cathinones ("Bath Salts") (United States)

    ... cathinones? Behavioral therapy can be used to treat addiction to synthetic cathinones. Examples include: cognitive-behavioral therapy contingency management, or motivational incentives—providing rewards to ...

  3. Synthetic approaches to uniform polymers. (United States)

    Ali, Monzur; Brocchini, Steve


    Uniform polymers are characterised by a narrow molecular weight distribution (MWD). Uniformity is also defined by chemical structure in respect of (1) monomer orientation, sequence and stereo-regularity, (2) polymer shape and morphology and (3) chemical functionality. The function of natural polymers such as polypeptides and polynucleotides is related to their conformational structure (e.g. folded tertiary structure). This is only possible because of their high degree of uniformity. While completely uniform synthetic polymers are rare, polymers with broad structure and MWD are widely used in medicine and the biomedical sciences. They are integral components in final dosage forms, drug delivery systems (DDS) and in implantable devices. Increasingly uniform polymers are being used to develop more complex medicines (e.g. delivery of biopharmaceuticals, enhanced formulations or DDS's for existing actives). In addition to the function imparted by any new polymer it will be required to meet stringent specifications in terms of cost containment, scalability, biocompatibility and performance. Synthetic polymers with therapeutic activity are also being developed to exploit their polyvalent properties, which is not possible with low molecular weight molecules. There is need to utilise uniform polymers for applications where the polymer may interact with the systemic circulation, tissues or cellular environment. There are also potential applications (e.g. stimuli responsive coatings) where uniform polymers may be used for their more defined property profile. While it is not yet practical to prepare synthetic polymers to the same high degree of uniformity as proteins, nature also effectively utilises many polymers with lower degrees of uniformity (e.g. polysaccharides, poly(amino acids), polyhydroxyalkanoates). In recent years it has become possible to prepare with practical experimental protocols sufficient quantities of polymers that display many aspects of uniformity. This

  4. Brave New Warfare: Autonomy in Lethal UAVs (United States)


    Executions,” United Nations General Assembly, May 28, 2010, bodies /hrcouncil/docs/14session/A.HRC.14.24.Add6.pdf. 34 Rique...capability 40 The Army’s Future Combat Sytems (FCS) program was canceled in May 2009 as part of... bodies /hrcouncil/docs/14session/A.HRC.14.24.Ad d6.pdf. Arkin, Ronald. Governing Lethal Behavior in Autonomous Robots. Boca Raton: CRC Press, 2009. doi

  5. Determining S-1 dosage at hospitals prioritizing cancer chemotherapy

    International Nuclear Information System (INIS)

    Morimoto, Shigefumi; Kitada, Noriaki; Anami, Setsuko


    Although it is recommended that the standard S-1 dosage should be based on how large the body surface area is, an on-site setting of the appropriate dosage is often lower than the standard one, depending on the individual's condition and considering possible side effects and so, on. Here, we investigated usage conditions for S-1 as a part of field training for expert pharmacists at our hospital that performs total clinical treatments. Decreases in dosage per day for elderly patients were although the standard dosage is generally determined according to the amount of a patient's body surface. We conducted a retrospective survey with a total 90 patients by creating a tree-diagram to identify a reduction standard. It was found that the S-1 dosage was decreased when there were side effects, aggravation in performance status, decrease in kidney function, old age, combined injection chemotherapy, and a decrease in radiation therapy performance. The dosage decreases without such medical reasons were seen in only 4 of the 90 patients. At hospitals giving priority to chemotherapy, it became clear that appropriate treatment was promoted by decreasing. The individual target dosage on the basis of daily medical examination. (author)

  6. Issues surrounding lethal injection as a means of capital punishment. (United States)

    Romanelli, Frank; Whisman, Tyler; Fink, Joseph L


    Lethal injection as a method of state-sanctioned capital punishment was initially proposed in the United States in 1977 and used for the first time in 1982. Most lethal injection protocols use a sequential drug combination of sodium thiopental, pancuronium bromide, and potassium chloride. Lethal injection was originally introduced as a more humane form of execution compared with existing mechanical methods such as electrocution, toxic gassing, hanging, or firing squad. Lethal injection has not, however, been without controversy. Several states are considering whether lethal injection meets constitutional scrutiny forbidding cruel and unusual punishment. Recently in the case of Ralph Baze and Thomas C. Bowling, Petitioners, v John D. Rees, Commissioner, Kentucky Department of Corrections et al, the United States Supreme Court upheld the constitutionality of the lethal injection protocol as carried out in the Commonwealth of Kentucky. Most of the debate has surrounded the dosing and procedures used in lethal injection and whether the drug combinations and measures for administering the drugs truly produce a timely, pain-free, and fail-safe death. Many have also raised issues regarding the "medicalization" of execution and the ethics of health care professionals' participation in any part of the lethal injection process. As a result of all these issues, the future of lethal injection as a means of execution in the United States is under significant scrutiny. Outcomes of ongoing legislative and judicial reviews might result in cessation of lethal injection in totality or in alterations involving specific drug combinations or administration procedures.

  7. Potential Clinical Uses of CDK Inhibitors: Lessons from Synthetic Lethality Screens

    Czech Academy of Sciences Publication Activity Database

    Vymětalová, Ladislava; Kryštof, Vladimír


    Roč. 35, č. 6 (2015), s. 1156-1174 ISSN 0198-6325 R&D Projects: GA MŠk(CZ) LO1204; GA ČR(CZ) GA15-15264S Institutional support: RVO:61389030 Keywords : cyclin-dependent kinase * inhibitor * cancer Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 9.135, year: 2015

  8. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer.


    Asim, Mohammad; Tarish, Firas; Zecchini, Heather I; Sanjiv, Kumar; Gelali, Eleni; Massie, Charles Edward; Baridi, Ajoeb; Warren, Anne Y; Zhao, Wanfeng; Ogris, Christoph; McDuffus, Leigh-Anne; Mascalchi, Patrice; Shaw, Greg; Dev, Harveer; Wadhwa, Karan


    Emerging data demonstrate homologous recombination (HR) defects in castration resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here, we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival...

  9. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer


    Asim, Mohammad; Tarish, Firas; Zecchini, Heather I.; Sanjiv, Kumar; Gelali, Eleni; Massie, Charles E.; Baridi, Ajoeb; Warren, Anne Y.; Zhao, Wanfeng; Ogris, Christoph; McDuffus, Leigh-Anne; Mascalchi, Patrice; Shaw, Greg; Dev, Harveer; Wadhwa, Karan


    This study was supported by the National Cancer Research Institute (National Institute of Health Research (NIHR) Collaborative Study: ‘Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT)” (grant G0500966/75466). This work was funded by a Cancer Research UK program grant (D.N.), the Swedish Research Council (T.H.), AFA insurance (T.H.), Swedish Cancer Society (T.H.), the Swedish Pain Relief Foundation (T.H.), the Torsten and Ragnar Söderberg Foundation (T.H.), AstraZeneca (T.H.) ...

  10. Genomewide Screen for Synthetic Lethal Interactions with Mutant KRAS in Lung Cancer (United States)


    platform is based on negative selection, i.e., gRNA clones of our interest are lost after selection, we have to address the technical...fragments and then these two fragments were ligated together. Finally, we cloned left arm and right arm of AAVS1 into this vector sequentially...DhCas9TRE3G BlastCAG TRE3G hCas9TRE3G BlastCAG hCas9 hCas9TRE3G 1st PCR 2nd PCR Fig. 1, Construction of inducible human codon optimized Cas9 (hCas9) through 2

  11. Synthetic Lethal Therapeutic Approaches for ARID1A-Mutated Ovarian Cancer (United States)


    Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and should not be an official Department of the Army position, policy or decision unless so designated by other documentation. REPORT DOCUMENTATION PAGE Form

  12. Lethal congenital contracture syndrome (LCCS) and other lethal arthrogryposes in Finland--an epidemiological study. (United States)

    Pakkasjärvi, Niklas; Ritvanen, Annukka; Herva, Riitta; Peltonen, Leena; Kestilä, Marjo; Ignatius, Jaakko


    Arthrogryposis multiplex congenita is a heterogeneous group of disorders characterized by multiple contractures with an estimated frequency of 1 in 3,000 births. With improving diagnostic methods, increasing numbers of fetuses with arthrogryposis are found. The pathogenetic mechanisms are relatively well known but the epidemiology and genetics of the prenatally lethal forms of arthrogryposis are less well known. In this study we collected all cases of a multiple contractures diagnosed in Finland during 1987-2002 including live born infants, stillbirths, and terminated pregnancies. Ninety-two cases of 214 suffered intrauterine demise (68 selective pregnancy terminations and 24 stillbirths) and 58 died in infancy. In 141 out of these cases the diagnosis could be included within lethal arthrogryposes, with a prevalence of 1 in 6,985 (1.43/10,000) births. Of these, 59 had spinal cord pathology at autopsy and thus were of neurogenic origin. Thirty-nine cases had lethal congenital contracture syndrome (LCCS) clinically characterized by total immobility of the fetus at all ultrasound examinations (12 weeks or later), multiple joint contractures in both upper and lower limbs, hydrops, and fetal death before the 32nd week of pregnancy. LCCS is noted as a unique Finnish disorder with a prevalence of 1 in 25,250 (0.40/10,000) births and is a major cause of lethal arthrogryposis in Finland.

  13. Quantum synthetic aperture radar (United States)

    Lanzagorta, Marco; Jitrik, Oliverio; Uhlmann, Jeffrey; Venegas-Andraca, Salvador E.


    Synthetic aperture radar (SAR) uses sensor motion to generate finer spatial resolution of a given target area. In this paper we explore the theoretical potential of quantum synthetic aperture quantum radar (QSAR). We provide theoretical analysis and simulation results which suggest that QSAR can provide improved detection performance over classical SAR in the high-noise low-brightness regime.

  14. Designing synthetic biology. (United States)

    Agapakis, Christina M


    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.

  15. Efficacy comparison of scopolamine (SCP) and diazepam (DZ) against soman-induced lethality in guinea pigs

    Energy Technology Data Exchange (ETDEWEB)

    Harris, L.W.; Gennings, C.; Carter, W.H.; Anderson, D.R.; Lennox, W.J.


    Diazepam (DZ) and scopolamine (SCP) are known to be beneficial when each is used in combination with atropine (AT) + oxime therapy against intoxication by soman, but the efficacy of each might be expected to vary with the dosage of AT. Thus, the therapeutic efficacy of SCP (5 doses; 0 - 0.86 mg/kg) versus DZ (5 doses; 0 - 5 mg/kg), when used in conjunction with AT (3 doses; 0.5 - S mg/kg) + 2-PAM (25 mg/kg) therapy, was tested in groups of pyridostigmine pretreated guinea pigs exposed to 1.6, 2.0, 2.5 or 3.2 LD5Os of soman. Response surface methodology was employed to describe the relationship between lethality and the AT/DZ or AT/SCP dosages. Results show that within the indicated dose ranges used, the efficacy of SCP is not dependent on the presence of AT, whereas AT is needed for DZ to maintain the lowest probability of death. These findings suggest that in guinea pigs SCP could supplement AT or replace DZ as therapy against nerve agent intoxication.

  16. Novel substituted phenoxyalkyl pyridinium oximes enhance survival and attenuate seizure-like behavior of rats receiving lethal levels of nerve agent surrogates. (United States)

    Chambers, Janice E; Meek, Edward C; Bennett, Joshua P; Bennett, W Shane; Chambers, Howard W; Leach, C Andrew; Pringle, Ronald B; Wills, Robert W


    Novel substituted phenoxyalkyl pyridinium oximes, previously shown to reactivate brain cholinesterase in rats treated with high sublethal dosages of surrogates of sarin and VX, were tested for their ability to prevent mortality from lethal doses of these two surrogates. Rats were treated subcutaneously with 0.6mg/kg nitrophenyl isopropyl methylphosphonate (NIMP; sarin surrogate) or 0.65mg/kg nitrophenyl ethyl methylphosphonate (NEMP; VX surrogate), dosages that were lethal within 24h to all tested rats when they received only 0.65mg/kg atropine at the time of initiation of seizure-like behavior (about 30min). If 146mmol/kg 2-PAM (human equivalent dosage) was also administered, 40% and 33% survival was obtained with NIMP and NEMP, respectively, while the novel Oximes 1 and 20 provided 65% and 55% survival for NIMP and 75 and 65% for NEMP, respectively. In addition, both novel oximes resulted in a highly significant decrease in time to cessation of seizure-like behavior compared to 2-PAM during the first 8h of observation. Brain cholinesterase inhibition was slightly less in novel oxime treated rats compared to 2-PAM in the 24h survivors. The lethality data indicate that 24h survival is improved by two of the novel oximes compared to 2-PAM. The cessation of seizure-like behavior data strongly suggest that these novel oximes are able to penetrate the blood-brain barrier and can combat the hypercholinergic activity that results in seizures. Therefore this oxime platform has exceptional promise as therapy that could both prevent nerve agent-induced lethality and attenuate nerve agent-induced seizures. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. Effects of DDE and PCB (Aroclor 1260) on experimentally poisoned little brown bats (Myotis lucifugus): Lethal brain concentrations (United States)

    Clark, D.R.; Stafford, C.J.


    Adult female little brown bats (Myotis lucifugus) were collected in a church attic in North East, Cecil County, Md. Mealworms (Tenebrio molitor) containing organochlorine pollutants were fed to the bats as follows: 5 bats were dosed at 480 ppm DDE, 12 at 150 ppm DDE, 5 at 1000 ppm polychlorinated biphenyl (PCB; Aroclor 1260), and 12 at 15 ppm PCB. Seven other bats were fed untreated mealworms. The objective was to elevate brain levels of DDE and PCB to lethality and measure these concentrations. During 40 d of dosage, one DDE-dosed bat and two PCB-dosed bats died after exhibiting the prolonged tremor that characterizes organochlorine poisoning. After dosage, surviving bats were starved to elevate brain levels of toxicants, and three additional DDE-dosed bats had tremors before dying. The mean brain concentration of DDE diagnostic of death was estimated as 603 ppm, range 540-670 ppm. This mean is 16-18% higher than means for Mexican free-tailed bats (Tadarida brasiliensis) and common grackles (Quiscalus quiscula), and may indicate less sensitivity. Lethal brain concentrations of Aroclor 1260 were 1300 and 1500 ppm. Such values appear to be higher than values (Aroclor 1254) for brown-headed cowbirds (Molothrus ater). During starvation, DDE-dosed bats lost weight about 24% faster than controls. If smaller amounts of stored DDE cause increases in metabolic rates of nonfeeding bats, as during hibernation or migration, the result could be premature energy depletion and increased mortality.

  18. Fourteen days oral administration of therapeutic dosage of some ...

    African Journals Online (AJOL)

    Fourteen days oral administration of therapeutic dosage of some antibiotics reduced serum testosterone in male rats. FO Awobajo, Y Raji, II Olatunji-Bello, FT Kunle-Alabi, AO Adesanya, TO Awobajo ...

  19. Integrated effect of seeding rate, herbicide dosage and application ...

    African Journals Online (AJOL)

    Integrated effect of seeding rate, herbicide dosage and application timing on durum wheat ( Triticum turgidum l. var durum) yield, yield components and wild oat (avena fatua l.) control in south eastern Ethiopia.

  20. Buccal Dosage Forms: General Considerations for Pediatric Patients. (United States)

    Montero-Padilla, Soledad; Velaga, Sitaram; Morales, Javier O


    The development of an appropriate dosage form for pediatric patients needs to take into account several aspects, since adult drug biodistribution differs from that of pediatrics. In recent years, buccal administration has become an attractive route, having different dosage forms under development including tablets, lozenges, films, and solutions among others. Furthermore, the buccal epithelium can allow quick access to systemic circulation, which could be used for a rapid onset of action. For pediatric patients, dosage forms to be placed in the oral cavity have higher requirements for palatability to increase acceptance and therapy compliance. Therefore, an understanding of the excipients required and their functions and properties needs to be particularly addressed. This review is focused on the differences and requirements relevant to buccal administration for pediatric patients (compared to adults) and how novel dosage forms can be less invasive and more acceptable alternatives.

  1. Dosage compensation of serine-4 transfer RNA in Drosophila melanogaster

    International Nuclear Information System (INIS)

    Birchler, J.A.; Owenby, R.K.; Jacobson, K.B.


    A dosage series of the X chromosome site for serine-4 transfer RNA consisting of one of three copies in females and one to two in males was constructed to test whether transfer RNA expression is governed by dosage compensation. A dosage effect on the level of the serine-4 isoacceptor was observed in both females and males when the structural locus was varied. However, in males, each dose had a relatively greater expression so the normal one dose was slightly greater than the total female value and the duplicated male had the highest relative expression of all the types examined. Serine-4 levels in males and females from an isogenic Oregon-R stock were similar. Thus the transfer RNA levels conform to the expectations of dosage compensation

  2. Liquid dosage forms with antibacterial activity

    Directory of Open Access Journals (Sweden)

    O. I. Mykhalyk


    Ioddicerinum is used in clinical practice .In the State Formulary of drugs large group of medicines is represented by 5-nitrofuran derivatives (Furacilin, Furazolidone, Furaplast, Lifusolum. Currently the most effective antiseptics include surfactants (Chlorhexidine. The newest agents with wide range of indications comprise Miramistinum, Decametoxine. A well-known Ethakridine lactate (syn. Rivanolum belongs to acridine group and it is used in a variety of dosage forms. Dioxidin as a quinoxaline derivative is an active ingredient of the drug Dioxisolum.In Ukraine since 2000, a new class of drugs, namely derivatives of fluorene, was introduced into medical practice. Its derivatives are well-known antivirals Florenal and Amixin .Search for highly efficient broad-spectrum agents among fluorenes led to the creation of Flurenizide, which is the Preparation with antimicrobial, antichlamydial, immunomodulting, antioxidant, hepatoprotective, antiinflammatory and antiviral actions. Indicators of antiviral activity of Flurenizide exceed those of Amixin.Based on Flurenizide new liquid medicines have been developed to treat skin infections. Among them are Flumexide (2 % suspension of Flurenizide in 30% aqueous solution of Dimexidum, antiseptic solution of 1% Flupetsal, liquid antydemodex agent Flulotion.Development of various pharmaceutical compositions used on Flurenizide is important in treatment of skin infections.

  3. Lethal photosensitization of biofilm-grown bacteria (United States)

    Wilson, Michael


    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. Lethal fish hook attachment - An unusual occurrence. (United States)

    Byard, Roger W


    A 39-year-old fisherman is reported who was dragged into the water from a boat after he became entangled in fishing line. His death was attributed to salt water drowning. At autopsy the cause of death was confirmed and the mechanism of the lethal event elucidated. Specifically, a large fish hook attached to line was embedded in his right wrist. The hook had passed beneath flexor tendons and had firmly attached him to fishing line that was being dropped from the vessel. There were no other significant injuries or underlying diseases present. This case demonstrates another rare situation in the commercial fishing industry that may result in a victim being dragged from a boat and drowned. Copyright © 2012 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

  5. Immunopathologic responses to non-lethal sepsis. (United States)

    Ebong, S J; Call, D R; Bolgos, G; Newcomb, D E; Granger, J I; O'Reilly, M; Remick, D G


    Although sepsis causes significant morbidity and mortality, its basic pathology is still not well understood. We investigated the inflammatory and physiologic alterations of non-lethal sepsis using cecal ligation and puncture (CLP), a model that induces peritonitis due to mixed intestinal flora, reproducing the complex immunology of sepsis. Groups of mice were subjected to CLP (25G needle) or sham surgery, had minimitters implanted to continuously monitor temperature and activity, and were sacrificed daily for 6 days. There was significant hypothermia (6-13 hrs post-surgery), and decreases in activity (to day 4) and weight (to day 3) but no mortality in the CLP group. Blood analyses of the CLP-treated mice showed reduced hemoglobin, platelets, lymphocytes, monocytes, and neutrophils, compared to sham animals. Both groups had nearly equivalent neutrophil influx into the peritoneum. Plasma and peritoneal G-CSF, IL-6, as well as the murine chemokines KC and MIP2-alpha were significantly higher in the CLP-treated mice at day 1. Plasma and peritoneal TNF were low (<70 pg/mL). While there was elevated IL-1beta in the peritoneum of the CLP-treated mice, this cytokine was not detected in the plasma in either treatment group. Cytokines were not detected in the pulmonary airspace of the CLP-treated mice and PMNs were not recruited to this site. Our data shows altered immunopathology in non-lethal sepsis with significant blood and cytokine alterations. Since there was 100% survival, the inflammatory response was appropriate and probably even protective.

  6. Synthetic biological networks

    International Nuclear Information System (INIS)

    Archer, Eric; Süel, Gürol M


    Despite their obvious relationship and overlap, the field of physics is blessed with many insightful laws, while such laws are sadly absent in biology. Here we aim to discuss how the rise of a more recent field known as synthetic biology may allow us to more directly test hypotheses regarding the possible design principles of natural biological networks and systems. In particular, this review focuses on synthetic gene regulatory networks engineered to perform specific functions or exhibit particular dynamic behaviors. Advances in synthetic biology may set the stage to uncover the relationship of potential biological principles to those developed in physics. (review article)

  7. Synthetic Base Fluids (United States)

    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.

  8. Evaluation of students' knowledge about paediatric dosage calculations. (United States)

    Özyazıcıoğlu, Nurcan; Aydın, Ayla İrem; Sürenler, Semra; Çinar, Hava Gökdere; Yılmaz, Dilek; Arkan, Burcu; Tunç, Gülseren Çıtak


    Medication errors are common and may jeopardize the patient safety. As paediatric dosages are calculated based on the child's age and weight, risk of error in dosage calculations is increasing. In paediatric patients, overdose drug prescribed regardless of the child's weight, age and clinical picture may lead to excessive toxicity and mortalities while low doses may delay the treatment. This study was carried out to evaluate the knowledge of nursing students about paediatric dosage calculations. This research, which is of retrospective type, covers a population consisting of all the 3rd grade students at the bachelor's degree in May, 2015 (148 students). Drug dose calculation questions in exam papers including 3 open ended questions on dosage calculation problems, addressing 5 variables were distributed to the students and their responses were evaluated by the researchers. In the evaluation of the data, figures and percentage distribution were calculated and Spearman correlation analysis was applied. Exam question on the dosage calculation based on child's age, which is the most common method in paediatrics, and which ensures right dosages and drug dilution was answered correctly by 87.1% of the students while 9.5% answered it wrong and 3.4% left it blank. 69.6% of the students was successful in finding the safe dose range, and 79.1% in finding the right ratio/proportion. 65.5% of the answers with regard to Ml/dzy calculation were correct. Moreover, student's four operation skills were assessed and 68.2% of the students were determined to have found the correct answer. When the relation among the questions on medication was examined, a significant relation (correlation) was determined between them. It is seen that in dosage calculations, the students failed mostly in calculating ml/dzy (decimal). This result means that as dosage calculations are based on decimal values, calculations may be ten times erroneous when the decimal point is placed wrongly. Moreover, it

  9. Effects of lethal and non-lethal malaria on the mononuclear phagocyte system

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Tosta


    Full Text Available The effects ofone non-lethal species ofmalarialparasite, Plasmodium yoelii, and one lethal species, P. berghei, on the mononuclear phagocyte system (MPS of BALB/c mice were studied. P. yoelii caused a greater and more sustained expansion and activation of the MPS, and the two major populations of spleen phagocytic cells-red pulp and marginal zone macrophages - exhibited a greater increase in numbers in this infection. During the course of P. berghei mataria, the spleen was progressively occupied by haematopoietic tissue and, at the terminal stage of infection, an extensive depletion of lymphocytes and macrophages was apparent. The possibility was suggested that the outcome of mataria may be inftuenced by the particular way the parasite interacts with the MPS.

  10. Synthetic Biological Membrane (SBM) (United States)

    National Aeronautics and Space Administration — The ultimate goal of the Synthetic Biological Membrane project is to develop a new type of membrane that will enable the wastewater treatment system required on...

  11. Hybridization with synthetic oligonucleotides

    Energy Technology Data Exchange (ETDEWEB)

    Szostak, J.W.; Stiles, J.I.; Tye, B.K.; Sherman, F.; Wu, R.


    Procedures are described for the use of synthetic oligonucleotides for Southern blot experiments and gene bank screening, and the effect of various mismatches on the efficiency of hybridization is demonstrated. The following topics are discussed: sensitivity vs. specificity, hybridization of a 12-mer to the lambda endolysin gene; hybridization of oligonucleotide probes to the E. coli lac operator; hybridization of synthetic probes to the CYC1 gene of yeast; and cloning eucaryotic genes. (HLW)

  12. Mammalian Synthetic Biology


    Martella, Andrea; Pollard, Steven M; Dai, Junbiao; Cai, Yizhi


    The enabling technologies of synthetic biology are opening up new opportunities for engineering and enhancement of mammalian cells. This will stimulate diverse applications in many life science sectors such as regenerative medicine, development of biosensing cell lines, therapeutic protein production, and generation of new synthetic genetic regulatory circuits. Harnessing the full potential of these new engineering-based approaches requires the design and assembly of large DNA constructs-pote...

  13. Parental genome dosage imbalance deregulates imprinting in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Pauline E Jullien


    Full Text Available In mammals and in plants, parental genome dosage imbalance deregulates embryo growth and might be involved in reproductive isolation between emerging new species. Increased dosage of maternal genomes represses growth while an increased dosage of paternal genomes has the opposite effect. These observations led to the discovery of imprinted genes, which are expressed by a single parental allele. It was further proposed in the frame of the parental conflict theory that parental genome imbalances are directly mirrored by antagonistic regulations of imprinted genes encoding maternal growth inhibitors and paternal growth enhancers. However these hypotheses were never tested directly. Here, we investigated the effect of parental genome imbalance on the expression of Arabidopsis imprinted genes FERTILIZATION INDEPENDENT SEED2 (FIS2 and FLOWERING WAGENINGEN (FWA controlled by DNA methylation, and MEDEA (MEA and PHERES1 (PHE1 controlled by histone methylation. Genome dosage imbalance deregulated the expression of FIS2 and PHE1 in an antagonistic manner. In addition increased dosage of inactive alleles caused a loss of imprinting of FIS2 and MEA. Although FIS2 controls histone methylation, which represses MEA and PHE1 expression, the changes of PHE1 and MEA expression could not be fully accounted for by the corresponding fluctuations of FIS2 expression. Our results show that parental genome dosage imbalance deregulates imprinting using mechanisms, which are independent from known regulators of imprinting. The complexity of the network of regulations between expressed and silenced alleles of imprinted genes activated in response to parental dosage imbalance does not support simple models derived from the parental conflict hypothesis.

  14. Lethal and sublethal effects of pesticides in the management of Polyphagotarsonemus latus (Banks) (Acari: Tarsonemidae) on Capsicum annuum L. (United States)

    Breda, Mariana O; Oliveira, José V; Esteves Filho, Alberto B; Barbosa, Douglas Rs; Santos, Andrezo A


    The evaluation of lethal and sublethal effects is of great importance for a complete assessment of the total impact of chemical compounds upon pest populations and the development of management strategies. In this study, we evaluated the lethal and sublethal effects of different synthetic and botanical products on the broad mite Polyphagotarsonemus latus (Banks), a major pest of Capsicum annuum L. and other crops. Abamectin had the highest lethal effect on P. latus, followed by spiromesifen, azadirachtin, neem oil and nitrogen fertiliser + citric acid. The sublethal effects of the products were indicated by the influence on mite population growth, affecting the numbers of females, males, larvae, pupae and eggs. Furthermore, a negative instantaneous rate of increase in P. latus and repellent effects were observed. The lethal and sublethal effects of abamectin, spiromesifen, azadirachtin and neem oil significantly affect P. latus population growth, as well as causing repellence to this mite on C. annuum, and they should be considered in the integrated pest management of this mite. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  15. Perinatal-lethal Gaucher disease presenting as hydrops fetalis ...

    African Journals Online (AJOL)

    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.

  16. Dosage compensation is less effective in birds than in mammals

    Directory of Open Access Journals (Sweden)

    Itoh Yuichiro


    Full Text Available Abstract Background In animals with heteromorphic sex chromosomes, dosage compensation of sex-chromosome genes is thought to be critical for species survival. Diverse molecular mechanisms have evolved to effectively balance the expressed dose of X-linked genes between XX and XY animals, and to balance expression of X and autosomal genes. Dosage compensation is not understood in birds, in which females (ZW and males (ZZ differ in the number of Z chromosomes. Results Using microarray analysis, we compared the male:female ratio of expression of sets of Z-linked and autosomal genes in two bird species, zebra finch and chicken, and in two mammalian species, mouse and human. Male:female ratios of expression were significantly higher for Z genes than for autosomal genes in several finch and chicken tissues. In contrast, in mouse and human the male:female ratio of expression of X-linked genes is quite similar to that of autosomal genes, indicating effective dosage compensation even in humans, in which a significant percentage of genes escape X-inactivation. Conclusion Birds represent an unprecedented case in which genes on one sex chromosome are expressed on average at constitutively higher levels in one sex compared with the other. Sex-chromosome dosage compensation is surprisingly ineffective in birds, suggesting that some genomes can do without effective sex-specific sex-chromosome dosage compensation mechanisms.

  17. Lethal and sub-lethal effects of five pesticides used in rice farming on the earthworm Eisenia fetida

    NARCIS (Netherlands)

    Rico, Andreu; Sabater, Consuelo; Castillo, María Ángeles


    The toxicity of five pesticides typically used in rice farming (trichlorfon, dimethoate, carbendazim, tebuconazole and prochloraz) was evaluated on different lethal and sub-lethal endpoints of the earthworm Eisenia fetida. The evaluated endpoints included: avoidance behaviour after an exposure

  18. Histone locus regulation by the Drosophila dosage compensation adaptor protein CLAMP. (United States)

    Rieder, Leila E; Koreski, Kaitlin P; Boltz, Kara A; Kuzu, Guray; Urban, Jennifer A; Bowman, Sarah K; Zeidman, Anna; Jordan, William T; Tolstorukov, Michael Y; Marzluff, William F; Duronio, Robert J; Larschan, Erica N


    The conserved histone locus body (HLB) assembles prior to zygotic gene activation early during development and concentrates factors into a nuclear domain of coordinated histone gene regulation. Although HLBs form specifically at replication-dependent histone loci, the cis and trans factors that target HLB components to histone genes remained unknown. Here we report that conserved GA repeat cis elements within the bidirectional histone3-histone4 promoter direct HLB formation in Drosophila In addition, the CLAMP (chromatin-linked adaptor for male-specific lethal [MSL] proteins) zinc finger protein binds these GA repeat motifs, increases chromatin accessibility, enhances histone gene transcription, and promotes HLB formation. We demonstrated previously that CLAMP also promotes the formation of another domain of coordinated gene regulation: the dosage-compensated male X chromosome. Therefore, CLAMP binding to GA repeat motifs promotes the formation of two distinct domains of coordinated gene activation located at different places in the genome. © 2017 Rieder et al.; Published by Cold Spring Harbor Laboratory Press.

  19. Tumor clone dynamics in lethal prostate cancer. (United States)

    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; S de Bono, Johann; Demichelis, Francesca; Attard, Gerhardt


    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. Copyright © 2014, American Association for the Advancement of Science.

  20. Non lethal Raine syndrome and differential diagnosis. (United States)

    Elalaoui, Siham Chafai; Al-Sheqaih, Nada; Ratbi, Ilham; Urquhart, Jill E; O'Sullivan, James; Bhaskar, Sanjeev; Williams, Simon S; Elalloussi, Mustapha; Lyahyai, Jaber; Sbihi, Leila; Cherkaoui Jaouad, Imane; Sbihi, Abdelhafid; Newman, William G; Sefiani, Abdelaziz


    Raine syndrome is a rare autosomal recessive bone dysplasia characterized by characteristic facial features with exophthalmos and generalized osteosclerosis. Amelogenesis imperfecta, hearing loss, seizures, and intracerebral calcification are apparent in some affected individuals. Originally, Raine syndrome was originally reported as a lethal syndrome. However, recently a milder phenotype, compatible with life, has been described. Biallelic variants inFAM20C, encoding aGolgi casein kinase involved in biomineralisation, have been identified in affected individuals. We report here a consanguineous Moroccan family with two affected siblingsa girl aged 18 and a boy of 15years. Clinical features, including learning disability, seizures and amelogenesis imperfecta, initially suggested a diagnosis of Kohlschutter-Tonz syndrome. However,a novel homozygous FAM20Cvariantc.676T > A, p.(Trp226Arg) was identified in the affected siblings. Our report reinforces that Raine syndrome is compatible with life, and that mild hypophosphatemia and amelogenesis imperfecta are key features of the attenuated form. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. Dose-response tests and semi-field evaluation of lethal and sub-lethal effects of slow release pyriproxyfen granules (Sumilarv®0.5G) for the control of the malaria vectors Anopheles gambiae sensu lato. (United States)

    Mbare, Oscar; Lindsay, Steven W; Fillinger, Ulrike


    Recently research has shown that larviciding can be an effective tool for integrated malaria vector control. Nevertheless, the uptake of this intervention has been hampered by the need to re-apply larvicides frequently. There is a need to explore persistent, environmentally friendly larvicides for malaria vector control to reduce intervention efforts and costs by reducing the frequency of application. In this study, the efficacy of a 0.5% pyriproxyfen granule (Surmilarv®0.5G, Sumitomo Chemicals) was assessed for the control of Anopheles gambiae sensu stricto and Anopheles arabiensis, the major malaria vectors in sub-Saharan Africa. Dose-response and standardized field tests were implemented following standard procedures of the World Health Organization's Pesticide Evaluation Scheme to determine: (i) the susceptibility of vectors to this formulation; (ii) the residual activity and appropriate retreatment schedule for field application; and, (iii) sub-lethal impacts on the number and viability of eggs laid by adults after exposure to Sumilarv®0.5G during larval development. Anopheles gambiae s.s. and An. arabiensis were highly susceptible to Sumilarv®0.5G. Estimated emergence inhibition (EI) values were very low and similar for both species. The minimum dosage that completely inhibited adult emergence was between 0.01-0.03 parts per million (ppm) active ingredient (ai). Compared to the untreated control, an application of 0.018 ppm ai prevented 85% (95% confidence interval (CI) 82%-88%) of adult emergence over six weeks under standardized field conditions. A fivefold increase in dosage of 0.09 ppm ai prevented 97% (95% CI 94%-98%) emergence. Significant sub-lethal effects were observed in the standardized field tests. Female An. gambiae s.s. that were exposed to 0.018 ppm ai as larvae laid 47% less eggs, and females exposed to 0.09 ppm ai laid 74% less eggs than females that were unexposed to the treatment. Furthermore, 77% of eggs laid by females exposed to 0

  2. Orodispersible dosage forms: biopharmaceutical improvements and regulatory requirements. (United States)

    Cilurzo, Francesco; Musazzi, Umberto M; Franzé, Silvia; Selmin, Francesca; Minghetti, Paola


    Orodispersible dosage forms have a growing presence in the pharmaceutical market because their administration can improve the bioavailability of some drugs and their prescription can ameliorate patient adherence and/or compliance. Here, we review the main features of orodispersible tablets, including oral lyophilisates, and orodispersible films along with their main production technologies. We summarize the bioavailability data and critically discussed their potential to improve patient adherence and/or compliance. We revisit this information in light of both the European Union (EU) and US regulatory frameworks, focusing on the differences in the definitions of such dosage forms and the requirements for marketing authorization. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Enhanced chromatin accessibility of the dosage compensated Drosophila male X-chromosome requires the CLAMP zinc finger protein. (United States)

    Urban, Jennifer; Kuzu, Guray; Bowman, Sarah; Scruggs, Benjamin; Henriques, Telmo; Kingston, Robert; Adelman, Karen; Tolstorukov, Michael; Larschan, Erica


    The essential process of dosage compensation is required to equalize gene expression of X-chromosome genes between males (XY) and females (XX). In Drosophila, the conserved Male-specific lethal (MSL) histone acetyltransferase complex mediates dosage compensation by increasing transcript levels from genes on the single male X-chromosome approximately two-fold. Consistent with its increased levels of transcription, the male X-chromosome has enhanced chromatin accessibility, distinguishing it from the autosomes. Here, we demonstrate that the non-sex-specific CLAMP (Chromatin-linked adaptor for MSL proteins) zinc finger protein that recognizes GA-rich sequences genome-wide promotes the specialized chromatin environment on the male X-chromosome and can act over long genomic distances (~14 kb). Although MSL complex is required for increasing transcript levels of X-linked genes, it is not required for enhancing global male X-chromosome chromatin accessibility, and instead works cooperatively with CLAMP to facilitate an accessible chromatin configuration at its sites of highest occupancy. Furthermore, CLAMP regulates chromatin structure at strong MSL complex binding sites through promoting recruitment of the Nucleosome Remodeling Factor (NURF) complex. In contrast to the X-chromosome, CLAMP regulates chromatin and gene expression on autosomes through a distinct mechanism that does not involve NURF recruitment. Overall, our results support a model where synergy between a non-sex-specific transcription factor (CLAMP) and a sex-specific cofactor (MSL) creates a specialized chromatin domain on the male X-chromosome.

  4. Synthetic guide star generation (United States)

    Payne, Stephen A [Castro Valley, CA; Page, Ralph H [Castro Valley, CA; Ebbers, Christopher A [Livermore, CA; Beach, Raymond J [Livermore, CA


    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.

  5. Synthetic Aperture Sequential Beamforming

    DEFF Research Database (Denmark)

    Kortbek, Jacob; Jensen, Jørgen Arendt; Gammelmark, Kim Løkke


    A synthetic aperture focusing (SAF) technique denoted Synthetic Aperture Sequential Beamforming (SASB) suitable for 2D and 3D imaging is presented. The technique differ from prior art of SAF in the sense that SAF is performed on pre-beamformed data contrary to channel data. The objective...... is stored. The second stage applies the focused image lines from the first stage as input data. The SASB method has been investigated using simulations in Field II and by off-line processing of data acquired with a commercial scanner. The performance of SASB with a static image object is compared with DRF...

  6. Mining of lethal recessive genetic variation in Danish cattle

    DEFF Research Database (Denmark)

    Das, Ashutosh


    The widespread use of artificial insemination in cattle breeding Worldwide leads to reduced effective population sizes and increased inbreeding levels. Increased inbreeding result in increased probalility of expression of recessive defective alleles, which probably is reflected in a decline...... in fertility. The primary objective of this PhD projekt was to identify recessive lethal gentic variants in the main Danish dairy cattle breed. Holstein-Friesian utilzing next generation sequencing (NGS) data. This study shows a potential for the use of the NGS-based reverse genetic approach in identifying...... lethal or semi-lethal recessive gentic variation...

  7. 75 FR 76259 - Oral Dosage Form New Animal Drugs; Tylosin (United States)


    .... FDA-2010-N-0002] Oral Dosage Form New Animal Drugs; Tylosin AGENCY: Food and Drug Administration, HHS... Huvepharma AD. The ANADA provides for use of tylosin tartrate soluble powder in drinking water of chickens... Blvd., Sophia 1407, Bulgaria, filed ANADA 200-473 that provides for use of PHARMASIN (tylosin tartrate...

  8. Software for Dosage Individualization of Voriconazole for Immunocompromised Patients (United States)

    VanGuilder, Michael; Donnelly, J. Peter; Blijlevens, Nicole M. A.; Brüggemann, Roger J. M.; Jelliffe, Roger W.; Neely, Michael N.


    The efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice. PMID:23380734

  9. Effect of lead acetate administered orally at different dosage levels ...

    African Journals Online (AJOL)

    The project was conducted to evaluate the effect of lead administered as lead acetate at different dosage levels via drinking water in broiler chicks. Thirty-five healthy chicks were divided into seven groups (five chicks each) and one group was kept as un-medicated control. Groups A, B, C, D, E and F were medicated with ...

  10. 21 CFR 201.55 - Statement of dosage. (United States)


    ... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Statement of dosage. 201.55 Section 201.55 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS..., depending upon the conditions being treated, it may not be possible in all cases to present an informative...

  11. Dosage plasmatique et globulaire du magnesium dans l'exploration ...

    African Journals Online (AJOL)

    Objectives: The allergic rhinitis represents a real public health problem. The goal of this survey is to value the interest of the dosage plasmatical and globular of magnesium in the diagnosis of the allergic rhinitis. Materials and methods : Analytic and prospective survey of 80 files, on one period of 4 years and 5 months (from ...

  12. Quality of 'Climax' blueberries after low dosage electron beam irradiation

    International Nuclear Information System (INIS)

    Miller, W.R.; McDonald, R.E.; McCollum, T.G.; Smittle, B.J.


    Fruit of 'Climax' rabbiteye blueberries (Vaccinium ashei Reade) were irradiated by a linear accelerator at 0, 0.25, 0.5, 0.75, 1.0, and 1.25 kGy and evaluated for various quality attributes after storage for 1, 3, 7, or 14 days at 1C plus 2 days at 15C, respectively. Weight loss increased during storage and averaged 4.2% after the final inspection and was not affected by irradiation dosage. About 5% of total berries were decayed after 14 days at 1C, about 6% after the final inspection at 15C, but decay was not affected by the level of irradiation. Electrolyte leakage, skin color, total soluble solids, acidity, and pH were also not affected by irradiation dosage. There was a significant decline in berry firmness, flavor, and texture as dosage increased. Berries treated at 1.0 kGy or above were softer and had lower flavor and texture preference scores than berries treated at lower dosages or nontreated berries

  13. Whole-body vibration dosage alters leg blood flow

    NARCIS (Netherlands)

    Lythgo, Noel; Eser, Prisca; de Groot, Patricia; Galea, Mary

    The effect of whole-body vibration dosage on leg blood flow was investigated. Nine healthy young adult males completed a set of 14 random vibration and non-vibration exercise bouts whilst squatting on a Galileo 900 plate. Six vibration frequencies ranging from 5 to 30 Hz (5 Hz increments) were used

  14. 75 FR 67031 - Oral Dosage Form New Animal Drugs; Domperidone (United States)


    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 520 [Docket No. FDA-2010-N-0002] Oral Dosage Form New Animal Drugs; Domperidone AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA) is amending the animal drug...

  15. 76 FR 59023 - Oral Dosage Form New Animal Drugs; Tylosin (United States)


    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 520 [Docket No. FDA-2011-N-0003] Oral Dosage Form New Animal Drugs; Tylosin AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA) is amending the animal drug...

  16. 77 FR 3927 - Oral Dosage Form New Animal Drugs; Deracoxib (United States)


    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 520 [Docket No. FDA-2011-N-0003] Oral Dosage Form New Animal Drugs; Deracoxib AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA) is amending the animal drug...

  17. 76 FR 40808 - Oral Dosage Form New Animal Drugs; Amprolium (United States)


    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 520 [Docket No. FDA-2011-N-0003] Oral Dosage Form New Animal Drugs; Amprolium AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA) is amending the animal drug...

  18. 76 FR 78149 - Oral Dosage Form New Animal Drugs; Estriol (United States)


    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 520 [Docket No. FDA-2011-N-0003] Oral Dosage Form New Animal Drugs; Estriol AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA) is amending the animal drug...

  19. 76 FR 18648 - Oral Dosage Form New Animal Drugs; Robenacoxib (United States)


    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 520 [Docket No. FDA-2011-N-0003] Oral Dosage Form New Animal Drugs; Robenacoxib AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA) is amending the animal drug...

  20. quality evaluation of paracetamol in the bulk, dosage forms

    African Journals Online (AJOL)

    Prince Acheampong

    High Performance Liquid Chromatography has been used to evolve an analytical procedure for the evaluation of ... assay of paracetamol-codeine combination drug as well as estimation of the amount of constituents in ... paracetamol in the bulk powder, dosage forms and biological fluids such as blood and urine for easier.

  1. Fuzzy-based dosage model of aqueous decoction of Adansonia ...

    African Journals Online (AJOL)

    However, in the area of traditional medicine, no much attention has been given to its enhancement with the use of information technology especially in the area of herbal prescription. ... The mass of herb and volume of solvent were used as input parameters to design the dosage model, and simulated using MATLAB.

  2. Biowaiver monographs for immediate release solid oral dosage forms: cimetidine.

    NARCIS (Netherlands)

    Jantratid, E; Prakongpan, S; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Barends, D M


    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned

  3. Dosage Compensation of an Aneuploid Genome in Mouse Spermatogenic Cells

    Czech Academy of Sciences Publication Activity Database

    Jansa, Petr; Homolka, David; Blatný, Radek; Mistrik, M.; Bartek, Jiří; Forejt, Jiří


    Roč. 90, č. 6 (2014), 124/1-124/9 ISSN 0006-3363 R&D Projects: GA ČR GA13-08078S Institutional support: RVO:68378050 Keywords : gene dosage * male sterility * segmental trisomy * meiotic silencing of unsynapsed chromatin * DOWN - SYNDROME * MAMMALIAN MEIOSIS Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.318, year: 2014

  4. Dosage compensation and demasculinization of X chromosomes in Drosophila. (United States)

    Bachtrog, Doris; Toda, Nicholas R T; Lockton, Steven


    The X chromosome of Drosophila shows a deficiency of genes with male-biased expression, whereas mammalian X chromosomes are enriched for spermatogenesis genes expressed premeiosis and multicopy testis genes. Meiotic X-inactivation and sexual antagonism can only partly account for these patterns. Here, we show that dosage compensation (DC) in Drosophila may contribute substantially to the depletion of male genes on the X. To equalize expression between X-linked and autosomal genes in the two sexes, male Drosophila hypertranscribe their single X, whereas female mammals silence one of their two X chromosomes. We combine fine-scale mapping data of dosage compensated regions with genome-wide expression profiles and show that most male-biased genes on the D. melanogaster X are located outside dosage compensated regions. Additionally, X-linked genes that have newly acquired male-biased expression in D. melanogaster are less likely to be dosage compensated, and parental X-linked genes that gave rise to an autosomal male-biased retrocopy are more likely located within compensated regions. This suggests that DC contributes to the observed demasculinization of X chromosomes in Drosophila, both by limiting the emergence of male-biased expression patterns of existing X genes, and by contributing to gene trafficking of male genes off the X. Copyright 2010 Elsevier Ltd. All rights reserved.

  5. A system for dosage-based functional genomics in poplar (United States)

    Isabelle M. Henry; Matthew S. Zinkgraf; Andrew T. Groover; Luca Comai


    Altering gene dosage through variation in gene copy number is a powerful approach to addressing questions regarding gene regulation, quantitative trait loci, and heterosis, but one that is not easily applied to sexually transmitted species. Elite poplar (Populus spp) varieties are created through interspecific hybridization, followed by...

  6. Formulation of Croton penduliflorus seed into tablet dosage form ...

    African Journals Online (AJOL)

    Formulation of Croton penduliflorus seed into tablet dosage form. GC Onunkwo. Abstract. No Abstract. Global Journal of Medical Sciences Vol. 5(1) 2006: 29-33. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT ·

  7. Formulation and evaluation of tablet dosage form of Hunteria ...

    African Journals Online (AJOL)

    The present study was aimed at formulating and evaluating tablet dosage form of Hunteria umbellata (HU) seed aqueous and purified extracts. HU seeds were dried, pulverized and the powder macerated in water to obtain aqueous extract, while alkaloidal extraction process was used to obtain purified extract. Extracts ...

  8. Spectrophotometric Determination of Cilostazol in Tablet Dosage Form

    African Journals Online (AJOL)

    Purpose: To develop simple, rapid and selective spectrophotometric methods for the determination of cilostazol in tablet dosage form. Methods: Cilostazol was dissolved in 50 % methanol and its absorbance was scanned by ultraviolet (UV) spectrophotometry. Both linear regression equation and standard absorptivity were ...

  9. What Are Synthetic Cannabinoids? (United States)

    ... market and are intended to produce the same effects as illegal drugs. Some of these substances may have been around for years but have reentered the market in altered chemical forms, or due to renewed popularity. False Advertising Synthetic cannabinoid products are often labeled "not for ...

  10. Towards a synthetic chloroplast.

    Directory of Open Access Journals (Sweden)

    Christina M Agapakis


    Full Text Available The evolution of eukaryotic cells is widely agreed to have proceeded through a series of endosymbiotic events between larger cells and proteobacteria or cyanobacteria, leading to the formation of mitochondria or chloroplasts, respectively. Engineered endosymbiotic relationships between different species of cells are a valuable tool for synthetic biology, where engineered pathways based on two species could take advantage of the unique abilities of each mutualistic partner.We explored the possibility of using the photosynthetic bacterium Synechococcus elongatus PCC 7942 as a platform for studying evolutionary dynamics and for designing two-species synthetic biological systems. We observed that the cyanobacteria were relatively harmless to eukaryotic host cells compared to Escherichia coli when injected into the embryos of zebrafish, Danio rerio, or taken up by mammalian macrophages. In addition, when engineered with invasin from Yersinia pestis and listeriolysin O from Listeria monocytogenes, S. elongatus was able to invade cultured mammalian cells and divide inside macrophages.Our results show that it is possible to engineer photosynthetic bacteria to invade the cytoplasm of mammalian cells for further engineering and applications in synthetic biology. Engineered invasive but non-pathogenic or immunogenic photosynthetic bacteria have great potential as synthetic biological devices.

  11. Synthetic Metabolic Pathways

    DEFF Research Database (Denmark)

    topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Synthetic Metabolic Pathways: Methods and Protocols aims to ensure successful results in the further study...

  12. Synthetic growth reference charts

    NARCIS (Netherlands)

    Hermanussen, Michael; Stec, Karol; Aßmann, Christian; Meigen, Christof; Van Buuren, Stef


    Objectives: To reanalyze the between-population variance in height, weight, and body mass index (BMI), and to provide a globally applicable technique for generating synthetic growth reference charts. Methods: Using a baseline set of 196 female and 197 male growth studies published since 1831, common

  13. A formidable synthetic challenge

    Indian Academy of Sciences (India)

    Isolation and characterization of maoecrystal V, a C19 terpenoid, having potent and selective cytotoxicity towards HeLa cells was recently reported. Unusually complex pentacyclic molecular structure, presence of spirofused rings and several stereogenic centres posed a great synthetic challenge. In this short review, efforts ...

  14. Synthetic antiferromagnetic spintronics (United States)

    Duine, R. A.; Lee, Kyung-Jin; Parkin, Stuart S. P.; Stiles, M. D.


    Spintronic and nanomagnetic devices often derive their functionality from layers of different materials and the interfaces between them. We discuss the opportunities that arise from synthetic antiferromagnets consisting of two or more ferromagnetic layers that are separated by metallic spacers or tunnel barriers and have antiparallel magnetizations.

  15. Genetics Home Reference: platyspondylic lethal skeletal dysplasia, Torrance type (United States)

    ... cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies. ... for Links Data Files & API Site Map Subscribe Customer Support Copyright Privacy Accessibility FOIA Viewers & ...

  16. Maths anxiety and medication dosage calculation errors: A scoping review. (United States)

    Williams, Brett; Davis, Samantha


    A student's accuracy on drug calculation tests may be influenced by maths anxiety, which can impede one's ability to understand and complete mathematic problems. It is important for healthcare students to overcome this barrier when calculating drug dosages in order to avoid administering the incorrect dose to a patient when in the clinical setting. The aim of this study was to examine the effects of maths anxiety on healthcare students' ability to accurately calculate drug dosages by performing a scoping review of the existing literature. This review utilised a six-stage methodology using the following databases; CINAHL, Embase, Medline, Scopus, PsycINFO, Google Scholar, Trip database ( and Grey Literature report ( After an initial title/abstract review of relevant papers, and then full text review of the remaining papers, six articles were selected for inclusion in this study. Of the six articles included, there were three experimental studies, two quantitative studies and one mixed method study. All studies addressed nursing students and the presence of maths anxiety. No relevant studies from other disciplines were identified in the existing literature. Three studies took place in the U.S, the remainder in Canada, Australia and United Kingdom. Upon analysis of these studies, four factors including maths anxiety were identified as having an influence on a student's drug dosage calculation abilities. Ultimately, the results from this review suggest more research is required in nursing and other relevant healthcare disciplines regarding the effects of maths anxiety on drug dosage calculations. This additional knowledge will be important to further inform development of strategies to decrease the potentially serious effects of errors in drug dosage calculation to patient safety. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Center on Survivability and Lethality (CSL) Research Faculty



    NPS has a strong history in teaching and research in aircraft survivability and air defense lethality. On Jan. 30, the Naval Postgraduate School (NPS) announced the creation of the Center for Survivability and Lethality. The new center builds upon the pioneering work of Distinguished Professor Emeritus Robert Ball, who founded the first and only course on all aspects of aircraft combat survivability at NPS in the 1970s and wrote the field’s ‘bible,’ The Fundamentals of Aircraft Comba...

  18. Sonographic features of lethal multiple pterygium syndrome at 14 weeks. (United States)

    Chen, Min; Chan, Gavin Shueng Wai; Lee, Chin Peng; Tang, Mary Hoi Yin


    Lethal multiple pterygium syndrome is a rare inherited disorder. Previous reports suggest that the diagnosis may be based on prenatal sonographic demonstration of severe limb flexion, absence of fetal motion, and a large cystic hygroma in the second and third trimesters. We present the sonographic features and postmortem features of a fetus with lethal multiple pterygium syndrome at 13 weeks of gestation, which shows that the condition can possibly be diagnosed in the first trimester of pregnancy.

  19. Lethal synergy involving bicyclomycin: an approach for reviving old antibiotics. (United States)

    Malik, Muhammad; Li, Liping; Zhao, Xilin; Kerns, Robert J; Berger, James M; Drlica, Karl


    One way to address the growing problem of antimicrobial resistance is to revive old compounds that may have intrinsic lethal activity that is obscured by protective factors. Bicyclomycin is an old inhibitor of the Rho transcription terminator that by itself shows little rapid lethal activity. However, bicyclomycin participates in bacteriostatic synergy, which raises the possibility that conditions for lethal synergy may exist, perhaps through a suppression of protective factors. Bicyclomycin was combined with bacteriostatic inhibitors of gene expression, and bactericidal activity was measured with several cultured Gram-negative pathogens. When used alone, bicyclomycin failed to rapidly kill growing cultures of Escherichia coli; however, the additional presence of bacteriostatic concentrations of tetracycline, chloramphenicol or rifampicin led to rapid killing. Four other pathogen species, Acinetobacter baumannii, Klebsiella pneumoniae, Salmonella enterica serotype Typhimurium and Shigella dysenteriae, also exhibited enhanced killing when bicyclomycin was combined with tetracycline or rifampicin. This lethal synergy was achieved at low concentrations (slightly above the MIC) for all agents tested in combinations. Follow-up work with E. coli indicated that lethal synergy arose from a blockage of transcription elongation. Moreover, lethal synergy was reduced when bicyclomycin was added 60 min before tetracycline, suggesting that bicyclomycin induces a protective factor. The action of bicyclomycin illustrates the potential present in a largely abandoned antibacterial agent; it exhibits lethal synergy when coadministered with known, bacteriostatic inhibitors of gene expression. The identification of protective factors, which are currently uncharacterized, may reveal new ways to promote the lethal action of some old antibiotics. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved

  20. Molecular Epidemiology Investigation of Obesity and Lethal Prostate Cancer (United States)


    compelling evidence linking obesity to aggressive prostate cancer, but the underlying causes of this relationship are unclear. In this study we used whole...1 AWARD NUMBER: W81XWH-14-1-0250 TITLE: Molecular Epidemiology Investigation of Obesity and Lethal Prostate Cancer PRINCIPAL INVESTIGATOR: Ericka...TITLE AND SUBTITLE Molecular Epidemiology Investigation of Obesity and Lethal Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0250

  1. Natural and synthetic biomaterials for controlled drug delivery. (United States)

    Kim, Jang Kyoung; Kim, Hyung Jin; Chung, Jee-Young; Lee, Jong-Hwan; Young, Seok-Beom; Kim, Yong-Hee


    A wide variety of delivery systems have been developed and many products based on the drug delivery technology are commercially available. The development of controlled-release technologies accelerated new dosage form design by altering pharmacokinetic and pharmacodynamics profiles of given drugs, resulting in improved efficacy and safety. Various natural or synthetic polymers have been applied to make matrix, reservoir or implant forms due to the characteristics of polymers, especially ease of control for modifications of biocompatibility, biodegradation, porosity, charge, mechanical strength and hydrophobicity/hydrophilicity. Hydrogel is a hydrophilic, polymeric network capable of imbibing large amount of water and biological fluids. This review article introduces various applications of natural and synthetic polymer-based hydrogels from pharmaceutical, biomedical and bioengineering points of view.

  2. Synthetic antifreeze peptide and synthetic gene coding for its production



    A synthetic antifreeze peptide and a synthetic gene coding for the antifreeze peptide have been produced. The antifreeze peptide has a greater number of repeating amino acid sequences than is present in the native antifreeze peptides from winter flounder upon which the synthetic antifreeze peptide was modeled. Each repeating amino acid sequence has two polar amino acid residues which are spaced a controlled distance apart so that the antifreeze peptide may inhibit ice formation. The synthetic...

  3. Ecstasy tablets intoxication with lethal autcome

    Directory of Open Access Journals (Sweden)

    Đorđević Snežana


    Full Text Available Background. Ecstasy, 3,4-methylenedioxymethamphetamine (MDMA, is a synthetic compound increasingly popular as a recreational drug. Tablets known as ecstasy contain MDMA, but may also contain caffeine, ephedrine, paramethoxyamphetamine, 3,4-methylenedioxyamphetamine (MDA, amphetamine, methamphetamine, and ketamine. After absorption MDMA is metabolized to MDA, 4-hydroxy-3- metoxymetamphetamine (HMMA and 4-hydroxy-3- metoxyamphetamine (HMA. After that HMMA and HMA are conjugated and excreted by urine. The aim of this report was to confirm by toxicological post mortem analyses of poisoned person organs that ecstasy had been the cause of his death. Case report. We reported the death of a 17-year-old boy after the ingestion of ecstasy. MDMA and metabolites were determined by multicolumn high performance liquid chromatography with UV spectral detection (HPLC-UV. Toxicological tests showed the presence of MDMA in all samples. When examining post mortem material (the organs, the highest concentrations were measured in the stomach (835,97 μg/g and kidney (801,14 μg/g. The minimal concentration was in the liver (22,26 μg/g. Conclusion. The obtained results of MDMA and its metabolites concentrations showed abuse of a high dose of ecstasy. .

  4. Standardization in synthetic biology. (United States)

    Müller, Kristian M; Arndt, Katja M


    Synthetic Biology is founded on the idea that complex biological systems are built most effectively when the task is divided in abstracted layers and all required components are readily available and well-described. This requires interdisciplinary collaboration at several levels and a common understanding of the functioning of each component. Standardization of the physical composition and the description of each part is required as well as a controlled vocabulary to aid design and ensure interoperability. Here, we describe standardization initiatives from several disciplines, which can contribute to Synthetic Biology. We provide examples of the concerted standardization efforts of the BioBricks Foundation comprising the request for comments (RFC) and the Registry of Standardized Biological parts as well as the international Genetically Engineered Machine (iGEM) competition.

  5. Optical synthetic aperture radar (United States)

    Ilovitsh, Asaf; Zach, Shlomo; Zalevsky, Zeev


    A method is proposed for increasing the resolution of an object and overcoming the diffraction limit of an optical system installed on top of a moving imaging system, such as an airborne platform or satellite. The resolution improvement is obtained via a two-step process. First, three low resolution differently defocused images are captured and the optical phase is retrieved using an improved iterative Gershberg-Saxton based algorithm. The phase retrieval allows numerical back propagation of the field to the aperture plane. Second, the imaging system is shifted and the first step is repeated. The obtained optical fields at the aperture plane are combined and a synthetically increased lens aperture is generated along the direction of movement, yielding higher imaging resolution. The method resembles a well-known approach from the microwave regime called the synthetic aperture radar in which the antenna size is synthetically increased along the platform propagation direction. The proposed method is demonstrated via Matlab simulation as well as through laboratory experiment.

  6. Lethal means access and assessment among suicidal emergency department patients (United States)

    Betz, Marian E.; Miller, Matthew; Barber, Catherine; Beaty, Brenda; Miller, Ivan; Camargo, Carlos A.; Boudreaux, Edwin D.


    Background Reducing access to lethal means (especially firearms) might prevent suicide, but counseling of at-risk individuals about this strategy may not be routine. Among emergency department (ED) patients with suicidal ideation or attempts (SI/SA), we sought to describe home firearm access and examine ED provider assessment of access to lethal means. Methods This secondary analysis used data from the Emergency Department Safety Assessment and Follow-up Evaluation, a 3-phase, 8-center study of adult ED patients with SI/SA (2010-2013). Research staff surveyed participants about suicide-related factors (including home firearms) and later reviewed the ED chart (including documented assessment of lethal means access). Results Among 1358 patients with SI/SA, 11% (95%CI 10-13%) reported ≥1 firearm at home; rates varied across sites (range: 6% to 26%) but not over time. On chart review, 50% (95%CI 47-52%) of patients had documentation of lethal means access assessment. Frequency of documented assessment increased over study phases (40% to 60%, pfirearm ownership rates. Among the 337 (25%, 95%CI 23-27%) patients discharged to home, 55% (95%CI 49-60%) had no documentation of lethal means assessment; of these, 13% (95%CI 8-19; n=24) actually had ≥1 firearm at home. Among all those reporting ≥1 home firearm to study staff, only half (50%, 95%CI 42-59) had provider documentation of assessment of lethal means access. Conclusions Among these ED patients with SI/SA, many did not have documented assessment of home access to lethal means, including patients who were discharged home and had ≥1 firearm at home. PMID:26989850

  7. Abstractive Summarization of Drug Dosage Regimens for Supporting Drug Comparison. (United States)

    Ugon, Adrien; Berthelot, Hélène; Venot, Alain; Favre, Madeleine; Duclos, Catherine; Lamy, Jean-Baptiste


    Complicated dosage regimens often reduce adherence to drug treatments. The ease-of-administration must thus be taken into account when prescribing. Given one drug, there exists often several dosage regimens. Hence, comparison to similar drugs is difficult. Simplifying and summarizing them appears to be a required task for supporting General Practitioners to find the drug with the simplest regimen for the patient. We propose a summarization in two steps: first prunes out all low-importance information, and second proceed to fusion of remaining information. Rules for pruning and fusion strategies were designed by an expert in drug models. Evaluation was conducted on a dataset of 169 drugs. The agreement rate was 27.2%. We demonstrate that applying rules leads to a result that is correct by a computational point of view, but the result is often meaningless for the GP. We conclude with recommendations for further work.



    V. B. Khot*, D.A. Bhagwat, J. I. D'Souza, S. S. Shelake, S. V. Patil


    The purpose of this study was to optimize the best granulation techniques for development of tablet dosage form. The present study explains comparative study of different wet granulation techniques including Planetary mixer granulation, Rapid mixer granulation, Fluid bed granulation with Direct compression method. Similar formulations were used to evaluate Planetary mixer granulation, Rapid mixer granulation and Fluid bed granulation method. The granules prepared by different techniques were ...



    Kumar Vikash; Mishra Santosh Kumar; Lather Amit; Vikas; Singh Ranjit


    Pellets have been used in the pharmaceutical industry for more than four decades, with the advent of controlled release technology, that the full impact of the inherent advantages of pellets over single unit dosage forms have been realized, not only has focused on refining and optimizing existing pelletization techniques, but also focused on the development of novel approaches and procedures for manufacturing of pellets. The present review outlines the manufacturing and evaluation of pellets....

  10. Digital and conventional radiology techniques: comparison of dosage and costs

    International Nuclear Information System (INIS)

    Arranza, L.; Albornoz, C. de


    To compare the radiation dosage and costs in conventional and digital technologies. The study dealt with transverse sections. The dosage applied with conventional technology was measured in 254 patients who intertwined 402 explorations of 6 anatomic regions in 4 Radiodiagnostic Services. The dosage applied with digital technology was measured in 57 patients who underwent 95 explorations of the same anatomic region in one Radiodiagnostic Service. The costs of the 6 types of conventional and digital explorations performed were calculated for two Radiodiagnostic Service. The doses administered (mGy) using convectional/digital technology were as follows: chest PA 0.2/0.1; chest LAT 0.7/0.3; breast CC 7.0/8.4; breast LAT 7.0/7.8; breast OB 7.0/10.5; cervical spine AP 9.6/9.0; cervical spine LAT 21.9/29.6; pelvis AP 7.3/7.1; plain abdominal 6.5/2.2. The costs incurred (1992 pesetas) with the convectional/digital technologies: chest AP and LAT 1,393/2,973; portable chest 2,027/3,714; mammography 2,357/3,486; phlebography 12,718/14,023; hysterosalpingography 4,876/6,701; bone scientigraphy 1,633/2,839. Compared with conventional technology, digital imaging reduces the radiation doses received by the patients, except in the case of mammography. The costs associated with the use of digital technology are greater than those incurred with conventional technology, mainly due to the costs of amortization. the use of digital technology is more justified when: 1) it is very necessary to reduce the dosage; 2) studies of chest and abdomen predominant; 3) the volume of utilization is high; 4) staff management is flexible , and 5) the cost of purchasing the equipment is lower. (Author) 10 refs

  11. Effects of DDE on experimentally poisoned free-tailed bats (Tadarida brasiliensis): Lethal brain concentrations (United States)

    Clark, D.R.; Kroll, J.C.


    Adult female free-tailed bats (Tadarida brasiliensis) were collected at Bracken Cave, Texas, and shipped to the Patuxent Wildlife Research Center. Treated mealworms (Tenebrio molitor) containing 107 ppm DDE were fed to 17 bats; five other bats were fed untreated mealworms. After 40 days on dosage, during which one dosed bat was killed accidentally, four dosed bats were frozen and the remaining 17 were starved to death. The objective was to elevate brain levels of DDE to lethality and measure these concentrations. After the feeding period, dosed bats weighed less than controls. After starvation, the body condition of dosed bats was poorer than that of controls even though there was no difference in the amounts of carcass fat. During starvation, dosed bats lost weight faster than controls. Also, four dosed bats exhibited the prolonged tremoring that characterizes DDE poisoning. DDE increased in brains of starving bats as fat was metabolized. The estimated mean brain concentration of DDE diagnostic of death was 519 ppm with a range of 458-564 ppm. These values resemble diagnostic levels known for two species of passerine birds, but they exceed published levels for two free-tailed bats from Carlsbad Caverns, New Mexico.

  12. Characterization of the male-specific lethal 3 gene in the oriental river prawn, Macrobrachium nipponense. (United States)

    Zhang, Y P; Sun, S M; Fu, H T; Ge, X P; Qiao, H; Zhang, W Y; Xiong, Y W; Jiang, S F; Gong, Y S; Jin, S B


    In this study, male-specific lethal 3 homolog (Mnmsl3) was cloned and characterized from the freshwater prawn Macrobrachium nipponense (Crustacea: Decapoda: Palaemonidae) by rapid amplification of cDNA ends. The deduced amino acid sequences of Mnmsl3 showed high-sequence homology to the insect Msl3 and contained a conserved chromatin organization modifier domain and an MORF4-related gene domain. Real-time quantitative reverse transcription-polymerase chain reaction showed that the Mnmsl3 gene was expressed in all the investigated tissues, with the highest level of expression in the testis. The expression level of Mnmsl3 between males and females was different in the gonad (testis or ovary), abdominal ganglion, and heart. The results revealed that the Mnmsl3 gene might play roles in regulating chromatin and in dosage compensation of M. nipponense. Real-time quantitative reverse transcription-polymerase chain reaction also revealed that Mnmsl3 mRNA expression was significantly increased in both 5 and 20 days post-larvae after metamorphosis, suggesting that Mnmsl3 plays complex and important roles in the early embryonic development and sex differentiation of M. nipponense.

  13. Prevalence and trends of cellulosics in pharmaceutical dosage forms. (United States)

    Mastropietro, David J; Omidian, Hossein


    Many studies have shown that cellulose derivatives (cellulosics) can provide various benefits when used in virtually all types of dosage forms. Nevertheless, the popularity of their use in approved drug products is rather unknown. This research reports the current prevalence and trends of use for 15 common cellulosics in prescription drug products. The cellulosics were powdered and microcrystalline cellulose (MCC), ethyl cellulose, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hypromellose (HPMC), HPMC phthalate, HPMC acetate succinate, cellulose acetate (CA), CA phthalate, sodium (Na) and calcium (Ca) carboxymethylcellulose (CMC), croscarmellose sodium (XCMCNa), methyl cellulose, and low substituted HPC. The number of brand drug products utilizing each cellulosics was determined using the online drug index Rxlist. A total of 607 brand products were identified having one or more of the cellulosics as an active or inactive ingredient. An array of various dosage forms was identified and revealed HPMC and MCC to be the most utilized cellulosics in all products followed by XCMCNa and HPC. Many products contained two or more cellulosics in the formulation (42% containing two, 23% containing three, and 4% containing 4-5). The largest combination occurrence was HPMC with MCC. The use of certain cellulosics within different dosage form types was found to contain specific trends. All injectables utilized only CMCNa, and the same with all ophthalmic solutions utilizing HPMC, and otic suspensions utilizing HEC. Popularity and trends regarding cellulosics use may occur based on many factors including functionality, safety, availability, stability, and ease of manufacturing.

  14. QR encoded smart oral dosage forms by inkjet printing. (United States)

    Edinger, Magnus; Bar-Shalom, Daniel; Sandler, Niklas; Rantanen, Jukka; Genina, Natalja


    The use of inkjet printing (IJP) technology enables the flexible manufacturing of personalized medicine with the doses tailored for each patient. In this study we demonstrate, for the first time, the applicability of IJP in the production of edible dosage forms in the pattern of a quick response (QR) code. This printed pattern contains the drug itself and encoded information relevant to the patient and/or healthcare professionals. IJP of the active pharmaceutical ingredient (API)-containing ink in the pattern of QR code was performed onto a newly developed porous and flexible, but mechanically stable substrate with a good absorption capacity. The printing did not affect the mechanical properties of the substrate. The actual drug content of the printed dosage forms was in accordance with the encoded drug content. The QR encoded dosage forms had a good print definition without significant edge bleeding. They were readable by a smartphone even after storage in harsh conditions. This approach of efficient data incorporation and data storage combined with the use of smart devices can lead to safer and more patient-friendly drug products in the future. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Synthetic cannabis and respiratory depression. (United States)

    Jinwala, Felecia N; Gupta, Mayank


    In recent years, synthetic cannabis use has been increasing in appeal among adolescents, and its use is now at a 30 year peak among high school seniors. The constituents of synthetic cannabis are difficult to monitor, given the drug's easy accessibility. Currently, 40 U.S. states have banned the distribution and use of some known synthetic cannabinoids, and have included these drugs in the Schedule I category. The depressive respiratory effect in humans caused by synthetic cannabis inhalation has not been thoroughly investigated in the medical literature. We are the first to report, to our knowledge, two cases of self-reported synthetic cannabis use leading to respiratory depression and necessary intubation.

  16. Prevention of lethal graft-versus-host disease following allogeneic bone marrow transplantation in mice by short course administration of LF 08-0299. (United States)

    Annat, J; Churaqui, E; Dutartre, P; Bruley-Rosset, M


    We investigated the ability of LF 08--0299, a new immunosuppressive compound, to prevent murine graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). A short term LF 08--0299 treatment at optimal dosage protected more than 75% of recipient mice from lethal GVHD induced either across minor antigens alone or the full H2 barrier. Furthermore, LF 08--0299 still prevented lethal GVHD when treatment was delayed to 10 days post-BMT. Long-term LF 08--0299-treated survivors were free of clinical signs of GVHD, and histopathologic examination of liver, skin, and intestines was normal, demonstrating that recipient mice did not develop chronic GVHD. We assessed the immunocompetence of long-term surviving recipient mice. Results from MLR and CTL assays were weak whereas responses against unrelated H2 antigens were reduced but still preserved. Moreover, in vivo transfer experiments demonstrated that spleen cells from long-term survivors were unable to induce lethal GVHD in irradiated recipients of host origin, while spleen cells injected in irradiated recipients of a host-unrelated H2 were fully competent to induce a lethal GVHD. Together these results indicate that stable chimeric recipient mice were specifically tolerant to host antigens. We further showed that while LF 08--0299 can protect recipient mice from lethal GVHD, it also preserved a graft-versus-leukemia effect when mice were inoculated with P815 tumor cells. These data suggest that LF 08--0299 may be a novel pharmaceutical agent that would prevent GVHD in human unrelated bone marrow transplantation.

  17. Effects of lethal and non-lethal malaria on the mononuclear phagocyte system

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Tosta


    Full Text Available The effects ofone non-lethal species ofmalarialparasite, Plasmodium yoelii, and one lethal species, P. berghei, on the mononuclear phagocyte system (MPS of BALB/c mice were studied. P. yoelii caused a greater and more sustained expansion and activation of the MPS, and the two major populations of spleen phagocytic cells-red pulp and marginal zone macrophages - exhibited a greater increase in numbers in this infection. During the course of P. berghei mataria, the spleen was progressively occupied by haematopoietic tissue and, at the terminal stage of infection, an extensive depletion of lymphocytes and macrophages was apparent. The possibility was suggested that the outcome of mataria may be inftuenced by the particular way the parasite interacts with the MPS.Estudou-se o efeito da infecção causada por espécie letal (Plasmodium berghei e não- letal (P. yoelii de plasmódio sobre o sistema de fagócitos mononucleares de camundongo BALB/c. O P. yoelii causou maior e mais prolongada expansão e ativação do sistema de macrófagos. As duas mais importantes populações de fagócitos esplênicos - macrófagos de polpa vermelha e da zona marginal - exibiam maior aumento do número de células nesta infecção. Durante a evolução da malária por P. berghei, o baço foi progressivamente ocupado por tecido hematopoiético e, na fase terminal da infecção, observou-se significativa depleção dos linfócitos e macrófagos esplênicos. Os dados apresentados indicam que a evolução da malária depende do tipo de interação entre o plasmódio e o sistema de fagócitos mononucleares.

  18. Synthetic cannabinoids revealing adrenoleukodystrophy. (United States)

    Fellner, Avi; Benninger, Felix; Djaldetti, Ruth


    We report a 41-year-old man who presented with a first generalized tonic-clonic seizure after recent consumption of a synthetic cannabinoid. MRI showed extensive bilateral, mainly frontal, white matter lesions. Blood analysis for very long chain fatty acids was compatible with adrenoleukodystrophy, and a missense mutation in the ABCD1 gene confirmed the diagnosis. We hypothesize that cannabinoid use might have contributed to metabolic decompensation with subacute worsening of the underlying condition. Copyright © 2015 Elsevier Ltd. All rights reserved.


    Directory of Open Access Journals (Sweden)

    Silviu Eduard Dinca


    Full Text Available During the past few years, in the recent post-crisis aftermath, global asset managers are constantly searching new ways to optimize their investment portfolios while financial and banking institutions around the world are exploring new alternatives to better secure their financing and refinancing demands altogether with the enhancement of their risk management capabilities. We will exhibit herewith a comparison between the true-sale and synthetic CDO securitizations as financial markets-based funding, investment and risks mitigation techniques, highlighting certain key structuring and implementation specifics on each of them.

  20. [An analysis for affecting factors to dosage of Chinese medicine during Jin and Yuan dynasty]. (United States)

    Zhang, Wei; Zhang, Ruixian; Han, Yao


    For studying medical works during the Jin and Yuan dynasty, author discussed the factors affect the dosage of medicine that doctors in that period believed to affect the dosage of medicine. Author found that doctors in that period developed the dosage theory in terms of compatibility of medicines, onset time, and onset region of a disease.

  1. Crossover suppressors and balanced recessive lethals in Caenorhabditis elegans

    International Nuclear Information System (INIS)

    Herman, R.K.


    Two dominant suppressors of crossing over have been identified following x-ray treatment of the small nematode C. elegans. They suppress crossing over in linkage group II (LGII) about 100-fold and 50-fold and are both tightly linked to LGII markers. One, called C1, segregates independently of all other linkage groups and is homozygous fertile. The other is a translocation involving LGII and X. The translocation also suppresses crossing over along the right half of X and is homozygous lethal. C1 has been used as a balancer of LGII recessive lethal and sterile mutations induced by EMS. The frequencies of occurrence of lethals and steriles were approximately equal. Fourteen mutations were assigned to complementation groups and mapped. They tended to map in the same region where LGII visibles are clustered

  2. Analysis of time of death of prenatally lethal Steeloid mutations

    International Nuclear Information System (INIS)

    Rinchik, E.M.; Cummings, C.C.; Bangham, J.W.; Hunsicker, P.R.; Phipps, E.L.; Stelzner, K.F.


    Deletion mutations have been extremely useful in initiating the functional and molecular dissections of regions of the mouse genome. For the d-se and c regions, for example, it was observed that radiation mutations carrying lethal factors separable, by complementation analysis, from the primary d, se, or c mutation itself, could often be associated at both the genetic and molecular levels with multilocus chromosomal deletions. Since many of the Oak Ridge Sld mutations arose in radiation mutagenesis experiments, a substantial number may carry chromosomal deletions that involve the Sl locus in chromosome 10. Because of the great value of deletion mutations for the genetic and molecular analysis of chromosomal regions and complex genetic loci, they have initiated a series of experiments designed to test whether radiation-induced Sld mutations carry other lethal factors, in addition to the lethality caused by severe alleles of the Sl locus itself, as one prescreen for identifying Sld's that are caused by deletions

  3. Prenatal diagnosis of lethal osteogenesis imperfecta in twin pregnancy. (United States)

    Morin, L R; Herlicoviez, M; Loisel, J C; Jacob, B; Feuilly, C; Stanescu, V


    Lethal osteogenesis imperfecta was diagnosed at 27 weeks amenorrea in one fetus of a bichorial twin pregnancy. Sonographic findings included: short-limb dwarfism, hypotrophy and hypoechoic bones. The affected fetus was so translucent that only the normal fetus could be seen on plain in utero radiography. The affected fetus died immediately after birth. Postmortem radiography and histology were typical of lethal osteogenesis imperfecta of type IIA. Aids to the etiological diagnosis of in utero dwarfism are presented. Sonographic features correlated with neonatal death are described.

  4. Synthetic collective intelligence. (United States)

    Solé, Ricard; Amor, Daniel R; Duran-Nebreda, Salva; Conde-Pueyo, Núria; Carbonell-Ballestero, Max; Montañez, Raúl


    Intelligent systems have emerged in our biosphere in different contexts and achieving different levels of complexity. The requirement of communication in a social context has been in all cases a determinant. The human brain, probably co-evolving with language, is an exceedingly successful example. Similarly, social insects complex collective decisions emerge from information exchanges between many agents. The difference is that such processing is obtained out of a limited individual cognitive power. Computational models and embodied versions using non-living systems, particularly involving robot swarms, have been used to explore the potentiality of collective intelligence. Here we suggest a novel approach to the problem grounded in the genetic engineering of unicellular systems, which can be modified in order to interact, store memories or adapt to external stimuli in collective ways. What we label as Synthetic Swarm Intelligence defines a parallel approach to the evolution of computation and swarm intelligence and allows to explore potential embodied scenarios for decision making at the microscale. Here, we consider several relevant examples of collective intelligence and their synthetic organism counterparts. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Mechanisms and evolutionary patterns of mammalian and avian dosage compensation.

    Directory of Open Access Journals (Sweden)

    Philippe Julien

    Full Text Available As a result of sex chromosome differentiation from ancestral autosomes, male mammalian cells only contain one X chromosome. It has long been hypothesized that X-linked gene expression levels have become doubled in males to restore the original transcriptional output, and that the resulting X overexpression in females then drove the evolution of X inactivation (XCI. However, this model has never been directly tested and patterns and mechanisms of dosage compensation across different mammals and birds generally remain little understood. Here we trace the evolution of dosage compensation using extensive transcriptome data from males and females representing all major mammalian lineages and birds. Our analyses suggest that the X has become globally upregulated in marsupials, whereas we do not detect a global upregulation of this chromosome in placental mammals. However, we find that a subset of autosomal genes interacting with X-linked genes have become downregulated in placentals upon the emergence of sex chromosomes. Thus, different driving forces may underlie the evolution of XCI and the highly efficient equilibration of X expression levels between the sexes observed for both of these lineages. In the egg-laying monotremes and birds, which have partially homologous sex chromosome systems, partial upregulation of the X (Z in birds evolved but is largely restricted to the heterogametic sex, which provides an explanation for the partially sex-biased X (Z expression and lack of global inactivation mechanisms in these lineages. Our findings suggest that dosage reductions imposed by sex chromosome differentiation events in amniotes were resolved in strikingly different ways.

  6. Gene expression dosage regulation in an allopolyploid fish.

    Directory of Open Access Journals (Sweden)

    I Matos

    Full Text Available How allopolyploids are able not only to cope but profit from their condition is a question that remains elusive, but is of great importance within the context of successful allopolyploid evolution. One outstanding example of successful allopolyploidy is the endemic Iberian cyprinid Squalius alburnoides. Previously, based on the evaluation of a few genes, it was reported that the transcription levels between diploid and triploid S. alburnoides were similar. If this phenomenon occurs on a full genomic scale, a wide functional ''diploidization'' could be related to the success of these polyploids. We generated RNA-seq data from whole juvenile fish and from adult livers, to perform the first comparative quantitative transcriptomic analysis between diploid and triploid individuals of a vertebrate allopolyploid. Together with an assay to estimate relative expression per cell, it was possible to infer the relative sizes of transcriptomes. This showed that diploid and triploid S. alburnoides hybrids have similar liver transcriptome sizes. This in turn made it valid to directly compare the S. alburnoides RNA-seq transcript data sets and obtain a profile of dosage responses across the S. alburnoides transcriptome. We found that 64% of transcripts in juveniles' samples and 44% in liver samples differed less than twofold between diploid and triploid hybrids (similar expression. Yet, respectively 29% and 15% of transcripts presented accurate dosage compensation (PAA/PA expression ratio of 1 instead of 1.5. Therefore, an exact functional diploidization of the triploid genome does not occur, but a significant down regulation of gene expression in triploids was observed. However, for those genes with similar expression levels between diploids and triploids, expression is not globally strictly proportional to gene dosage nor is it set to a perfect diploid level. This quantitative expression flexibility may be a strong contributor to overcome the genomic shock

  7. Dependence of 'CT clearance' on dosage and time

    International Nuclear Information System (INIS)

    Kaltenborn, H.A.; Klose, K.J.; Dexheimer, C.; Steinijans, V.


    The contrast medium dose used in CT renal function analysis corresponds to about 1 ml/kg body weight at a measurement interval of 5 or 10 minutes. In the present study the dependence of 'CT clearance' on dosage and time was examined in 12 healthy subjects. The amount of clearance was directly proportional to the employed contrast medium dose and to the length of the measurement interval. On account of the superior signal-to-noise ratio, the higher dose (1 ml/kg body weight) will continue to be prefered in future. The measurement interval can be limited to 10 minutes. (orig.) [de

  8. [Dosage of ionized calcium in osteo-articular pathology]. (United States)

    Eisinger, J; Schiano, A


    The dosage of calcium ionized serum using a selective electrode, was performed in a series of controls and patients with osteo-articular diseases. Normal values were 43 mg/l between 20 and 50 years of age, and 41 mg/l after 60 years. The level of ionized calcium, when given as a percentage of total blood calcium, did not decrease with age (normal value : 44%). It was increased in hyper-parathyroidism, rhumatoid polyarthritis and lytic bone metastasis. It did not vary in Paget's disease, osteoporosis, osteomalacia, condensing metastasis, Kahler's disease and spasmophilia. The ionized calcium in definitely diminished in hypoparathyroidism.

  9. Space Synthetic Biology Project (United States)

    Howard, David; Roman, Monsi; Mansell, James (Matt)


    Synthetic biology is an effort to make genetic engineering more useful by standardizing sections of genetic code. By standardizing genetic components, biological engineering will become much more similar to traditional fields of engineering, in which well-defined components and subsystems are readily available in markets. Specifications of the behavior of those components and subsystems can be used to model a system which incorporates them. Then, the behavior of the novel system can be simulated and optimized. Finally, the components and subsystems can be purchased and assembled to create the optimized system, which most often will exhibit behavior similar to that indicated by the model. The Space Synthetic Biology project began in 2012 as a multi-Center effort. The purpose of this project was to harness Synthetic Biology principals to enable NASA's missions. A central target for application was to Environmental Control & Life Support (ECLS). Engineers from NASA Marshall Space Flight Center's (MSFC's) ECLS Systems Development Branch (ES62) were brought into the project to contribute expertise in operational ECLS systems. Project lead scientists chose to pursue the development of bioelectrochemical technologies to spacecraft life support. Therefore, the ECLS element of the project became essentially an effort to develop a bioelectrochemical ECLS subsystem. Bioelectrochemical systems exploit the ability of many microorganisms to drive their metabolisms by direct or indirect utilization of electrical potential gradients. Whereas many microorganisms are capable of deriving the energy required for the processes of interest (such as carbon dioxide (CO2) fixation) from sunlight, it is believed that subsystems utilizing electrotrophs will exhibit smaller mass, volume, and power requirements than those that derive their energy from sunlight. In the first 2 years of the project, MSFC personnel conducted modeling, simulation, and conceptual design efforts to assist the

  10. Life after the synthetic cell

    DEFF Research Database (Denmark)

    Rasmussen, Steen


    Nature asked eight synthetic-biology experts about the implications for science and society of the “synthetic cell” made by the J. Craig Venter Institute (JCVI). The institute's team assembled, modified and implanted a synthesized genome into a DNA-free bacterial shell to make a self-replicating ......Nature asked eight synthetic-biology experts about the implications for science and society of the “synthetic cell” made by the J. Craig Venter Institute (JCVI). The institute's team assembled, modified and implanted a synthesized genome into a DNA-free bacterial shell to make a self...

  11. Synthetic biology and occupational risk. (United States)

    Howard, John; Murashov, Vladimir; Schulte, Paul


    Synthetic biology is an emerging interdisciplinary field of biotechnology that involves applying the principles of engineering and chemical design to biological systems. Biosafety professionals have done an excellent job in addressing research laboratory safety as synthetic biology and gene editing have emerged from the larger field of biotechnology. Despite these efforts, risks posed by synthetic biology are of increasing concern as research procedures scale up to industrial processes in the larger bioeconomy. A greater number and variety of workers will be exposed to commercial synthetic biology risks in the future, including risks to a variety of workers from the use of lentiviral vectors as gene transfer devices. There is a need to review and enhance current protection measures in the field of synthetic biology, whether in experimental laboratories where new advances are being researched, in health care settings where treatments using viral vectors as gene delivery systems are increasingly being used, or in the industrial bioeconomy. Enhanced worker protection measures should include increased injury and illness surveillance of the synthetic biology workforce; proactive risk assessment and management of synthetic biology products; research on the relative effectiveness of extrinsic and intrinsic biocontainment methods; specific safety guidance for synthetic biology industrial processes; determination of appropriate medical mitigation measures for lentiviral vector exposure incidents; and greater awareness and involvement in synthetic biology safety by the general occupational safety and health community as well as by government occupational safety and health research and regulatory agencies.

  12. Finding Hope in Synthetic Biology. (United States)

    Takala, Tuija


    For some, synthetic biology represents great hope in offering possible solutions to many of the world's biggest problems, from hunger to sustainable development. Others remain fearful of the harmful uses, such as bioweapons, that synthetic biology can lend itself to, and most hold that issues of biosafety are of utmost importance. In this article, I will evaluate these points of view and conclude that although the biggest promises of synthetic biology are unlikely to become reality, and the probability of accidents is fairly substantial, synthetic biology could still be seen to benefit humanity by enhancing our ethical understanding and by offering a boost to world economy.

  13. Synthetic Aperture Compound Imaging

    DEFF Research Database (Denmark)

    Hansen, Jens Munk

    Medical ultrasound imaging is used for many purposes, e.g. for localizing and classifying cysts, lesions, and other processes. Almost any mass is first observed using B-mode imaging and later classified using e.g. color flow, strain, or attenuation imaging. It is therefore important that the B......, it is demonstrated through theoretical considerations that the compound effect achieved is close to a theoretical maximum for the amount of compounding attainable and using a -pitch convex array transducer, the first in-vivo images are created. The computational demands for an implementation are massive...... and the limiting factor is the amount of memory IO resources available. An equally high demand for memory throughput is found in the computer gaming industry, where a large part of the processing takes place on the graphics processing unit (GPU). Using the GPU, a framework for synthetic aperture imaging...

  14. Transionospheric synthetic aperture imaging

    CERN Document Server

    Gilman, Mikhail; Tsynkov, Semyon


    This landmark monograph presents the most recent mathematical developments in the analysis of ionospheric distortions of SAR images and offers innovative new strategies for their mitigation. As a prerequisite to addressing these topics, the book also discusses the radar ambiguity theory as it applies to synthetic aperture imaging and the propagation of radio waves through the ionospheric plasma, including the anisotropic and turbulent cases. In addition, it covers a host of related subjects, such as the mathematical modeling of extended radar targets (as opposed to point-wise targets) and the scattering of radio waves off those targets, as well as the theoretical analysis of the start-stop approximation, which is used routinely in SAR signal processing but often without proper justification. The mathematics in this volume is clean and rigorous – no assumptions are hidden or ambiguously stated. The resulting work is truly interdisciplinary, providing both a comprehensive and thorough exposition of the field,...

  15. Synthetic antibiofilm peptides. (United States)

    de la Fuente-Núñez, César; Cardoso, Marlon Henrique; de Souza Cândido, Elizabete; Franco, Octavio Luiz; Hancock, Robert E W


    Bacteria predominantly exist as multicellular aggregates known as biofilms that are associated with at least two thirds of all infections and exhibit increased adaptive resistance to conventional antibiotic therapies. Therefore, biofilms are major contributors to the global health problem of antibiotic resistance, and novel approaches to counter them are urgently needed. Small molecules of the innate immune system called host defense peptides (HDPs) have emerged as promising templates for the design of potent, broad-spectrum antibiofilm agents. Here, we review recent developments in the new field of synthetic antibiofilm peptides, including mechanistic insights, synergistic interactions with available antibiotics, and their potential as novel antimicrobials against persistent infections caused by biofilms. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Dominant-lethal mutations and heritable translocations in mice

    Energy Technology Data Exchange (ETDEWEB)

    Generoso, W.M.


    Chromosome aberrations are a major component of radiation or chemically induced genetic damage in mammalian germ cells. The types of aberration produced are dependent upon the mutagen used and the germ-cell stage treated. For example, in male meiotic and postmeiotic germ cells certain alkylating chemicals induce both dominant-lethal mutations and heritable translocations while others induce primarily dominant-lethal mutations. Production of these two endpoints appears to be determined by the stability of alkylation products with the chromosomes. If the reaction products are intact in the male chromosomes at the time of sperm entry, they may be repaired in fertilized eggs. If repair is not effected and the alkylation products persist to the time of pronuclear chromosome replication, they lead to chromatid-type aberrations and eventually to dominant-lethality. The production of heritable translocations, on the other hand, requires a transformation of unstable alkylation products into suitable intermediate lesions. The process by which these lesions are converted into chromosome exchange within the male genome takes place after sperm enters the egg but prior to the time of pronuclear chromosome replication (i.e., chromosome-type). Thus, dominant-lethal mutations result from both chromatid- and chromosome-type aberrations while heritable translocations result primarily from the latter type. DNA target sites associated with the production of these two endpoints are discussed.

  17. Perforated appendicitis presenting as a thigh abscess: A lethal ...

    African Journals Online (AJOL)

    Typical cases of acute appendicitis have excellent treatment outcomes, if managed appropriately.1 We discuss an unusual case of perforated retrocaecal appendicitis that presented as a right thigh abscess without prominent abdominal symptoms, which highlights the lethal nature of advanced appendicitis even when ...

  18. Perinatal lethal type II osteogenesis imperfecta: a case report | Ayadi ...

    African Journals Online (AJOL)

    We report a new case of osteogenesis imperfecta (OI) type II which is a perinatal lethal form. First trimester ultrasound didn't identified abnormalities. Second trimester ultrasound showed incurved limbs, narrow chest, with hypomineralization and multiple fractures of ribs and long bones. Parents refused pregnancy ...

  19. The "Lethal Chamber": Further Evidence of the Euthanasia Option. (United States)

    Elks, Martin A.


    Historical discussions of the euthanasia or "lethal chamber" option in relation to people with mental retardation are presented. The paper concludes that eugenic beliefs in the primacy of heredity over environment and the positive role of natural selection may have condoned the poor conditions characteristic of large, segregated institutions and…

  20. [Generalized and lethal pentastomiasis due to Armillifer grandis (Hett, 1915)]. (United States)

    Cagnard, V; Nicolas-Randegger, J; Dago Akribi, A; Rain, B; Nozais, J P; Essoh Nomel, P; Ette, M; Doucet, J; Assale N'Dri, G


    The authors described a case of generalised and lethal Pentastomiasis by a five years old girl. The most heavy parasitised organs are the lungs and the brain. Considering the age of the child and the uncommon density of the parasites, the authors suggest that the symptoms may follow the casual ingestion of a gravid female worm.

  1. Lethality of the aqeous extracts of Acacia nilotica, Guiera ...

    African Journals Online (AJOL)

    Cytotoxic activity indicated by lethal effects (that is mortality rate) of aqueous extracts of fruits of Acacia nilotica, stem bark of Kigelia africana, roots of Securidaca longepedunculata, and leaves of Guiera senegalensis on the culex mosquito larva was investigated by direct contact method. Larvicidal effects were observed with ...

  2. Dominant-lethal mutations and heritable translocations in mice

    International Nuclear Information System (INIS)

    Generoso, W.M.


    Chromosome aberrations are a major component of radiation or chemically induced genetic damage in mammalian germ cells. The types of aberration produced are dependent upon the mutagen used and the germ-cell stage treated. For example, in male meiotic and postmeiotic germ cells certain alkylating chemicals induce both dominant-lethal mutations and heritable translocations while others induce primarily dominant-lethal mutations. Production of these two endpoints appears to be determined by the stability of alkylation products with the chromosomes. If the reaction products are intact in the male chromosomes at the time of sperm entry, they may be repaired in fertilized eggs. If repair is not effected and the alkylation products persist to the time of pronuclear chromosome replication, they lead to chromatid-type aberrations and eventually to dominant-lethality. The production of heritable translocations, on the other hand, requires a transformation of unstable alkylation products into suitable intermediate lesions. The process by which these lesions are converted into chromosome exchange within the male genome takes place after sperm enters the egg but prior to the time of pronuclear chromosome replication (i.e., chromosome-type). Thus, dominant-lethal mutations result from both chromatid- and chromosome-type aberrations while heritable translocations result primarily from the latter type. DNA target sites associated with the production of these two endpoints are discussed

  3. Fighting Lethal Yellowing Disease for Coconut Farmers (CIFSRF ...

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

    Copra is the dried kernel of the coconut, which is used to extract coconut oil. Coconut is the main income source for the coastal region's poor farmers. Over the past 10 years, Côte d'Ivoire lethal yellowing disease has destroyed more than 350 hectares of coconut and caused losses of 12,000 tons of copra per year.

  4. Brine shrimp lethality bioassay of selected Indian medicinal plants. (United States)

    Padmaja, R; Arun, P C; Prashanth, D; Deepak, M; Amit, A; Anjana, M


    Ethanolic extracts of six Indian medicinal plants, piperine, guggulsterone E and guggulsterone Z were tested for cytotoxicity using brine shrimp lethality test. Piper longum showed most potent cytotoxic activity. Piperine, guggulsterone E and guggulsterone Z showed potent activity with LC(50) 2.4, 8.9 and 4.9, respectively. Copyright 2002 Elsevier Science B.V.

  5. Papaya Lethal Yellowing Virus (PLYV) Infects Vasconcellea cauliflora

    NARCIS (Netherlands)

    Amaral, P.P.R.; Resende, de R.O.; Souza, M.T.


    Papaya lethal yellowing virus (PLYV) é um dos três vírus descritos infectando mamoeiros (Carica papaya L.) no Brasil. Vasconcellea cauliflora (Jacq.) A. DC., antes denominada de Carica cauliflora (Jacq.), é uma reconhecida fonte de resistência natural ao Papaya ringspot virus (PRSV), causador da

  6. Median lethal dose (LD 50 ) evaluation of some polyherbal ...

    African Journals Online (AJOL)

    The polyherbal preparations reported here are traditionally used in Northern Nigeria for the treatment of wide range of illnesses. The aim of this study was to evaluate the acute toxicity potential of 70% ethanol extracts of forty polyherbal products by determining their median lethal dose (LD50) estimates intraperitoneally and ...

  7. Brine shrimp lethality and antimicrobial studies on the seeds of ...

    African Journals Online (AJOL)

    Garcinia kola (Family, Guttiferae) is employed in a variety of therapies ranging from skin, gastrointestinal, chest to tumour problems. Preparations of the stem and roots are used as antitumour in traditional medicine but the potential of the seeds as antitumour had not yet been investigated hence the brine-shrimp lethality and ...

  8. Brine Shrimp Lethality of Alkaloids from Croton sylvaticus Hoechst ...

    African Journals Online (AJOL)

    Euphorbiaceae) and evaluated for their brine shrimp lethality. Julocrotine, a glutarimide alkaloid, was very toxic in vitro with a LC50 (95% confidence interval) value of 0.074 (0.052-0.105) μg/ml. Lupeol and penduliflaworosin were not toxic. The structures ...

  9. Drosophila simulans Lethal hybrid rescue mutation (Lhr) rescues ...

    Indian Academy of Sciences (India)

    in the hybrids. Materials and methods. Fly stocks .... toradiography following usual methods (see Chatterjee and. Mukherjee 1981). ... vigor as their sisters. It, therefore, appears that Lhr can sup- press the larval male lethality caused by presence of only melanogaster X chromosome in the hybrid genome. In re- ciprocal cross ...

  10. Radiographic and prenatal ultrasound features of perinatal lethal ...

    African Journals Online (AJOL)

    Hypophosphatasia is a genetic disorder that is characterised by deficient activity of the enzyme alkaline phosphatase. Clinically, it can present as a lethal infantile form, an intermediate childhood form with rachitic changes and premature deciduous tooth loss or a mild adult form with a tendency for fractures and bone pain.

  11. The Lethal "Femme Fatale" in the Noir Tradition. (United States)

    Boozer, Jack


    Traces the lethal seductress through Hollywood's "noir" history from "Double Indemnity" (1944) to "The Last Seduction" (1996). Examines how this figure largely abjures traditional romance and passive domesticity, choosing instead to apply her sexuality to homicidal plots toward greed. Argues that her narrative…

  12. Gamma scintigraphy in the evaluation of pharmaceutical dosage forms

    Energy Technology Data Exchange (ETDEWEB)

    Davis, S.S.; Hardy, J.G.; Newman, S.P.; Wilding, I.R. (Pharmaceutical Profiles Ltd., Nottingham (United Kingdom))


    Gamma-scintigraphy is applied extensively in the development and evaluation of pharmaceutical drug delivery systems. It is used particularly for monitoring formulations in the gastrointestinal and respiratory tracts. The radiolabelling is generally achieved by the incorporation of an appropriate technetium-99m or indium-111 labelled radiopharmaceutical into the formulation. In the case of complex dosage forms, such as enteric-coated tablets, labelling is best undertaken by the addition of a non-radioactive tracer such as samarium-152 or erbium-170 followed by neutron activation of the final product. Systems investigated include tablets and multiparticulates for oral administration, enemas and suppositories, metered dose inhalers and nebulisers, and nasal sprays and drops. Gamma-scintigraphy provides information on the deposition, dispersion and movement of the formulation. The combination of such studies with the assay of drug levels in blood or urine specimens, pharmacoscintigraphy, provides information concerning the sites of drug release and absorption. Data acquired from the scintigraphic evaluation of pharmaceutical dosage forms are now being used increasingly at all stages of product development, from the assessment of prototype delivery systems to supporting the product licence application. (orig.).

  13. Gamma ray dosage and mutation breeding in St. Augustinegrass

    International Nuclear Information System (INIS)

    Busey, P.


    Stolon pieces of St. Augustinegrass [Stenotaphrum secundatum (Walt.) Kuntze] were irradiated with gamma rays in an attempt to cause mutations. A practical dosage for most genotypes was 4,500 rads. This dosage caused considerable (50%) growth retardation and a mean survival of about 40% of single-node cuttings. However, Bitterblue and another accession were entirely killed at 4,000 rads. At 4,500 rads, up to 7% recognizable mutants of accession FA-243 were obtained. This proportion resulted when irradiated cuttings were propagated clonally and observed for 1.5 years in replicated microplots. In addition to morphological variants, a chimeral anthocyanin change was noticed. From this chimera arose a stable genotype with green stolons and white stigmas, whereas the source genotype (FA-243) had red stolons and purple stigmas. Associated reduction in fertility from 56 to 0.6% suggested that the mutation arose as a small chromosome deletion. Mutation breeding is effective in improving St. Augustinegrass when easily recognizable variants are needed

  14. Stability of pharmaceutical salts in solid oral dosage forms. (United States)

    Nie, Haichen; Byrn, Stephen R; Zhou, Qi Tony


    Using pharmaceutical salts in solid dosage forms can raise stability concerns, especially salt dissociation which can adversely affect the product performance. Therefore, a thorough understanding of the salt instability encountered in solid-state formulations is imperative to ensure the product quality. The present article uses the fundamental theory of acid base, ionic equilibrium, relationship of pH and solubility as a starting point to illustrate and interpret the salt formation and salt disproportionation in pharmaceutical systems. The criteria of selecting the optimal salt form and the underlying theory of salt formation and disproportionation are reviewed in detail. Factors influencing salt stability in solid dosage forms are scrutinized and discussed with the case studies. In addition, both commonly used and innovative strategies for preventing salt dissociations in formulation, on storage and during manufacturing will be suggested herein. This article will provide formulation scientists and manufacturing engineers an insight into the mechanisms of salt disproportionation and salt formation, which can help them to avoid and solve the instability issues of pharmaceutical salts in the product design.

  15. Gamma scintigraphy in the evaluation of pharmaceutical dosage forms

    International Nuclear Information System (INIS)

    Davis, S.S.; Hardy, J.G.; Newman, S.P.; Wilding, I.R.


    Gamma-scintigraphy is applied extensively in the development and evaluation of pharmaceutical drug delivery systems. It is used particularly for monitoring formulations in the gastrointestinal and respiratory tracts. The radiolabelling is generally achieved by the incorporation of an appropriate technetium-99m or indium-111 labelled radiopharmaceutical into the formulation. In the case of complex dosage forms, such as enteric-coated tablets, labelling is best undertaken by the addition of a non-radioactive tracer such as samarium-152 or erbium-170 followed by neutron activation of the final product. Systems investigated include tablets and multiparticulates for oral administration, enemas and suppositories, metered dose inhalers and nebulisers, and nasal sprays and drops. Gamma-scintigraphy provides information on the deposition, dispersion and movement of the formulation. The combination of such studies with the assay of drug levels in blood or urine specimens, pharmacoscintigraphy, provides information concerning the sites of drug release and absorption. Data acquired from the scintigraphic evaluation of pharmaceutical dosage forms are now being used increasingly at all stages of product development, from the assessment of prototype delivery systems to supporting the product licence application. (orig.)

  16. Blue light dosage affects carotenoids and tocopherols in microgreens. (United States)

    Samuolienė, Giedrė; Viršilė, Akvilė; Brazaitytė, Aušra; Jankauskienė, Julė; Sakalauskienė, Sandra; Vaštakaitė, Viktorija; Novičkovas, Algirdas; Viškelienė, Alina; Sasnauskas, Audrius; Duchovskis, Pavelas


    Mustard, beet and parsley were grown to harvest time under selected LEDs: 638+660+731+0% 445nm; 638+660+731+8% 445nm; 638+660+731+16% 445nm; 638+660+731+25% 445nm; 638+660+731+33% 445nm. From 1.2 to 4.3 times higher concentrations of chlorophylls a and b, carotenoids, α- and β-carotenes, lutein, violaxanthin and zeaxanthin was found under blue 33% treatment in comparison to lower blue light dosages. Meanwhile, the accumulation of metabolites, which were not directly connected with light reactions, such as tocopherols, was more influenced by lower (16%) blue light dosage, increasing about 1.3 times. Thus, microgreen enrichment of carotenoid and xanthophyll pigments may be achieved using higher (16-33%) blue light intensities. Changes in metabolite quantities were not the result of changes of other carotenoid concentration, but were more influenced by light treatment and depended on the species. Significant quantitative changes in response to blue light percentage were obtained for both directly and not directly light-dependent metabolite groups. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Emergence of 3D Printed Dosage Forms: Opportunities and Challenges. (United States)

    Alhnan, Mohamed A; Okwuosa, Tochukwu C; Sadia, Muzna; Wan, Ka-Wai; Ahmed, Waqar; Arafat, Basel


    The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such an extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry.

  18. RFID Tag Helix Antenna Sensors for Wireless Drug Dosage Monitoring (United States)

    Huang, Haiyu; Zhao, Peisen; Chen, Pai-Yen; Ren, Yong; Liu, Xuewu; Ferrari, Mauro; Hu, Ye; Akinwande, Deji


    Miniaturized helix antennas are integrated with drug reservoirs to function as RFID wireless tag sensors for real-time drug dosage monitoring. The general design procedure of this type of biomedical antenna sensors is proposed based on electromagnetic theory and finite element simulation. A cost effective fabrication process is utilized to encapsulate the antenna sensor within a biocompatible package layer using PDMS material, and at the same time form a drug storage or drug delivery unit inside the sensor. The in vitro experiment on two prototypes of antenna sensor-drug reservoir assembly have shown the ability to monitor the drug dosage by tracking antenna resonant frequency shift from 2.4–2.5-GHz ISM band with realized sensitivity of 1.27 \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}$\\mu~{\\rm l}/{\\rm MHz}$\\end{document} for transdermal drug delivery monitoring and 2.76-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}$\\mu~{\\rm l}/{\\rm MHz}$\\end{document} sensitivity for implanted drug delivery monitoring. PMID:27170865

  19. ORODISPERSIBLE TABLET: A Patient Friendly Dosage Form (a Review

    Directory of Open Access Journals (Sweden)

    C. K. Rameesa


    Full Text Available Background: The most common and preferred route of drug administration is through the oral route. Orodispersible tablets are gaining importance among novel oral drug delivery system as they have improved patient compliance and have some additional advantages compared to other formulation. They are also solid unit dosage forms, which disintegrate in the mouth within a minute in the presence of saliva due to superdisintegrants in the formulation. Thus this type of drug delivery helps a proper per oral administration in pediatric and geriatric population where swallowing is a matter of trouble. Various scientists have prepared orodispersible tablets by following various methods. However, the most common method is the direct compression method. Other special methods are Freeze Drying,Tablet Molding, Sublimation, Spray Drying, Mass extrusion, Phase transition process, etc. Since these tablets dissolve directly in the mouth, so, their taste is also an important factor. Various approaches have been taken in order to mask the bitter taste of the drug. A number of scientists have explored several drugs in this field. Like all other solid dosage forms, they are also evaluated in the field of hardness, friability, wetting time, moisture uptake, disintegration test and dissolution test.

  20. Resveratrol Antagonizes Antimicrobial Lethality and Stimulates Recovery of Bacterial Mutants.

    Directory of Open Access Journals (Sweden)

    Yuanli Liu

    Full Text Available Reactive oxygen species (ROS; superoxide, peroxide, and hydroxyl radical are thought to contribute to the rapid bactericidal activity of diverse antimicrobial agents. The possibility has been raised that consumption of antioxidants in food may interfere with the lethal action of antimicrobials. Whether nutritional supplements containing antioxidant activity are also likely to interfere with antimicrobial lethality is unknown. To examine this possibility, resveratrol, a popular antioxidant dietary supplement, was added to cultures of Escherichia coli and Staphylococcus aureus that were then treated with antimicrobial and assayed for bacterial survival and the recovery of mutants resistant to an unrelated antimicrobial, rifampicin. Resveratrol, at concentrations likely to be present during human consumption, caused a 2- to 3-fold reduction in killing during a 2-hr treatment with moxifloxacin or kanamycin. At higher, but still subinhibitory concentrations, resveratrol reduced antimicrobial lethality by more than 3 orders of magnitude. Resveratrol also reduced the increase in reactive oxygen species (ROS characteristic of treatment with quinolone (oxolinic acid. These data support the general idea that the lethal activity of some antimicrobials involves ROS. Surprisingly, subinhibitory concentrations of resveratrol promoted (2- to 6-fold the recovery of rifampicin-resistant mutants arising from the action of ciprofloxacin, kanamycin, or daptomycin. This result is consistent with resveratrol reducing ROS to sublethal levels that are still mutagenic, while the absence of resveratrol allows ROS levels to high enough to kill mutagenized cells. Suppression of antimicrobial lethality and promotion of mutant recovery by resveratrol suggests that the antioxidant may contribute to the emergence of resistance to several antimicrobials, especially if new derivatives and/or formulations of resveratrol markedly increase bioavailability.

  1. A Multivariate Model of Stakeholder Preference for Lethal Cat Management (United States)

    Wald, Dara M.; Jacobson, Susan K.


    Identifying stakeholder beliefs and attitudes is critical for resolving management conflicts. Debate over outdoor cat management is often described as a conflict between two groups, environmental advocates and animal welfare advocates, but little is known about the variables predicting differences among these critical stakeholder groups. We administered a mail survey to randomly selected stakeholders representing both of these groups (n = 1,596) in Florida, where contention over the management of outdoor cats has been widespread. We used a structural equation model to evaluate stakeholder intention to support non-lethal management. The cognitive hierarchy model predicted that values influenced beliefs, which predicted general and specific attitudes, which in turn, influenced behavioral intentions. We posited that specific attitudes would mediate the effect of general attitudes, beliefs, and values on management support. Model fit statistics suggested that the final model fit the data well (CFI = 0.94, RMSEA = 0.062). The final model explained 74% of the variance in management support, and positive attitudes toward lethal management (humaneness) had the largest direct effect on management support. Specific attitudes toward lethal management and general attitudes toward outdoor cats mediated the relationship between positive (p<0.05) and negative cat-related impact beliefs (p<0.05) and support for management. These results supported the specificity hypothesis and the use of the cognitive hierarchy to assess stakeholder intention to support non-lethal cat management. Our findings suggest that stakeholders can simultaneously perceive both positive and negative beliefs about outdoor cats, which influence attitudes toward and support for non-lethal management. PMID:24736744

  2. Influence of temperature and pressure on the lethality of ultrasound

    International Nuclear Information System (INIS)

    Raso, J.; Pagan, R.; Condon, S.; Sala, F.J.


    A specially designed resistometer was constructed, and the lethal effect on Yersinia enterocolitica of ultrasonic waves (UW) at different static pressures (manosonication [MS]) and of combined heat-UW under pressure treatments (manothermosonication [MTS]) was investigated. During MS treatments at 30 degrees C and 200 kPa, the increase in the amplitude of UW of 20 kHz from 21 to 150 micrometers exponentially decreased decimal reduction time values (D(MS)) from 4 to 0.37 min. When pressure was increased from 0 to 600 kPa at a constant amplitude (150 micrometers) and temperature (30 degrees C), D(MS) values decreased from 1.52 to 0.20 min. The magnitude of this decrease in D(MS) declined progressively as pressure was increased. The influence of pressure on D(MS) values was greater with increased amplitude of UW. Pressure alone of as much as 600 kPa did not influence the heat resistance of Y. enterocolitica (D60 = 0.094; zeta = 5.65). At temperatures of as much as 58 degrees C, the lethality of UW under pressure was greater than that of heat treatment alone at the same temperature. At higher temperatures, this difference disappeared. Heat and UW under pressure seemed to act independently. The lethality of MTS treatments appeared to result from the added effects of UW under pressure and the lethal effect of heat. The individual contributions of heat and of UW under pressure to the total lethal effect of MTS depended on temperature. The inactivating effect of UW was not due to titanium particles eroded from the sonication horn. The addition to the MS media of cysteamine did not increase the resistance of Y. enterocolitica to MS treatment. MS treatment caused cell disruption

  3. Accidental administration of Syntometrine in adult dosage to the newborn.


    Whitfield, M F; Salfield, S A


    The clinical course is described of an infant who accidentally received an adult dose of Syntometrine (synthetic oxytocin + ergometrine) at delivery. The infant soon became ill with convulsions and ventilatory failure, and later with water intoxication. Similar reported cases are reviewed and recommendations are given for the management of future cases.

  4. Synthetic biology and metabolic engineering. (United States)

    Stephanopoulos, Gregory


    Metabolic engineering emerged 20 years ago as the discipline occupied with the directed modification of metabolic pathways for the microbial synthesis of various products. As such, it deals with the engineering (design, construction, and optimization) of native as well as non-natural routes of product synthesis, aided in this task by the availability of synthetic DNA, the core enabling technology of synthetic biology. The two fields, however, only partially overlap in their interest in pathway engineering. While fabrication of biobricks, synthetic cells, genetic circuits, and nonlinear cell dynamics, along with pathway engineering, have occupied researchers in the field of synthetic biology, the sum total of these areas does not constitute a coherent definition of synthetic biology with a distinct intellectual foundation and well-defined areas of application. This paper reviews the origins of the two fields and advances two distinct paradigms for each of them: that of unit operations for metabolic engineering and electronic circuits for synthetic biology. In this context, metabolic engineering is about engineering cell factories for the biological manufacturing of chemical and pharmaceutical products, whereas the main focus of synthetic biology is fundamental biological research facilitated by the use of synthetic DNA and genetic circuits.

  5. Synthetic cannabinoids: new matrix addiction

    Directory of Open Access Journals (Sweden)

    Antsyborov A.V.


    Full Text Available the majority of synthetic cannabinoids (SC, belongs to the group of so-called designer drugs distributed through illegal online shopping. The first reports of this group of psychoactive substances appeared in the 70s of the last century. Today, according to various estimates, there are over 160 varieties of synthetic cannabinoids, and this figure is increasing annually due to the synthesis of new substances in the group. This group of substances is designed to «copy» the psychoactive effects of cannabis. Initially, these substances were created solely for research purposes, to study the endocannabinoid system of the person. Natural THC is a partial agonist of cannabinoid receptors. Synthetic cannabinoids are full agonists CB1R and CB2R types of cannabinoid receptors. Most countries in the world, including Russia, at the legislative level have taken restrictive measures for preventing the spread of this group of substances. In order to circumvent the legislative measures, the producers of synthetic cannabinoids regularly changing the chemical formula. Each year, an increasing number of emergency hospital admissions associated with the use of synthetic cannabinoids in the peer-reviewed literature describes the deaths directly attributable to medical complications after taking synthetic cannabinoids. Numerous studies have proven the possibility of developing psychological dependence due to the use of synthetic cannabinoids. The proposed review of the literature is presented for the purpose of organizing data in the field of synthetic cannabinoids.

  6. Synthetic peptides for antibody production

    NARCIS (Netherlands)

    N.D. Zegers (Netty)


    textabstractSynthetic peptides are useful tools for the generation of antibodies. The use of antibodies as specific reagents in inununochemical assays is widely applied. In this chapter, the application of synthetic peptides for the generation of antibodies is described. The different steps

  7. Synthetic peptides for antibody production

    NARCIS (Netherlands)

    Zegers, N.D.


    Synthetic peptides are useful tools for the generation of antibodies. The use of antibodies as specific reagents in inununochemical assays is widely applied. In this chapter, the application of synthetic peptides for the generation of antibodies is described. The different steps that lead to the

  8. Imaging with Synthetic Aperture Radar

    CERN Document Server

    Massonnet, Didier


    Describing a field that has been transformed by the recent availability of data from a new generation of space and airborne systems, the authors offer a synthetic geometrical approach to the description of synthetic aperture radar, one that addresses physicists, radar specialists, as well as experts in image processing.  

  9. Synthetic biology of polyketide synthases

    DEFF Research Database (Denmark)

    Yuzawa, Satoshi; Backman, Tyler W.H.; Keasling, Jay D.


    ). The modules are composed of enzymatic domains that share sequence and functional similarity across all known PKSs. We have used the nomenclature of synthetic biology to classify the enzymatic domains and modules as parts and devices, respectively, and have generated detailed lists of both. In addition, we...... realize the potential that synthetic biology approaches bring to this class of molecules....

  10. General Requirements to the Preparation of Tinctures, Decoctions. Dosage of Phytopreparations

    Directory of Open Access Journals (Sweden)

    I.B. Yershovа


    Full Text Available The article describes the advantages and disadvantages of using herbal medicine, general information for the collection of medicinal plants. According to the World Health Organization, the classification of herbal medicine is an integral part of traditional medicine. It refers to the variety of metabolic therapy. This treatment meets the requirements of pathogenetic therapy. Currently, more than 30 % of medicines on the pharmaceutical market have herbal origin. According to the World Health Organization, about 80 % of the world population use mainly traditional medicines of natural origin within the framework of primary health care system. Analysis of publications on phytotherapy revealed insufficient coverage of contraindications and side effects of certain plants. This was the basis for opening in our magazine this column, and we wanted to start with what would be the advantages and disadvantages of phytotherapy. Benefits of herbal medi­cine: biological proximity of the active substances of plants and active substances of the body, harmony therapy for the human body, the prolonged effect of herbal medicines after the completion of therapy, the opportunity to prepare a wide variety of different dosage forms, for both indoor and outdoor use, compatibility with many synthetic pharmaceuticals drugs, comprehensive multilateral action of plants, no side effects, simplicity and ease of preparation of herbal remedies at home, the availability for the majority of patients due to the low cost of the medicines. Limitations of herbal medicine: the complexity of the standardization of the treatment effect of herbal drugs, the complexity of establishing a dose, selectivity of diseases, in which typical herbal remedies are prescribed, the risk of poisoning, particularly in self-collection of medicinal plants. The article also provides methods for the preparation of various forms of herbal remedies, dosage for adults and children. With all the advantages of

  11. An Overview of Crowd Control Theory and Considerations for the Employment of Non-Lethal Weapons

    National Research Council Canada - National Science Library

    Grieger, Dion


    .... In campaigns such as these, there is a case for the use of non-lethal weapons to complement the existing range of traditional weapons in order to help bridge the gap between responding with lethal...

  12. Computing with synthetic protocells. (United States)

    Courbet, Alexis; Molina, Franck; Amar, Patrick


    In this article we present a new kind of computing device that uses biochemical reactions networks as building blocks to implement logic gates. The architecture of a computing machine relies on these generic and composable building blocks, computation units, that can be used in multiple instances to perform complex boolean functions. Standard logical operations are implemented by biochemical networks, encapsulated and insulated within synthetic vesicles called protocells. These protocells are capable of exchanging energy and information with each other through transmembrane electron transfer. In the paradigm of computation we propose, protoputing, a machine can solve only one problem and therefore has to be built specifically. Thus, the programming phase in the standard computing paradigm is represented in our approach by the set of assembly instructions (specific attachments) that directs the wiring of the protocells that constitute the machine itself. To demonstrate the computing power of protocellular machines, we apply it to solve a NP-complete problem, known to be very demanding in computing power, the 3-SAT problem. We show how to program the assembly of a machine that can verify the satisfiability of a given boolean formula. Then we show how to use the massive parallelism of these machines to verify in less than 20 min all the valuations of the input variables and output a fluorescent signal when the formula is satisfiable or no signal at all otherwise.

  13. Synthetic biology: lessons from the history of synthetic organic chemistry. (United States)

    Yeh, Brian J; Lim, Wendell A


    The mid-nineteenth century saw the development of a radical new direction in chemistry: instead of simply analyzing existing molecules, chemists began to synthesize them--including molecules that did not exist in nature. The combination of this new synthetic approach with more traditional analytical approaches revolutionized chemistry, leading to a deep understanding of the fundamental principles of chemical structure and reactivity and to the emergence of the modern pharmaceutical and chemical industries. The history of synthetic chemistry offers a possible roadmap for the development and impact of synthetic biology, a nascent field in which the goal is to build novel biological systems.

  14. Dose–response tests and semi-field evaluation of lethal and sub-lethal effects of slow release pyriproxyfen granules (Sumilarv®0.5G) for the control of the malaria vectors Anopheles gambiae sensu lato (United States)


    Background Recently research has shown that larviciding can be an effective tool for integrated malaria vector control. Nevertheless, the uptake of this intervention has been hampered by the need to re-apply larvicides frequently. There is a need to explore persistent, environmentally friendly larvicides for malaria vector control to reduce intervention efforts and costs by reducing the frequency of application. In this study, the efficacy of a 0.5% pyriproxyfen granule (Surmilarv®0.5G, Sumitomo Chemicals) was assessed for the control of Anopheles gambiae sensu stricto and Anopheles arabiensis, the major malaria vectors in sub-Saharan Africa. Methods Dose–response and standardized field tests were implemented following standard procedures of the World Health Organization’s Pesticide Evaluation Scheme to determine: (i) the susceptibility of vectors to this formulation; (ii) the residual activity and appropriate retreatment schedule for field application; and, (iii) sub-lethal impacts on the number and viability of eggs laid by adults after exposure to Sumilarv®0.5G during larval development. Results Anopheles gambiae s.s. and An. arabiensis were highly susceptible to Sumilarv®0.5G. Estimated emergence inhibition (EI) values were very low and similar for both species. The minimum dosage that completely inhibited adult emergence was between 0.01-0.03 parts per million (ppm) active ingredient (ai). Compared to the untreated control, an application of 0.018 ppm ai prevented 85% (95% confidence interval (CI) 82%-88%) of adult emergence over six weeks under standardized field conditions. A fivefold increase in dosage of 0.09 ppm ai prevented 97% (95% CI 94%-98%) emergence. Significant sub-lethal effects were observed in the standardized field tests. Female An. gambiae s.s. that were exposed to 0.018 ppm ai as larvae laid 47% less eggs, and females exposed to 0.09 ppm ai laid 74% less eggs than females that were unexposed to the treatment. Furthermore, 77

  15. Nanofibrous solid dosage form of living bacteria prepared by electrospinning

    Directory of Open Access Journals (Sweden)

    I. Wagner


    Full Text Available The aim of this work was to investigate the suitability of electrospinning for biodrug delivery and to develop an electrospinning-based method to produce vaginal drug delivery systems. Lactobacillus acidophilus bacteria were encapsulated into nanofibers of three different polymers (polyvinyl alcohol and polyvinylpyrrolidone with two different molar masses. Shelf life of the bacteria could be enhanced by the exclusion of water and by preparing a solid dosage form, which is an advantageous and patient-friendly way of administration. The formulations were stored at –20, 7 and 25°C, respectively. Viability testing showed that the nanofibers can provide long term stability for huge amounts of living bacteria if they are kept at (or below 7°C. Furthermore, all kinds of nanowebs prepared in this work dissolved instantly when they got in contact with water, thus the developed biohybrid nanowebs can provide new potential ways for curing bacterial vaginosis.

  16. Spectrophotometric determination of fluoride in dosage forms and dental preparations. (United States)

    Săndulescu, R; Florean, E; Roman, L; Mirel, S; Oprean, R; Suciu, P


    The method is based upon the reaction between fluoride ions and the coloured complex of Fe(III) with methyl salicylate to form the stable, colourless hexaflouride complex of iron. The conditions of the method (pH, time and combination ratio) were studied and a standard curve was obtained for 0.01-0.08 mg NaF ml-1, at 525 nm. A study was conducted on interference with complexing anions of Fe(III), cations that react with fluoride ions and with common ingredients of dosage forms and dental preparations. The method was validated and the results showed good precision (100.16 +/- = 2.33%) comparable with that of other analytical methods. Good results were obtained in the spectrophotometric determination of fluoride ions in a stomatological gel and in a toothpaste.

  17. A quick method for testing recessive lethal damage with a diploid strain of Aspergillus nidulans

    International Nuclear Information System (INIS)

    Morpurgo, G.; Puppo, S.; Gualandi, G.; Conti, L.


    A simple method capable of detecting recessive lethal damage in a diploid strain of Aspergillus nidulans is described. The method scores the recessive lethals on the 1st, the 3rd and the 5th chromosomes, which represent about 40% of the total map of A. nidulans. Two examples of induced lethals, with ultraviolet irradiation and methyl methanesulfonate are shown. The frequency of lethals may reach 36% of the total population with UV irradiation. (Auth.)

  18. Effects of maternal psychotropic drug dosage on birth outcomes

    Directory of Open Access Journals (Sweden)

    Michielsen LA


    Full Text Available Laura A Michielsen,1 Frank MMA van der Heijden,1 Paddy KC Janssen,2 Harold JH Kuijpers11Vincent van Gogh Institute for Psychiatry, Venlo, the Netherlands; 2Department of Pharmacy, VieCuri Medical Centre, Venlo, the NetherlandsBackground: The aim of this retrospective study was to explore the relationship between psychotropic medication dosage and birth outcomes.Methods: A total of 136 women were enrolled, who had an active mental disorder, were taking medication to prevent a relapse, or had a history of postpartum depression or psychosis. Medication use was evaluated for the three trimesters and during labor. Based on the defined daily dose, medication use was classified into three groups. Primary outcome variables included the infant gestational age at birth, birth weight, and Apgar scores at one and 5 minutes.Results: Our study showed a significantly higher incidence of Apgar score ≤7 at 5 minutes in women taking psychotropic drugs as compared with the group taking no medication, respectively (16.3% versus 0.0%, P=0.01. There was no significant difference between the two groups in Apgar score at one minute or in gestational age and birth weight. The results showed no significant differences in gestational age, birth weight, or Apgar scores for a low–intermediate or high dose of a selective serotonin reuptake inhibitor and for a low or intermediate dose of an antipsychotic.Conclusion: This study does not indicate a relationship between doses of selective serotonin reuptake inhibitors and antipsychotics and adverse neonatal outcomes.Keywords: pregnancy, psychotropic medication, dosage, birth outcomes

  19. Struvite precipitation from urine with electrochemical magnesium dosage. (United States)

    Hug, Alexandra; Udert, Kai M


    When magnesium is added to source-separated urine, struvite (MgNH(4)PO(4)·6H(2)O) precipitates and phosphorus can be recovered. Up to now, magnesium salts have been used as the main source of magnesium. Struvite precipitation with these salts works well but is challenging in decentralized reactors, where high automation of the dosage and small reactor sizes are required. In this study, we investigated a novel approach for magnesium dosage: magnesium was electrochemically dissolved from a sacrificial magnesium electrode. We demonstrated that this process is technically simple and economically feasible and thus interesting for decentralized reactors. Linear voltammetry and batch experiments at different anode potentials revealed that the anode potential must be higher than -0.9 V vs. NHE (normal hydrogen electrode) to overcome the strong passivation of the anode. An anode potential of -0.6 V vs. NHE seemed to be suitable for active magnesium dissolution. For 13 subsequent cycles at this potential, we achieved an average phosphate removal rate of 3.7 mg P cm(-2) h(-1), a current density of 5.5 mA cm(-2) and a current efficiency of 118%. Some magnesium carbonate (nesquehonite) accumulated on the anode surface; as a consequence, the current density decreased slightly, but the current efficiency was not affected. The energy consumption for these experiments was 1.7 W h g P(-1). A cost comparison showed that sacrificial magnesium electrodes are competitive with easily soluble magnesium salts such as MgCl(2) and MgSO(4), but are more expensive than dosing with MgO. Energy costs for the electrochemical process were insignificant. Dosing magnesium electrochemically could thus be a worthwhile alternative to dosing magnesium salts. Due to the simple reactor and handling of magnesium, this may well be a particularly interesting approach for decentralized urine treatment. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. An improved brine shrimp larvae lethality microwell test method. (United States)

    Zhang, Yi; Mu, Jun; Han, Jinyuan; Gu, Xiaojie


    This article described an improved brine shrimp larvae lethality microwell test method. A simply designed connecting vessel with alternative photoperiod was used to culture and collect high yield of active Artemia parthenogenetica nauplii for brine shrimp larvae lethality microwell test. Using this method, pure A. parthenogenetica nauplii suspension was easily cultured and harvested with high density about 100-150 larvae per milliliter and the natural mortality was reduced to near zero by elimination of unnecessary artificial disturbance. And its sensitivity was validated by determination of LC(50)-24 h of different reference toxicants including five antitumor agents, two pesticides, three organic pollutants, and four heavy metals salts, most of which exhibited LC(50)-24 h between 0.07 and 58.43 mg/L except for bleomycin and mitomycin C with LC(50)-24 h over 300 mg/L.

  1. Hematologic syndrome in man modeled from mammalian lethality

    International Nuclear Information System (INIS)

    Jones, T.D.


    Data on acute radiation lethality due to failure of the hematologic system in rats, mice, dogs, swine, monkeys and man are analyzed. Based on the available data, the mortality incidences for 1-100% levels can be computed directly if one has only an estimate of the dose lethal to 50% of the population (LD 50 ) for the mammalian strain and radiation environment of interest. The sole restriction is that the dose profile to the marrow be moderately uniform. If an LD 50 for any exposure situation has been measured, then one can readily scale to any desired situation through implicit-biological and empirical-physical relationships. The LD 50 for man, exposed to an isotropic cloud of photons, and knowledge of the bone-marrow dose profiles readily permit evaluation of the model for other levels of human mortality from different irradiating particles, partial body irradiation and spatially dependent and/or mixed radiation environments. (author)

  2. Dominant lethals following administration of tritium (THO) to rat males

    International Nuclear Information System (INIS)

    Yagova, A.; Baev, I.; Bajrakova, A.


    Adult rat males were given a single intraperitoneal tritium (THO) injection at 0,01 or 0,001 mCi/g body weight (1/100 or 1/1000 of LDsub(50/30), respectively). Twelve days after treatment each male was mated to 3-5 intact females, and the latter were replaced by fresh ones every 12 following days over a 120-day period. Mated females were killed to score conceptions, corpora lutea, and live and dead embryos. Estimations were made of F 1 prenatal death rate (according to Bateman, 1958) and the frequency of induction of dominant lethal mutations (according to Roehrborn, 1970). The results observed indicated paternal exposure to tritium (THO) to produce dominant lethals both in pre- and post-meiotic germ cells in the rat. The extent of the genetic damage studied was found to depend on the amount of activity administered as well as on the time interval between treatment and conception. (author)

  3. Spicing things up: synthetic cannabinoids. (United States)

    Spaderna, Max; Addy, Peter H; D'Souza, Deepak Cyril


    Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally. The availability, acute subjective effects-including self-reports posted on Erowid-laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed. Spice is sold under the guise of potpourri or incense. Unlike delta-9-tetrahydrocannabinol, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid receptor full agonists. Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention. Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing. Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned. There is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans. The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug detection tests for synthetic cannabinoids need to become clinically available.

  4. Synthetic Biology and Personalized Medicine (United States)

    Jain, K.K.


    Synthetic biology, application of synthetic chemistry to biology, is a broad term that covers the engineering of biological systems with structures and functions not found in nature to process information, manipulate chemicals, produce energy, maintain cell environment and enhance human health. Synthetic biology devices contribute not only to improve our understanding of disease mechanisms, but also provide novel diagnostic tools. Methods based on synthetic biology enable the design of novel strategies for the treatment of cancer, immune diseases metabolic disorders and infectious diseases as well as the production of cheap drugs. The potential of synthetic genome, using an expanded genetic code that is designed for specific drug synthesis as well as delivery and activation of the drug in vivo by a pathological signal, was already pointed out during a lecture delivered at Kuwait University in 2005. Of two approaches to synthetic biology, top-down and bottom-up, the latter is more relevant to the development of personalized medicines as it provides more flexibility in constructing a partially synthetic cell from basic building blocks for a desired task. PMID:22907209

  5. Brine shrimp lethality bioassay of selected Centaurea L. species (Asteraceae

    Directory of Open Access Journals (Sweden)

    Janaćković P.


    Full Text Available Ether extracts of 15 Centaurea L. species (Asteraceae methanol extracts of 12species, and cnicin isolated from C. derventana were tested for general bioactivity using the brine shrimp lethality test. Cnicin showed the most potent activity with LC50 0.2. Also, ether extract of C. splendens showed significant activity with LC50 7.3, as did methanol extract of C. arenaria with LC50 12.4.

  6. TaS2 nanosheet-based room-temperature dosage meter for nitric oxide

    Directory of Open Access Journals (Sweden)

    Qiyuan He


    Full Text Available A miniature dosage meter for toxic gas is developed based on TaS2 nanosheets, which is capable of indicating the toxic dosage of trace level NO at room temperature. The TaS2 film-based chemiresistor shows an irreversible current response against the exposure of NO. The unique non-recovery characteristic makes the TaS2 film-based device an ideal indicator of total dosage of chronicle exposure.

  7. Bistatic synthetic aperture radar (United States)

    Yates, Gillian

    Synthetic aperture radar (SAR) allows all-weather, day and night, surface surveillance and has the ability to detect, classify and geolocate objects at long stand-off ranges. Bistatic SAR, where the transmitter and the receiver are on separate platforms, is seen as a potential means of countering the vulnerability of conventional monostatic SAR to electronic countermeasures, particularly directional jamming, and avoiding physical attack of the imaging platform. As the receiving platform can be totally passive, it does not advertise its position by RF emissions. The transmitter is not susceptible to jamming and can, for example, operate at long stand-off ranges to reduce its vulnerability to physical attack. This thesis examines some of the complications involved in producing high-resolution bistatic SAR imagery. The effect of bistatic operation on resolution is examined from a theoretical viewpoint and analytical expressions for resolution are developed. These expressions are verified by simulation work using a simple 'point by point' processor. This work is extended to look at using modern practical processing engines for bistatic geometries. Adaptations of the polar format algorithm and range migration algorithm are considered. The principal achievement of this work is a fully airborne demonstration of bistatic SAR. The route taken in reaching this is given, along with some results. The bistatic SAR imagery is analysed and compared to the monostatic imagery collected at the same time. Demonstrating high-resolution bistatic SAR imagery using two airborne platforms represents what I believe to be a European first and is likely to be the first time that this has been achieved outside the US (the UK has very little insight into US work on this topic). Bistatic target characteristics are examined through the use of simulations. This also compares bistatic imagery with monostatic and gives further insight into the utility of bistatic SAR.

  8. Synthetic biology for therapeutic applications. (United States)

    Abil, Zhanar; Xiong, Xiong; Zhao, Huimin


    Synthetic biology is a relatively new field with the key aim of designing and constructing biological systems with novel functionalities. Today, synthetic biology devices are making their first steps in contributing new solutions to a number of biomedical challenges, such as emerging bacterial antibiotic resistance and cancer therapy. This review discusses some synthetic biology approaches and applications that were recently used in disease mechanism investigation and disease modeling, drug discovery and production, as well as vaccine development and treatment of infectious diseases, cancer, and metabolic disorders.

  9. The Ethics of Synthetic Biology

    DEFF Research Database (Denmark)

    Christiansen, Andreas

    The dissertation analyses and discusses a number of ethical issues that have been raised in connection with the development of synthetic biology. Synthetic biology is a set of new techniques for DNA-level design and construction of living beings with useful properties. The dissertation especially......) popular responsesto them succeed, and whether the objections are ultimately persuasive.2. Given that synthetic biology is a new technology, there is a certain degree of uncertainty about its ultimate effects, and many perceive the technology as risky. I discuss two common approaches in risk regulation...

  10. Vocal function exercises for normal voice: The effects of varying dosage. (United States)

    Bane, Maria; Angadi, Vrushali; Dressler, Emily; Andreatta, Richard; Stemple, Joseph


    This study examined the effect of varying dosage of vocal function exercise (VFE) home practice on attainment of pre-established maximum phonation time (MPT) goals in individuals with normal voice. High dosage VFE practice was expected to result in greatest MPT. The overarching goal of this study was to contribute to a VFE dosage-response curve, potentially including a point of observable toxicity. Twenty-eight females ages 18-25 with normal voice participated in this pre-post longitudinal group study. Participants were randomly assigned to one of three experimental groups and completed a six-week VFE protocol with practice twice daily. The low dosage group performed each exercise once, the traditional group twice, and the high dosage group four times. The primary outcome measure was MPT as performed on the fourth VFE using the prescribed semi-occluded vocal tract posture. No toxic effects were observed. MPT increased for all participants, with significant improvement for traditional and high dosage groups. High dosage VFEs may yield more rapid improvement in MPT, however benefits must be weighed against the risk of increased attrition. Low dosage VFEs insufficiently improved MPT. Further research on dosage is warranted, and should include individuals with disordered voice.

  11. Comparing the effectiveness of sexual communication disruption in the oriental fruit moth (Grapholitha molesta) using different combinations and dosages of its pheromone blend. (United States)

    Charlton, R E; Cardé, R T


    The relative efficacy of disruptant blends comprised of different combinations of the Oriental fruit moth's pheromone components was determined in field tests. Disruption was evaluated by comparing male moth catch at synthetic and female-baited traps in disruptant and non-treatment areas. Three atmospheric dosages of a 8-dodecenyl acetate (93.5%Z∶6.5%E) blend, representing two successive 10-fold decreases in concentration (2.5 × 10(-2) g/hectare/day to 2.5 × 10(-4) g/hectare/day) were tested alone and in combination with an additional percentage of (Z)-8-dodecen-1-ol. Male moth orientation to traps was eliminated in plots exposed to the two highest binary acetate dosages. However, significantly more males were captured in synthetic-baited traps in the lowest acetate-alone treatment, indicating a diminution of disruption efficiency. In contrast, inclusion of (Z)-8-dodecen-1-ol in the disruptant blend effected essentially complete disruption of orientation at all concentrations tested. Mating success ofG. molesta pairs confined in small cages apparently was not affected by the presence of relatively high concentrations of the binary acetate and the acetate-alcohol blends. This suggests that habituation and/or adaptation of male response, at least for comparatively "close-range" behaviors, did not occur.

  12. Development of a Synthetic Lethal Drug Combination That Targets the Energy Generation Triangle for Liver Cancer Therapy (United States)


    extracted from Hep3B cells after an eight-hour treatment with FDG, DPI, and/or PER. The increase in the ADP/ATP and AMP /ATP ratios in response to the...response to FDG/DPI/PER treatment. (A) The HK2i/DPI/PER triple-combination decreases HCC cellular energy levels. After 8 h drug treatment, AMP , ADP, ATP

  13. A Potent and Selective Quinoxalinone-Based STK33 Inhibitor Does Not Show Synthetic Lethality in KRAS-Dependent Cells. (United States)

    Weïwer, Michel; Spoonamore, James; Wei, Jingqiang; Guichard, Boris; Ross, Nathan T; Masson, Kristina; Silkworth, Whitney; Dandapani, Sivaraman; Palmer, Michelle; Scherer, Christina A; Stern, Andrew M; Schreiber, Stuart L; Munoz, Benito


    The KRAS oncogene is found in up to 30% of all human tumors. In 2009, RNAi experiments revealed that lowering mRNA levels of a transcript encoding the serine/threonine kinase STK33 was selectively toxic to KRAS-dependent cancer cell lines, suggesting that small-molecule inhibitors of STK33 might selectively target KRAS-dependent cancers. To test this hypothesis, we initiated a high-throughput screen using compounds in the Molecular Libraries Small Molecule Repository (MLSMR). Several hits were identified, and one of these, a quinoxalinone derivative, was optimized. Extensive SAR studies were performed and led to the chemical probe ML281 that showed low nanomolar inhibition of purified recombinant STK33 and a distinct selectivity profile as compared to other STK33 inhibitors that were reported in the course of these studies. Even at the highest concentration tested (10 μM), ML281 had no effect on the viability of KRAS-dependent cancer cells. These results are consistent with other recent reports using small-molecule STK33 inhibitors. Small molecules having different chemical structures and kinase-selectivity profiles are needed to fully understand the role of STK33 in KRAS-dependent cancers. In this regard, ML281 is a valuable addition to small-molecule probes of STK33.

  14. Tissue Harmonic Synthetic Aperture Imaging

    DEFF Research Database (Denmark)

    Rasmussen, Joachim

    The main purpose of this PhD project is to develop an ultrasonic method for tissue harmonic synthetic aperture imaging. The motivation is to advance the field of synthetic aperture imaging in ultrasound, which has shown great potentials in the clinic. Suggestions for synthetic aperture tissue...... system complexity compared to conventional synthetic aperture techniques. In this project, SASB is sought combined with a pulse inversion technique for 2nd harmonic tissue harmonic imaging. The advantages in tissue harmonic imaging (THI) are expected to further improve the image quality of SASB....... The first part of the scientific contribution investigates an implementation of pulse inversion for THI on the experimental ultrasound system SARUS. The technique is initially implemented for linear array transducers and then expanded for convex array transducers. The technique is evaluated based on spatial...

  15. Adaptive Synthetic Forces: Situation Awareness

    National Research Council Canada - National Science Library

    Hill, Randall


    ...: perception, comprehension, and prediction. Building on these ideas, we developed techniques for improving the situation awareness in synthetic helicopter pilots for the ModSAF military simulation by giving them more human-like perception...

  16. Designing synthetic networks in silico

    NARCIS (Netherlands)

    Smith, Robert W.; Sluijs, van Bob; Fleck, Christian


    Background: Evolution has led to the development of biological networks that are shaped by environmental signals. Elucidating, understanding and then reconstructing important network motifs is one of the principal aims of Systems & Synthetic Biology. Consequently, previous research has focused

  17. Synthetic Biology for Specialty Chemicals. (United States)

    Markham, Kelly A; Alper, Hal S


    In this review, we address recent advances in the field of synthetic biology and describe how those tools have been applied to produce a wide variety of chemicals in microorganisms. Here we classify the expansion of the synthetic biology toolbox into three different categories based on their primary function in strain engineering-for design, for construction, and for optimization. Next, focusing on recent years, we look at how chemicals have been produced using these new synthetic biology tools. Advances in producing fuels are briefly described, followed by a more thorough treatment of commodity chemicals, specialty chemicals, pharmaceuticals, and nutraceuticals. Throughout this review, an emphasis is placed on how synthetic biology tools are applied to strain engineering. Finally, we discuss organism and host strain diversity and provide a future outlook in the field.

  18. Is synthetic biology mechanical biology? (United States)

    Holm, Sune


    A widespread and influential characterization of synthetic biology emphasizes that synthetic biology is the application of engineering principles to living systems. Furthermore, there is a strong tendency to express the engineering approach to organisms in terms of what seems to be an ontological claim: organisms are machines. In the paper I investigate the ontological and heuristic significance of the machine analogy in synthetic biology. I argue that the use of the machine analogy and the aim of producing rationally designed organisms does not necessarily imply a commitment to mechanical biology. The ideal of applying engineering principles to biology is best understood as expressing recognition of the machine-unlikeness of natural organisms and the limits of human cognition. The paper suggests an interpretation of the identification of organisms with machines in synthetic biology according to which it expresses a strategy for representing, understanding, and constructing living systems that are more machine-like than natural organisms.

  19. Programming languages for synthetic biology. (United States)

    Umesh, P; Naveen, F; Rao, Chanchala Uma Maheswara; Nair, Achuthsankar S


    In the backdrop of accelerated efforts for creating synthetic organisms, the nature and scope of an ideal programming language for scripting synthetic organism in-silico has been receiving increasing attention. A few programming languages for synthetic biology capable of defining, constructing, networking, editing and delivering genome scale models of cellular processes have been recently attempted. All these represent important points in a spectrum of possibilities. This paper introduces Kera, a state of the art programming language for synthetic biology which is arguably ahead of similar languages or tools such as GEC, Antimony and GenoCAD. Kera is a full-fledged object oriented programming language which is tempered by biopart rule library named Samhita which captures the knowledge regarding the interaction of genome components and catalytic molecules. Prominent feature of the language are demonstrated through a toy example and the road map for the future development of Kera is also presented.

  20. In Vitro Evaluation of Sub-Lethal Concentrations of Plant-Derived Antifungal Compounds on FUSARIA Growth and Mycotoxin Production

    Directory of Open Access Journals (Sweden)

    Caterina Morcia


    Full Text Available Phytopathogenic fungi can lead to significant cereal yield losses, also producing mycotoxins dangerous for human and animal health. The fungal control based on the use of synthetic fungicides can be complemented by "green" methods for crop protection, based on the use of natural products. In this frame, the antifungal activities of bergamot and lemon essential oils and of five natural compounds recurrent in essential oils (citronellal, citral, cinnamaldehyde, cuminaldehyde and limonene have been evaluated against three species of mycotoxigenic fungi (Fusarium sporotrichioides, F. graminearum and F. langsethiae responsible for Fusarium Head Blight in small-grain cereals. The natural products concentrations effective for reducing or inhibiting the in vitro fungal growth were determined for each fungal species and the following scale of potency was found: cinnamaldehyde > cuminaldehyde > citral > citronellal > bergamot oil > limonene > lemon oil. Moreover, the in vitro mycotoxin productions of the three Fusaria strains exposed to sub-lethal concentrations of the seven products was evaluated. The three fungal species showed variability in response to the treatments, both in terms of inhibition of mycelial growth and in terms of modulation of mycotoxin production that can be enhanced by sub-lethal concentrations of some natural products. This last finding must be taken into account in the frame of an open field application of some plant-derived fungicides.

  1. Lethal and Sub-lethal Effects of Four Insecticides on the Aphidophagous Coccinellid Adalia bipunctata (Coleoptera: Coccinellidae). (United States)

    Depalo, Laura; Lanzoni, Alberto; Masetti, Antonio; Pasqualini, Edison; Burgio, Giovanni


    Conventional insecticide assays, which measure the effects of insecticide exposure on short-term mortality, overlook important traits, including persistence of toxicity or sub-lethal effects. Therefore, such approaches are especially inadequate for prediction of the overall impact of insecticides on beneficial arthropods. In this study, the side effects of four modern insecticides (chlorantraniliprole, emamectin benzoate, spinosad, and spirotetramat) on Adalia bipunctata (L.) (Coleoptera: Coccinellidae) were evaluated under laboratory conditions by exposition on treated potted plants. In addition to investigation of acute toxicity and persistence of harmful activity in both larvae and adults of A. bipunctata, demographic parameters were evaluated, to provide a comprehensive picture of the nontarget effects of these products. Field doses of the four insecticides caused detrimental effects to A. bipunctata; but in different ways. Overall, spinosad showed the best toxicological profile among the products tested. Emamectin benzoate could be considered a low-risk insecticide, but had high persistence. Chlorantraniliprole exhibited lethal effects on early instar larvae and adults, along with a long-lasting activity, instead spirotetramat showed a low impact on larval and adult mortality and can be considered a short-lived insecticide. However, demographic analysis demonstrated that chlorantraniliprole and spirotetramat caused sub-lethal effects. Our findings highlight that sole assessment of mortality can lead to underestimation of the full impact of pesticides on nontarget insects. Demographic analysis was demonstrated to be a sensitive method for detection of the sub-lethal effects of insecticides on A. bipunctata, and this approach should be considered for evaluation of insecticide selectivity. © The Author(s) 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail:

  2. The PA Endonuclease Inhibitor RO-7 Protects Mice from Lethal Challenge with Influenza A or B Viruses. (United States)

    Jones, Jeremy C; Marathe, Bindumadhav M; Vogel, Peter; Gasser, Rodolfo; Najera, Isabel; Govorkova, Elena A


    Current influenza treatment relies on a single class of antiviral drugs, the neuraminidase inhibitors (NAIs), raising concern over the potential emergence of resistant variants and necessitating the development of novel drugs. In recent years, investigational inhibitors targeting the endonuclease activity of the influenza acidic polymerase (PA) protein have yielded encouraging results, although there are only limited data on their in vivo efficacy. Here, we examined the antiviral potential of the PA endonuclease inhibitor RO-7 in prophylactic and therapeutic regimens in BALB/c mice inoculated with influenza A/California/04/2009 (H1N1)pdm09 or B/Brisbane/60/2008 viruses, which represent currently circulating antigenic variants. RO-7 was administered to mice intraperitoneally twice daily at dosages of 6, 15, or 30 mg/kg/day for 5 days, starting 4 h before or 24 or 48 h after virus inoculation, and showed no adverse effects. Prophylactic administration completely protected mice from lethal infection by influenza A or B virus. The level of therapeutic protection conferred depended upon the time of treatment initiation and RO-7 dosage, resulting in 60 to 100% and 80 to 100% survival with influenza A and B viruses, respectively. RO-7 treatment significantly decreased virus titers in the lung and lessened the extent and severity of lung damage. No PA endonuclease-inhibitor resistance was observed in viruses isolated from lungs of RO-7-treated mice, and the viruses remained susceptible to the drug at nanomolar concentrations in phenotypic assays. These in vivo efficacy results further highlight the potential of RO-7 for development as antiviral therapy for influenza A and B virus infections. Copyright © 2017 American Society for Microbiology.

  3. Generating realistic synthetic meteoroid orbits (United States)

    Vida, Denis; Brown, Peter G.; Campbell-Brown, Margaret


    Context. Generating a synthetic dataset of meteoroid orbits is a crucial step in analysing the probabilities of random grouping of meteoroid orbits in automated meteor shower surveys. Recent works have shown the importance of choosing a low similarity threshold value of meteoroid orbits, some pointing out that the recent meteor shower surveys produced false positives due to similarity thresholds which were too high. On the other hand, the methods of synthetic meteoroid orbit generation introduce additional biases into the data, thus making the final decision on an appropriate threshold value uncertain. Aims. As a part of the ongoing effort to determine the nature of meteor showers and improve automated methods, it was decided to tackle the problem of synthetic meteoroid orbit generation, the main goal being to reproduce the underlying structure and the statistics of the observed data in the synthetic orbits. Methods. A new method of generating synthetic meteoroid orbits using the Kernel Density Estimation method is presented. Several types of approaches are recommended, depending on whether one strives to preserve the data structure, the data statistics or to have a compromise between the two. Results. The improvements over the existing methods of synthetic orbit generation are demonstrated. The comparison between the previous and newly developed methods are given, as well as the visualization tools one can use to estimate the influence of different input parameters on the final data.

  4. Biowaiver monographs for immediate release solid oral dosage forms: piroxicam. (United States)

    Shohin, Igor E; Kulinich, Julia I; Ramenskaya, Galina V; Abrahamsson, Bertil; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Groot, D W; Barends, Dirk M; Dressman, Jennifer B


    Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing piroxicam in the free acid form are reviewed. Piroxicam solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA), and corresponding dissolution data are taken into consideration. The available data suggest that according to the current biopharmaceutics classification system (BCS) and all current guidances, piroxicam would be assigned to BCS Class II. The extent of piroxicam absorption seems not to depend on manufacturing conditions or excipients, so the risk of bioinequivalence in terms of area under the curve (AUC) is very low, but the rate of absorption (i.e., BE in terms of Cmax ) can be affected by the formulation. Current in vitro dissolution methods may not always reflect differences in terms of Cmax for BCS Class II weak acids; however, minor differences in absorption rate of piroxicam would not subject the patient to unacceptable risks: as piroxicam products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR piroxicam solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients, which are also present in IR solid oral drug products containing piroxicam, which have been approved in ICH or associated countries, for instance, those presented in Table 3 of this paper; (b) both the test and comparator drug products dissolve 85% in 30 min or less at pH 1.2, 4.5, and 6.8; and (c) the test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When not all of these conditions can be fulfilled, BE of the products should be established in vivo. © 2013 Wiley Periodicals, Inc. and the

  5. [Bladder tumor lethality. Results in the autonomous community of Rioja between 1975-1991]. (United States)

    Fernández Fernández, A; Gil Fabra, J; Fernández Ruíz, M; Angulo Castellanos, M G; Blanco Martín, E; Otero Mauricio, G


    Between 1975-1991, a total of 557 cases of bladder carcinoma were identified in the Autonomous Community of La Rioja (CAR) which were followed up to December 1994. The overall lethality was 21.9%. 492 cases with 22.35% lethality were identified in males. In females, however, there was 65 cases with 18.46% lethality. The comparison of males and females lethality resulted in p = 0.525. Lethality between cases diagnosed within each 5-year period analyzed is: 1975-1981: 177 cases, lethality 23.72%. 1982-1986: 168 cases, lethality 30.95%. 1987-1991: 212 cases, lethality 13.20%. Between the first and the second 5-year periods, p = 0.132; between the first and third 5-year periods p = 0.007 and between the second and third 5-year periods p CAR for a 22.35% lethality. Lethality is higher in males that in females but the difference is not statistically significant. In the last 5-year period assessed, 1987-1991, a reduction of lethality from bladder neoplasms has been documented.

  6. Freedom and Responsibility in Synthetic Genomics: The Synthetic Yeast Project. (United States)

    Sliva, Anna; Yang, Huanming; Boeke, Jef D; Mathews, Debra J H


    First introduced in 2011, the Synthetic Yeast Genome (Sc2.0) PROJECT is a large international synthetic genomics project that will culminate in the first eukaryotic cell (Saccharomyces cerevisiae) with a fully synthetic genome. With collaborators from across the globe and from a range of institutions spanning from do-it-yourself biology (DIYbio) to commercial enterprises, it is important that all scientists working on this project are cognizant of the ethical and policy issues associated with this field of research and operate under a common set of principles. In this commentary, we survey the current ethics and regulatory landscape of synthetic biology and present the Sc2.0 Statement of Ethics and Governance to which all members of the project adhere. This statement focuses on four aspects of the Sc2.0 PROJECT: societal benefit, intellectual property, safety, and self-governance. We propose that such project-level agreements are an important, valuable, and flexible model of self-regulation for similar global, large-scale synthetic biology projects in order to maximize the benefits and minimize potential harms. Copyright © 2015 by the Genetics Society of America.

  7. Photostability Issues in Pharmaceutical Dosage Forms and Photostabilization. (United States)

    Janga, Karthik Yadav; King, Tamara; Ji, Nan; Sarabu, Sandeep; Shadambikar, Gauri; Sawant, Sagar; Xu, Pengchong; Repka, Michael A; Murthy, S Narasimha


    Photodegradation is one of the major pathways of the degradation of drugs. Some therapeutic agents and excipients are highly sensitive to light and undergo significant degradation, challenging the quality and the stability of the final product. The adequate knowledge of photodegradation mechanisms and kinetics of photosensitive therapeutic entities or excipients is a pivotal aspect in the product development phase. Hence, various pharmaceutical regulatory agencies, across the world, mandated the industries to assess the photodegradation of pharmaceutical products from manufacturing stage till storage, as per the guidelines given in the International Conference on Harmonization (ICH). Recently, numerous formulation and/or manufacturing strategies has been investigated for preventing the photodegradation and enhancing the photostability of photolabile components in the pharmaceutical dosage forms. The primary focus of this review is to discuss various photodegradation mechanisms, rate kinetics, and the factors that influence the rate of photodegradation. We also discuss light-induced degradation of photosensitive lipids and polymers. We conclude with a brief note on different approaches to improve the photostability of photosensitive products.

  8. Fumigant dosages below maximum label rate control some soilborne pathogens

    Directory of Open Access Journals (Sweden)

    Shachaf Triky-Dotan


    Full Text Available The activity of commercial soil fumigants on some key soilborne pathogens was assessed in sandy loam soil under controlled conditions. Seven soil fumigants that are registered in California or are being or have been considered for registration were used in this study: dimethyl disulfide (DMDS mixed with chloropicrin (Pic (79% DMDS and 21% Pic, Tri-Con (50% methyl bromide and 50% Pic, Midas Gold (33% methyl iodide [MI] and 67% Pic, Midas Bronze (50% MI and 50% Pic, Midas (MI, active ingredient [a.i.] 97.8%, Pic (a.i. 99% trichloronitromethane and Pic-Clor 60 (57% Pic and 37% 1,3-dichloropropene [1–3,D]. Dose-response models were calculated for pathogen mortality after 24 hours of exposure to fumigants. Overall, the tested fumigants achieved good efficacy with dosages below the maximum label rate against the tested pathogens. In this study, Pythium ultimum and citrus nematode were sensitive to all the fumigants and Verticillium dahliae was resistant. For most fumigants, California regulations restrict application rates to less than the maximum (federal label rate, meaning that it is possible that the fumigants may not control major plant pathogens. This research provides information on the effectiveness of these alternatives at these lower application rates. The results from this study will help growers optimize application rates for registered fumigants (such as Pic and 1,3-D and will help accelerate the adoption of new fumigants (such as DMDS if they are registered in California.

  9. MicroRNAs in genetic disease: rethinking the dosage. (United States)

    Henrion-Caude, Alexandra; Girard, Muriel; Amiel, Jeanne


    To date, the general assumption was that most mutations interested protein-coding genes only. Thus, only few illustrations have mentioned here that mutations may occur in non-protein coding genes such as microRNAs (miRNAs). We thus report progress in delineating their contribution as phenotypic modulators, genetic switches and fine-tuners of gene expression. We reasoned that browsing their contribution to genetic disease may provide a framework for understanding the proper requirements to devise miRNA-based therapy strategies, in particular the relief of an appropriate dosage. Gain and loss of function of miRNA enforce the need to respectively antagonize or supply the miRNAs. We further categorized human disease according to the different ways in which the miRNA was altered arising either de novo, or inherited whether as a mendelian or as an epistatic trait, uncovering its role in epigenetics. We discuss how improving our knowledge on the contribution of miRNAs to genetic disease may be beneficial to devise appropriate gene therapy strategies.

  10. Inhibition of emetic and superantigenic activities of staphylococcal enterotoxin A by synthetic peptides. (United States)

    Maina, Edward K; Hu, Dong-Liang; Asano, Krisana; Nakane, Akio


    Staphylococcus aureus is a major human pathogen producing different types of toxins. Enterotoxin A (SEA) is the most common type among clinical and food-related strains. The aim of the present study was to estimate functional regions of SEA that are responsible for emetic and superantigenic activities using synthetic peptides. A series of 13 synthetic peptides corresponding to specific regions of SEA were synthesized, and the effect of these peptides on superantigenic activity of SEA including interferon γ (IFN-γ) production in mouse spleen cells, SEA-induced lethal shock in mice, spleen cell proliferation in house musk shrew, and emetic activity in shrews were assessed. Pre-treatment of spleen cells with synthetic peptides corresponding to the regions 21-40, 35-50, 81-100, or 161-180 of SEA significantly inhibited SEA-induced IFN-γ production and cell proliferation. These peptides also inhibited SEA-induced lethal shock. Interestingly, peptides corresponding to regions 21-40, 35-50 and 81-100 significantly inhibited SEA-induced emesis in house musk shrews, but region 161-180 did not. These findings indicated that regions 21-50 and 81-100 of SEA are important for both superantigenic and emetic activities of SEA molecule while region 161-180 is involved in superantigenic activity but not emetic activity of SEA. These regions could be important targets for therapeutic intervention against SEA exposure. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. a Step Toward Development of Printable Dosage Forms for Poorly Soluble Drugs

    DEFF Research Database (Denmark)

    Raijada, Dhara; Genina, Natalja; Fors, Daniela


    The purpose of this study was to formulate printable dosage forms for a poorly soluble drug (piroxicam; PRX) and to gain understanding of critical parameters to be considered during development of such dosage forms. Liquid formulations of PRX were printed on edible paper using piezoelectric inkjet...

  12. Estimated Effect of Epoetin Dosage on Survival among Elderly Hemodialysis Patients in the United States


    Zhang, Yi; Thamer, Mae; Cotter, Dennis; Kaufman, James; Hernán, Miguel A.


    Background and objectives: The common finding that low achieved hemoglobin in observational studies and high target hemoglobin in randomized trials each were associated with increased mortality and high epoetin dosage has suggested the possibility that high epoetin dosage might explain the increased mortality risk.

  13. Venomics, lethality and neutralization of Naja kaouthia (monocled cobra) venoms from three different geographical regions of Southeast Asia. (United States)

    Tan, Kae Yi; Tan, Choo Hock; Fung, Shin Yee; Tan, Nget Hong


    Previous studies showed that venoms of the monocled cobra, Naja kaouthia from Thailand and Malaysia are substantially different in their median lethal doses. The intraspecific venom variations of N. kaouthia, however, have not been fully elucidated. Here we investigated the venom proteomes of N. kaouthia from Malaysia (NK-M), Thailand (NK-T) and Vietnam (NK-V) through reverse-phase HPLC, SDS-PAGE and tandem mass spectrometry. The venom proteins comprise 13 toxin families, with three-finger toxins being the most abundant (63-77%) and the most varied (11-18 isoforms) among the three populations. NK-T has the highest content of neurotoxins (50%, predominantly long neurotoxins), followed by NK-V (29%, predominantly weak neurotoxins and some short neurotoxins), while NK-M has the least (18%, some weak neurotoxins but less short and long neurotoxins). On the other hand, cytotoxins constitute the main bulk of toxins in NK-M and NK-V venoms (up to 45% each), but less in NK-T venom (27%). The three venoms show different lethal potencies that generally reflect the proteomic findings. Despite the proteomic variations, the use of Thai monovalent and Neuro polyvalent antivenoms for N. kaouthia envenomation in the three regions is appropriate as the different venoms were neutralized by the antivenoms albeit at different degrees of effectiveness. Biogeographical variations were observed in the venom proteome of monocled cobra (Naja kaouthia) from Malaysia, Thailand and Vietnam. The Thai N. kaouthia venom is particularly rich in long neurotoxins, while the Malaysian and Vietnamese specimens were predominated with cytotoxins. The differentially expressed toxin profile accounts for the discrepancy in the lethal dose of the venom from different populations. Commercially available Thai antivenoms (monovalent and polyvalent) were able to neutralize the three venoms at different effective doses, hence supporting their uses in the three regions. While dose adjustment according to

  14. Left ventricular function during lethal and sublethal endotoxemia in swine

    International Nuclear Information System (INIS)

    Goldfarb, R.D.; Nightingale, L.M.; Kish, P.; Weber, P.B.; Loegering, D.J.


    Previous studies suggested that after a median lethal dose (LD 50 ) of endotoxin, cardiac contractility was depressed in nonsurviving dogs. The canine cardiovascular system is unlike humans in that dogs have a hepatic vein sphincter that is susceptible to adrenergic stimulation capable of raising hepatic and splanchnic venous pressures. The authors retested the hypothesis that lethality after endotoxin administration is associated with cardiac contractile depression in pigs, because of the hepatic circulation in this species is similar to that of humans. They compared cardiac mechanical function of pigs administered a high dose (250 μg/kg) or a low dose (100 μg/kg) endotoxin by use of the slope of the end-systolic pressure-diameter relationship (ESPDR) as well as other measurements of cardiac performance. In all the pigs administered a high dose, ESPDR demonstrated a marked, time-dependent depression whereas we observed no significant ESPDR changes after low endotoxin doses. The other cardiodynamic variables were uninterpretable, due to the significant changes in heart rate, end-diastolic diameter (preload), and aortic diastolic pressure (afterload). Plasma myocardia depressant factor activity accumulated in all endotoxin-administered animals, tending to be greater in the high-dose group. In this group, both subendocardial blood flow and global function were depressed, whereas pigs administered the low dose endotoxin demonstrated slight, but nonsignificant, increases in flow and function. These observations indicate that myocardial contractile depression is associated with a lethal outcome to high doses of endotoxin. Myocardial perfusion was measured using radiolabeled microspheres infused into the left atria

  15. [Tuberculosis: relevance of isoniazid dosage in prevention of liver side effects]. (United States)

    Negri, Lucie; Le Grusse, Jean; Séraissol, Patrick; Lavit, Michel; Houin, Georges; Gandia, Peggy


    Several recent studies have established a correlation between NAT2 polymorphism and hepatotoxicity induced by isoniazid. The objective of this work was to assess the place of isoniazid dosage, marker of acetylation phenotype, in clinical practice in the department of Haute-Garonne. Data from reportable disease of tuberculosis and the results of isoniazid dosage performed at the pharmacokinetics and clinical toxicology laboratory were used during the period 2009-2012. The current practice of dosage is far from being systematical: only 3.9% of patients who developed tuberculosis have benefited from isoniazid dosage. The isoniazid initial posology was adapted to the acetylation capacity for only 33.3% of patients. A decision tree was realized and used to identify populations (low metabolism) liable to benefit from isoniazid dosage. © 2014 Société Française de Pharmacologie et de Thérapeutique.

  16. Dosage effects of Waxy gene on the structures and properties of corn starch. (United States)

    Yangcheng, Hanyu; Blanco, Michael; Gardner, Candice; Li, Xuehong; Jane, Jay-Lin


    The objective of this study was to understand dosage effects of the Waxy gene on the structures of amylose and amylopectin and on the properties of corn starch. Reciprocal crossing of isogenic normal and waxy corn lines was conducted to develop hybrids with different dosages (0, 1, 2, 3) of Waxy gene in the endosperm. The amylose content of starch and proportions of branch chains of DP 17-30 and extra-long branch chains (DP>100) of amylopectin were positively correlated with the Waxy-gene dosage. Proportions of short (DPstarch were negatively correlated with the Waxy-gene dosage, indicating that amylose facilitated dissociation of the surrounding crystalline regions. These results helped us understand the function of granule-bound starch synthase I in the biosynthesis of amylose and amylopectin and impacts of Waxy-gene dosages on the properties of corn starch. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Meeting Report: Synthetic Biology Jamboree for Undergraduates (United States)

    Campbell, A. Malcolm


    The field of synthetic biology (the name is derived from an analogy to synthetic chemistry) has recognized itself as a "field" only since about 2002. Synthetic biology has gotten some high-profile attention recently, but most people are not aware the field even exists. Synthetic biologists apply engineering principles to genomic circuits to…

  18. Lethal subarachnoid bleeding under immunosuppressive therapy due to mycotic arteritis

    Energy Technology Data Exchange (ETDEWEB)

    Weigel, S.; Kloska, S.; Freund, M. [Dept. of Clinical Radiology, Univ. Hospital of Muenster, Muenster (Germany); Kehl, H.G. [Dept. of Pediatric Cardiology, Univ. Hospital of Muenster, Muenster (Germany)


    A subarachnoid haemorrhage (SAH) occurred 67 days after cardiac transplantation in 10-year-old girl with consecutive immunocompromising therapy. Neither digital subtraction angiography (DSA) nor computed tomographic angiography showed signs of intracranial vascular malformations. One month before the lethal SAH occurred, she had developed arterial hypertension and attacks of severe headache with cerebrospinal fluid (CSF) pleocytosis while CT scans showed an infarct of the left thalamus. Pathologic findings established the rare diagnosis of SAH due to aspergillosis-related mycotic arteritis. Imaging characteristics are presented. (orig.)

  19. Lethal and Legal The Ethics of Drone Strikes (United States)


    of warfare.6 Key rationales for the use of armed drones are that they are legal, effective, and ethical. According to White House spokesman James ...journalist James Foley in August 2014 was in retalia- tion for U.S. airstrikes in Iraq.98 These medium- and long-term second order effects caused by lethal...20Security%20 Detention%20in%20Non-International%20Armed%20Conflict.pdf. 36. Benjamin Wittes , “Amnesty International Responds,” Law- fare, October

  20. EXCALIBIR - A space experiment in orbital debris lethality (United States)

    Culp, Robert D.; Dickey, Michael R.


    The study proposes a space experiment using extended Space Shuttle external tanks to test the impact of orbital debris. The External Tank Calibrated Impact Response test, EXCALIBIR, is a low-cost low-risk, high-payoff approach to investigating the threat to resident space objects posed by untrackable orbital debris, to provide lethality data to the kinetic energy weapons community, and to aid in the testing of space and missile interceptor technology. This experiment is a feasible use of existing assets - the external tank, observation and data collection facilities, launch facilities, and interceptor technology and tests planned for other programs.

  1. Perinatal lethal type II osteogenesis imperfecta: a case report. (United States)

    Ayadi, Imene Dahmane; Hamida, Emira Ben; Rebeh, Rania Ben; Chaouachi, Sihem; Marrakchi, Zahra


    We report a new case of osteogenesis imperfecta (OI) type II which is a perinatal lethal form. First trimester ultrasound didn't identified abnormalities. Second trimester ultrasound showed incurved limbs, narrow chest, with hypomineralization and multiple fractures of ribs and long bones. Parents refused pregnancy termination; they felt that the diagnosis was late. At birth, the newborn presented immediate respiratory distress. Postnatal examination and bone radiography confirmed the diagnosis of OI type IIA. Death occurred on day 25 of life related to respiratory failure.

  2. Ultraviolet-B lethal damage on Pseudomonas aeruginosa

    International Nuclear Information System (INIS)

    Degiorgi, C.F.; Fernandez, R.O.; Pizarro, R.A.


    Pseudomonas aeruginosa has shown an increased sensitivity compared with that of Escherichia coli and Enterobacter cloacae, when they were exposed to 0.4 kJ/m2 of ultraviolet-B radiation. The rapid decay in cell viability observed in Pseudomonas aeruginosa after the irradiation was influenced by factors such as culture media and the presence of pyocyanine during the irradiation. The radioinduced lethal damage could be prevented by photoreactivating treatment, indicating that pyrimidine dimer formation was the mechanism causing bacterial death. The results indicate that several environmental conditions may act as protective agents against ultraviolet-B-induced damage

  3. Control theory meets synthetic biology. (United States)

    Del Vecchio, Domitilla; Dy, Aaron J; Qian, Yili


    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. © 2016 The Author(s).

  4. Synthetic biology, metaphors and responsibility. (United States)

    McLeod, Carmen; Nerlich, Brigitte


    Metaphors are not just decorative rhetorical devices that make speech pretty. They are fundamental tools for thinking about the world and acting on the world. The language we use to make a better world matters; words matter; metaphors matter. Words have consequences - ethical, social and legal ones, as well as political and economic ones. They need to be used 'responsibly'. They also need to be studied carefully - this is what we want to do through this editorial and the related thematic collection. In the context of synthetic biology, natural and social scientists have become increasingly interested in metaphors, a wave of interest that we want to exploit and amplify. We want to build on emerging articles and books on synthetic biology, metaphors of life and the ethical and moral implications of such metaphors. This editorial provides a brief introduction to synthetic biology and responsible innovation, as well as a comprehensive review of literature on the social, cultural and ethical impacts of metaphor use in genomics and synthetic biology. Our aim is to stimulate an interdisciplinary and international discussion on the impact that metaphors can have on science, policy and publics in the context of synthetic biology.

  5. Membrane properties for permeability testing: Skin versus synthetic membranes. (United States)

    Haq, Anika; Dorrani, Mania; Goodyear, Benjamin; Joshi, Vivek; Michniak-Kohn, Bozena


    Synthetic membranes that are utilized in diffusion studies for topical and transdermal formulations are usually porous thin polymeric sheets for example cellulose acetate (CA) and polysulfones. In this study, the permeability of human skin was compared using two synthetic membranes: cellulose acetate and Strat-M® membrane and lipophilic and hydrophilic compounds either as saturated or formulated solutions as well as marketed dosage forms. Our data suggests that hydrophilic compounds have higher permeation in Strat-M membranes compared with lipophilic ones. High variation in permeability values, a typical property of biological membranes, was not observed with Strat-M. In addition, the permeability of Strat-M was closer to that of human skin than that of cellulose acetate (CA > Strat-M > Human skin). Our results suggest that Strat-M with little or no lot to lot variability can be applied in pilot studies of diffusion tests instead of human skin and is a better substitute than a cellulose acetate. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. Microfluidic Technologies for Synthetic Biology

    Directory of Open Access Journals (Sweden)

    Sung Kuk Lee


    Full Text Available Microfluidic technologies have shown powerful abilities for reducing cost, time, and labor, and at the same time, for increasing accuracy, throughput, and performance in the analysis of biological and biochemical samples compared with the conventional, macroscale instruments. Synthetic biology is an emerging field of biology and has drawn much attraction due to its potential to create novel, functional biological parts and systems for special purposes. Since it is believed that the development of synthetic biology can be accelerated through the use of microfluidic technology, in this review work we focus our discussion on the latest microfluidic technologies that can provide unprecedented means in synthetic biology for dynamic profiling of gene expression/regulation with high resolution, highly sensitive on-chip and off-chip detection of metabolites, and whole-cell analysis.

  7. A sigmoidal transcriptional response: cooperativity, synergy and dosage effects. (United States)

    Veitia, Reiner A


    A sigmoidal transcriptional response (STR) is thought to act as a molecular switch to control gene expression. This nonlinear behaviour arises as a result of the cooperative recognition of a promoter/enhancer by transcription factors (TFs) and/or their synergy to attract the basal transcriptional machinery (BTM). Although this cooperation between TFs is additive in terms of energy, it leads to an exponential increase in affinity between the BTM and the pre-initiation complexes. This exponential increase in the strength of interactions is the principle that governs synergistic systems. Here, I propose a minimalist quasi-equilibrium model to explore qualitatively the STR taking into account cooperative recognition of the promoter/enhancer and synergy. Although the focus is on the effect of activators, a similar treatment can be applied to inhibitors. One of the main insights obtained from the model is that generation of a sigmoidal threshold is possible even in the absence of cooperative DNA binding provided the TFs synergistically interact with the BTM. On the contrary, when there is cooperative binding, the impact of synergy diminishes. It will also be shown that a sigmoidal response to a morphogenetic gradient can be used to generate a nested gradient of another morphogen. Previously, I had proposed that halving the amounts of TFs involved in sigmoidal transcriptional switches could account for the abnormal dominant phenotypes associated with some of these genes. This phenomenon, called haploinsufficiency (HI), has been recognised as the basis of many human diseases. Although a formal proof linking HI and a sigmoidal response is lacking, it is tempting to explore the model from the perspective of dosage effects.

  8. Mathematical modeling of drug release from lipid dosage forms. (United States)

    Siepmann, J; Siepmann, F


    Lipid dosage forms provide an interesting potential for controlled drug delivery. In contrast to frequently used poly(ester) based devices for parenteral administration, they do not lead to acidification upon degradation and potential drug inactivation, especially in the case of protein drugs and other acid-labile active agents. The aim of this article is to give an overview on the current state of the art of mathematical modeling of drug release from this type of advanced drug delivery systems. Empirical and semi-empirical models are described as well as mechanistic theories, considering diffusional mass transport, potentially limited drug solubility and the leaching of other, water-soluble excipients into the surrounding bulk fluid. Various practical examples are given, including lipid microparticles, beads and implants, which can successfully be used to control the release of an incorporated drug during periods ranging from a few hours up to several years. The great benefit of mechanistic mathematical theories is the possibility to quantitatively predict the effects of different formulation parameters and device dimensions on the resulting drug release kinetics. Thus, in silico simulations can significantly speed up product optimization. This is particularly useful if long release periods (e.g., several months) are targeted, since experimental trial-and-error studies are highly time-consuming in these cases. In the future it would be highly desirable to combine mechanistic theories with the quantitative description of the drug fate in vivo, ideally including the pharmacodynamic efficacy of the treatments. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Long-term effects of synthetic fibers on concrete pipes (United States)

    Farrokhi Gozarchi, Sasan

    The studies undertaken by this research were to evaluate the long-term performance and durability of synthetic fiber-reinforced concrete pipes. The target long-term performance is for 9000 hours. Two sets of pipes 8 ft. (2400 mm) long with inside diameters of 24 in. (600 mm) and 36 in. (1200 mm) were manufactured, with a wall thickness of 3 and 4 in., respectively. The pipes were produced based on ASTM C76, for a Class III type with a Wall B. The two set of pipes included RCP's (as control) and SYN-FRCP's. The SYN-FRCP's had several fiber dosages ranging from 6 lb/yd3 (3.5 kg/m 3) to 12 lb/yd3 (7.0 kg/m3) in order to evaluate the long-term performance of synthetic fiber-reinforced concrete pipes. The pipes were pre-cracked until the first visible crack was observed in the three-edge bearing test. As a result, the sustained load simulated, was calculated from the Peak D-load observed; and also the appropriate fiber dosages required for the 24. in (600 mm) and 36 in. (900 mm) pipes were obtained. Three of the 24 in. and three of the 36 in. pipes were installed in 7 ft. (2100 mm) and 8 ft. (2400 mm) wide trenches with 16 ft. (4800 mm) and 18 ft. (5500 mm) of cover respectively. The pipe was initially backfilled with native soil up to 2 ft. (600 mm) and 4 ft. (1200 mm) over the top of the pipe then backfilled again with pea-gravel weighing 100 lb/ft3, to a height of 14ft. to simulate the sustained loading. A type two installation was used during the development of the test setup. Once the long-term test set up was complete, the data was immediately recorded, and vertical deflections were observed from the time-dependent behavior of the pipes. It was observed from results obtained from the three-edge bearing test, that synthetic fibers improve the mechanical properties of concrete pipes, in dry-cast manufacturing. Also, it was observed from the time-dependent deformation, that there was no significant deformation of SYN-FRCP, while the shear capacity was enhanced. Based

  10. US Competitiveness in Synthetic Biology. (United States)

    Gronvall, Gigi Kwik


    Synthetic biology is an emerging technical field that aims to make biology easier to engineer; the field has applications in strategically important sectors for the US economy. While the United States currently leads in synthetic biology R&D, other nations are heavily investing in order to boost their economies, which will inevitably diminish the US leadership position. This outcome is not entirely negative--additional investments will expand markets--but it is critical that the US government take steps to remain competitive: There are applications from which the US population and economy may benefit; there are specific applications with importance for national defense; and US technical leadership will ensure that US experts have a leading role in synthetic biology governance, regulation, and oversight. Measures to increase competitiveness in S&T generally are broadly applicable for synthetic biology and should be pursued. However, the US government will also need to take action on fundamental issues that will affect the field's development, such as countering anti-GMO (genetically modified organism) sentiments and anti-GMO legislation. The United States should maintain its regulatory approach so that it is the product that is regulated, not the method used to create a product. At the same time, the United States needs to ensure that the regulatory framework is updated so that synthetic biology products do not fall into regulatory gaps. Finally, the United States needs to pay close attention to how synthetic biology applications may be governed internationally, such as through the Nagoya Protocol of the Convention on Biological Diversity, so that beneficial applications may be realized.

  11. Synthetic biology as red herring. (United States)

    Preston, Beth


    It has become commonplace to say that with the advent of technologies like synthetic biology the line between artifacts and living organisms, policed by metaphysicians since antiquity, is beginning to blur. But that line began to blur 10,000 years ago when plants and animals were first domesticated; and has been thoroughly blurred at least since agriculture became the dominant human subsistence pattern many millennia ago. Synthetic biology is ultimately only a late and unexceptional offshoot of this prehistoric development. From this perspective, then, synthetic biology is a red herring, distracting us from more thorough philosophical consideration of the most truly revolutionary human practice-agriculture. In the first section of this paper I will make this case with regard to ontology, arguing that synthetic biology crosses no ontological lines that were not crossed already in the Neolithic. In the second section I will construct a parallel case with regard to cognition, arguing that synthetic biology as biological engineering represents no cognitive advance over what was required for domestication and the new agricultural subsistence pattern it grounds. In the final section I will make the case with regard to human existence, arguing that synthetic biology, even if wildly successful, is not in a position to cause significant existential change in what it is to be human over and above the massive existential change caused by the transition to agriculture. I conclude that a longer historical perspective casts new light on some important issues in philosophy of technology and environmental philosophy. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Investigation of hexachlorophene for dominant lethal effects in the mouse. (United States)

    Kennedy, G L; Arnold, D W; Keplinger, M L; Calandra, J C


    Hexachlorophene (HCP) was studied for mutagenic effects in the dominant lethal test on mice. Groups of male mice were treated with either 2.5 or 5.0 mg hexachlorophene per kg body weight as a single intraperitoneal injection. Control animals were treated with the propylene glycol vehicle. Each male was mated with 3 untreated females for each of 8 consecutive weeks with the uterus of the females examined at mid-pregnancy for signs of early embryonic death. Treatment did not alter mating capacity and fertility of the males. The administration of hexachlorophene had no influence on pre- or post-implantation losses. An increase in early resorptions among female mice bred to males treated with the reference compound, methyl methanesulfonate (MMS) given a single i.p. injection of 100 mg/kg, indicated the susceptibility of the mouse strain used to a known mutagen. It is concluded that hexachlorophene at maximally tolerated doses is not mutagenic in the dominant lethal test in mice.

  13. Killing Range: Explaining Lethality Variance within a Terrorist Organization. (United States)

    Asal, Victor; Gill, Paul; Rethemeyer, R Karl; Horgan, John


    This paper presents an analysis of the Provisional Irish Republican Army's (PIRA) brigade level behavior during the Northern Ireland Conflict (1970-1998) and identifies the organizational factors that impact a brigade's lethality as measured via terrorist attacks. Key independent variables include levels of technical expertise, cadre age, counter-terrorism policies experienced, brigade size, and IED components and delivery methods. We find that technical expertise within a brigade allows for careful IED usage, which significantly minimizes civilian casualties (a specific strategic goal of PIRA) while increasing the ability to kill more high value targets with IEDs. Lethal counter-terrorism events also significantly affect a brigade's likelihood of killing both civilians and high-value targets but in different ways. Killing PIRA members significantly decreases IED fatalities but also significantly decreases the possibility of zero civilian IED-related deaths in a given year. Killing innocent Catholics in a Brigade's county significantly increases total and civilian IED fatalities. Together the results suggest the necessity to analyze dynamic situational variables that impact terrorist group behavior at the sub-unit level.

  14. Brine shrimp lethality bioassay of selected gymnosperm and angiosperm species

    Directory of Open Access Journals (Sweden)

    Janaćković Peđa T.


    Full Text Available Methanol extracts of selected species of flowering plants Anthemis cotula, A. ruthenica, Centaurea dubia (Asteraceae, Ajuga genevensis, A. chamaepitys, A. reptans, Micromeria albanica, M. cristata, M. dalmatica, M. juliana, Thymus tosevii (Lamiaceae and conifers - Abies alba, Picea omorika, Pinus heldreichii (Pinaceae and Taxus baccata (Taxaceae, as well as diethyl ether extracts of ten species Anthemis cotula, A. ruthenica, Centaurea dubia, Ajuga genevensis, A. chamaepitys, A. reptans, Micromeria albanica, M. cristata, M. dalmatica and M. juliana from two flowering plant families (Asteraceae and Lamiaceae were tested for general bioactivity using brine shrimp (Artemia salina lethality test. Lethal concentration (LC50 and 95% confidence intervals were determined by computer program LdP line. Out of fifteen tested methanol extracts, three possessed cytotoxic effect. Taxus baccata methanol extract showed the highest effect (LC50 = 18.60 μg/ml, while Thymus tosevii methanol extract expressed the lowest (LC50 = 842.50 μg/ml. All other analyzed species did not express significant cytotoxicity. Also, diethyl ether extracts of all tested species did not show significant cytotoxicity. The obtained results for methanol extracts which show certain cytotoxic effect could be guide for further phytochemical and pharmacological investigations. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 173029

  15. Treatment of lethal acetylsalicylic acid poisoning without hemodialysis. (United States)

    Ueno, Masahito; Oda, Jun; Soeda, Hiroshi; Uesugi, Hirotaka; Ueno, Keiko; Fujise, Yo; Yukioka, Tetsuo


    A woman aged in her 20s ingested approximately 99 g acetylsalicylic acid, and was transported to our hospital 2 h later. She was lucid, but complained of hearing loss and tinnitus. We performed gastric lavage and gave her activated charcoal several times. We attempted to maintain the urinary pH at 7.5 and output above 100 mL/h while preparing for urgent hemodialysis. It was revealed after discharge that the blood concentration of acetylsalicylic acid was 103.8 mg/dL on admission (lethal dose level) and had decreased to 35.4 mg/dL by the next morning. The half-life was 8.5 h. Hemodialysis is strongly recommended for patients who take a lethal dose of acetylsalicylic acid. However, by carefully evaluating the vital signs and urinary output and pH, while preparing for emergency hemodialysis, we consider that it is possible to treat acetylsalicylic acid poisoning by alkaline diuresis and critical supportive care.

  16. Lethal action of thermal neutron to living cells

    International Nuclear Information System (INIS)

    Kawai, Kenichi; Akahoshi, Mitsuhiko


    Using Amoeba Proteus (DNA content was 5x10 -10 g/cell), action mechanism of thermal neutron was described by using death of cells as an index. Using mononuclear type (M-type) and polynuclear type (P-type) of Amoeba, investigation was made as to whether the number of nucleus contained in cell was related to death of cell by radiation. As compared to gamma-ray, marked difference between sensitivity of both types of Amoeba was not recognized. It was suggested that nucleus was important as a place of death of cell by thermal neutron. In order to demonstrate that reaction of 31 P(n, γ) 32 Pwas a main cause of lethality, the following experiment was carried out. 1) In order to investigate that radical reaction was not a main cause of lethal action by thermal neutron, increase and decrease of radical reaction were observed by adding AET, Cysteine and BudR. As to thermal neutron action, effect of its chemical factors did not appeared. 2) In order to demonstrate that nuclear reaction of constituent atom of living body played an important part in death of cell, increase and decrease of nuclear reaction within cell were observed by taking Na 2 , B 4 and O 7 into Amoeba. It was suggested that nuclear reaction of cell constituent atom itself was important in death of cell. 3) Potentiation effect of gamma-ray and thermal neutron was investigated and its mechanism was discussed. (K. Serizawa)

  17. An outbreak of lethal adenovirus infection among different otariid species. (United States)

    Inoshima, Yasuo; Murakami, Tomoaki; Ishiguro, Naotaka; Hasegawa, Kazuhiro; Kasamatsu, Masahiko


    An outbreak of fatal fulminant hepatitis at a Japanese aquarium involved 3 otariids: a California sea lion (Zalophus californianus), a South African fur seal (Arctocephalus pusillus) and a South American sea lion (Otaria flavescens). In a span of about a week in February 2012, 3 otariids showed diarrhea and were acutely low-spirited; subsequently, all three animals died within a period of 3 days. Markedly increased aspartate amino transferase and alanine amino transferase activities were observed. Necrotic hepatitis and eosinophilic intranuclear inclusion bodies in liver hepatocytes and intestinal epithelial cells were observed in the South American sea lion on histological examination. Otarine adenovirus DNA was detected from the livers of all three animals by polymerase chain reaction and determination of the sequences showed that all were identical. These results suggest that a single otarine adenovirus strain may have been the etiological agent of this outbreak of fatal fulminant hepatitis among the different otariid species, and it may be a lethal threat to wild and captive otariids. This is the first evidence of an outbreak of lethal adenovirus infection among different otariid species. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Experimental evaluation of the relationship between lethal or non-lethal virulence and transmission success in malaria parasite infections

    Directory of Open Access Journals (Sweden)

    Nithiuthai S


    Full Text Available Abstract Background Evolutionary theory suggests that the selection pressure on parasites to maximize their transmission determines their optimal host exploitation strategies and thus their virulence. Establishing the adaptive basis to parasite life history traits has important consequences for predicting parasite responses to public health interventions. In this study we examine the extent to which malaria parasites conform to the predicted adaptive trade-off between transmission and virulence, as defined by mortality. The majority of natural infections, however, result in sub-lethal virulent effects (e.g. anaemia and are often composed of many strains. Both sub-lethal effects and pathogen population structure have been theoretically shown to have important consequences for virulence evolution. Thus, we additionally examine the relationship between anaemia and transmission in single and mixed clone infections. Results Whereas there was a trade-off between transmission success and virulence as defined by host mortality, contradictory clone-specific patterns occurred when defining virulence by anaemia. A negative relationship between anaemia and transmission success was found for one of the parasite clones, whereas there was no relationship for the other. Notably the two parasite clones also differed in a transmission phenotype (gametocyte sex ratio that has previously been shown to respond adaptively to a changing blood environment. In addition, as predicted by evolutionary theory, mixed infections resulted in increased anaemia. The increased anaemia was, however, not correlated with any discernable parasite trait (e.g. parasite density or with increased transmission. Conclusions We found some evidence supporting the hypothesis that there is an adaptive basis correlating virulence (as defined by host mortality and transmission success in malaria parasites. This confirms the validity of applying evolutionary virulence theory to biomedical

  19. Synthetic Phage for Tissue Regeneration

    Directory of Open Access Journals (Sweden)

    So Young Yoo


    Full Text Available Controlling structural organization and signaling motif display is of great importance to design the functional tissue regenerating materials. Synthetic phage, genetically engineered M13 bacteriophage has been recently introduced as novel tissue regeneration materials to display a high density of cell-signaling peptides on their major coat proteins for tissue regeneration purposes. Structural advantages of their long-rod shape and monodispersity can be taken together to construct nanofibrous scaffolds which support cell proliferation and differentiation as well as direct orientation of their growth in two or three dimensions. This review demonstrated how functional synthetic phage is designed and subsequently utilized for tissue regeneration that offers potential cell therapy.

  20. Synthetic biology and its promises

    Directory of Open Access Journals (Sweden)

    José Manuel De Cózar Escalante


    Full Text Available Synthetic biology is a new science and emerging technology, or rather a technoscience, which converges with others such as nanotechnology, information technology, robotics, artificial intelligence and neuroscience. All have common features that could have highly concerning social and environmental impacts. With its ambitious goals of controlling complexity, redesigning and creating new living entities, synthetic biology perfectly exemplifies the new bioeconomic reality. This requires expanding the focus of the discussion beyond the limited comparative analysis of risks and benefits, to address uncertainties, reassign responsibilities and initiate a thorough social assessment of what is at stake.

  1. Synthetic methodologies for carbon nanomaterials. (United States)

    Liu, Zhaoping; Zhou, Xufeng; Qian, Yitai


    Carbon nanomaterials have advanced rapidly over the last two decades and are among the most promising materials that have already changed and will keep on changing human life. Development of synthetic methodologies for these materials, therefore, has been one of the most important subjects of carbon nanoscience and nanotechnology, and forms the basis for investigating the physicochemical properties and applications of carbon nanomaterials. In this Research News article, several synthetic strategies, including solvothermal reduction, solvothermal pyrolysis, hydrothermal carbonization, and soft-chemical exfoliation are specifically discussed and highlighted, which have been developed for the synthesis of novel carbon nanomaterials over the last decade.

  2. Forward imaging for obstacle avoidance using ultrawideband synthetic aperture radar (United States)

    Nguyen, Lam H.; Wong, David C.; Stanton, Brian; Smith, Gregory


    In support of the Army vision for increased mobility, survivability, and lethality, we are investigating the use of ultra-wideband (UWB) synthetic aperture radar (SAR) technology to enhance unmanned ground vehicle missions. The ability of UWB radar technology to detect objects concealed by foilage could provide an important obstacle avoidance capability for robotic vehicles. This would improve the speed and maneuverability of these vehicles and consequently increase the probability of survivability of U.S. forces. This technology would address the particular challenges that confront robotic vehicles such as large rocks hidden in tall grass and voids such as ditches and bodies of water. ARL has designed and constructed an instrumentation-grade low frequency, UWB synthetic aperture radar for evaluation of the target signatures and underlying phenomenology of stationary tactical targets concealed by foilage and objects buried in the ground. The radar (named BoomSAR) is installed in teh basekt of a 30-ton boom lift and can be operated while the entire boom lift is driven forward slowly, with the boom arm extended as high as 45 m to generate a synthetic aperture. In this paper, we investigate the potential use of the UWB radar in the forward imaging configuration. The paper describes the forward imaging radar and test setup at Aberdeen Proving Ground, Maryland. We present imagery of "positive" obstacles such as trees, fences, wires, mines, etc., as well as "negative" obstacles such as ditches. Imagery of small targets such as plastic mines is also included. We provide eletromagnetic simulations of forward SAR imagery of plastic mines and compare that to the measurement data.

  3. Teacher factors contributing to dosage of the KiVa anti-bullying program. (United States)

    Swift, Lauren E; Hubbard, Julie A; Bookhout, Megan K; Grassetti, Stevie N; Smith, Marissa A; Morrow, Michael T


    The KiVa Anti-Bullying Program (KiVa) seeks to meet the growing need for anti-bullying programming through a school-based, teacher-led intervention for elementary school children. The goals of this study were to examine how intervention dosage impacts outcomes of KiVa and how teacher factors influence dosage. Participants included 74 teachers and 1409 4th- and 5th-grade students in nine elementary schools. Teachers and students completed data collection at the beginning and end of the school year, including measures of bullying and victimization, correlates of victimization (depression, anxiety, peer rejection, withdrawal, and school avoidance), intervention cognitions/emotions (anti-bullying attitudes, and empathy toward victims), bystander behaviors, and teacher factors thought to relate to dosage (self-efficacy for teaching, professional burnout, perceived principal support, expected effectiveness of KiVa, perceived feasibility of KiVa). The dosage of KiVa delivered to classrooms was measured throughout the school year. Results highlight dosage as an important predictor of change in bullying, victimization, correlates of victimization, bystander behavior, and intervention cognitions/emotions. Of the teacher factors, professional burnout uniquely predicted intervention dosage. A comprehensive structural equation model linking professional burnout to dosage and then to child-level outcomes demonstrated good fit. Implications for intervention design and implementation are discussed. Copyright © 2017 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.

  4. Application of DBNPA dosage for biofouling control in spiral wound membrane systems

    KAUST Repository

    Siddiqui, Amber


    Biocides may be used to control biofouling in spiral-wound reverse osmosis (RO) and nanofiltration (NF) systems. The objective of this study was to investigate the effect of biocide 2,2-dibromo-3-ni-trilopropionamide (DBNPA) dosage on biofouling control. Preventive biofouling control was studied applying a continuous dosage of substrate (0.5 mg/L) and DBNPA (1 mg/L). Curative biofouling control was studied on pre-grown biofilms, once again applying a continuous dosage of substrate (0.5 mg acetate C/L) and DBNPA (1 and 20 mg/L). Biofouling studies were performed in membrane fouling simulators (MFSs) supplied with biodegradable substrate and DBNPA. The pressure drop was monitored in time and at the end of the study, the accumulated biomass in MFS was quantified by adenosine triphosphate (ATP) and total organic carbon (TOC) analysis. Continuous dosage of DBNPA (1 mg/L) prevented pressure drop increase and biofilm accumulation in the MFSs during a run time of 7 d, showing that biofouling can be managed by preventive DBNPA dosage. For biofouled systems, continuous dosage of DBNPA (1 and 20 mg/L) inactivated the accumulated biomass but did not restore the original pressure drop and did not remove the accumulated inactive cells and extracellular polymeric substances (EPS), indicating DBNPA dosage is not suitable for curative biofouling control.

  5. Does a history of suicide attempt predict higher antipsychotic dosage in schizophrenia? (United States)

    Hettige, Nuwan C; Kennedy, James L; De Luca, Vincenzo


    Antipsychotic dosage is generally adjusted by physicians depending on the stability of the patient and the response to that particular drug. Our hypothesis is that patients with previous suicide attempt are prescribed higher doses of antipsychotics. We examined the dosage and patterns of antipsychotic use in regard to past suicidal behaviour. For this study, 304 subjects with schizophrenia spectrum disorders between the ages of 18 and 75 were recruited. A cross-sectional assessment was used for this study, in which data were collected from each patient through an interview and self-report questionnaires. The percentages of the Compendium of Pharmaceuticals and Specialties (CPS) maximum recommended daily dose were applied to standardize antipsychotic dosages across different treatments. We compared the standardized dosage of antipsychotics in schizophrenics with previous suicide attempts and those who have never attempted suicide. Applying the ANCOVA, our preliminary results show no significant difference (P = 0.467) in antipsychotic dosage in the attempters and non-attempters. The prescribed clozapine dosage fails to show a significant relationship with suicidal history (P >0.05). In summary, our analysis does not show antipsychotic dosage adjustment based on past suicide attempt, after controlling for the current suicidal ideation and hopelessness.

  6. A computer program for evaluating propellant heating and radiation dosage to crews of nuclear-powered rocket vehicles (United States)

    Lahti, G. P.


    Program evaluates propellant heating in a nuclear rocket stage. Program code employs infinite-medium buildup factors to calculate gamma dosage and employs the Albert-Welton kernal to calculate the fast neutron dosage.

  7. A Systems Biology Approach to Link Nuclear Factor Kappa B Activation with Lethal Prostate Cancer (United States)


    indolent participants. For each cytokine, the threshold for being ‘high’ was determined as being above the third quartile of the combined indolent identify genes associated with lethal prostate cancer. There were 115 PHS patients (83 indolent , 32 lethal). The DASL data is expressed as...difference between the mean log expression in the lethal group and in the indolent group. When the expression is larger in the indolent group, the result

  8. Where Synthetic Biology Meets ET (United States)

    Rothschild, Lynn J.


    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.

  9. Future of synthetic aperture radar (United States)

    Barath, F. T.


    The present status of the applications of Synthetic Aperture Radars (SARs) is reviewed, and the technology state-of-the art as represented by the Seasat-A and SIR-A SARs examined. The potential of SAR applications, and the near- and longer-term technology trends are assessed.

  10. Digital 'faces' of synthetic biology. (United States)

    Friedrich, Kathrin


    In silicio design plays a fundamental role in the endeavour to synthesise biological systems. In particular, computer-aided design software enables users to manage the complexity of biological entities that is connected to their construction and reconfiguration. The software's graphical user interface bridges the gap between the machine-readable data on the algorithmic subface of the computer and its human-amenable surface represented by standardised diagrammatic elements. Notations like the Systems Biology Graphical Notation (SBGN), together with interactive operations such as drag & drop, allow the user to visually design and simulate synthetic systems as 'bio-algorithmic signs'. Finally, the digital programming process should be extended to the wet lab to manufacture the designed synthetic biological systems. By exploring the different 'faces' of synthetic biology, I argue that in particular computer-aided design (CAD) is pushing the idea to automatically produce de novo objects. Multifaceted software processes serve mutually aesthetic, epistemic and performative purposes by simultaneously black-boxing and bridging different data sources, experimental operations and community-wide standards. So far, synthetic biology is mainly a product of digital media technologies that structurally mimic the epistemological challenge to take both qualitative as well as quantitative aspects of biological systems into account in order to understand and produce new and functional entities. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Synthetic peptides for diagnostic use

    NARCIS (Netherlands)

    Meloen, R.H.; Langedijk, J.P.M.; Langeveld, J.P.M.


    Synthetic peptides representing relevant B-cell epitopes are, potentially, ideal antigens to be used in diagnostic assays because of their superior properties with respect to quality control as compared to those of biologically derived molecules and the much higher specificity that sometimes can be

  12. Analysis of the Synthetic Jet

    Czech Academy of Sciences Publication Activity Database

    Dančová, Petra; Vít, Tomáš


    Roč. 2, č. 1 (2009), s. 11-17 ISSN 1803-0203 R&D Projects: GA AV ČR(CZ) IAA200760801 Institutional research plan: CEZ:AV0Z20760514 Keywords : synthetic jet * actuator * nominal frequency Subject RIV: BJ - Thermodynamics

  13. Methods for preparing synthetic freshwaters. (United States)

    Smith, E J; Davison, W; Hamilton-Taylor, J


    Synthetic solutions that emulate the major ion compositions of natural waters are useful in experiments aimed at understanding biogeochemical processes. Standard recipes exist for preparing synthetic analogues of seawater, with its relatively constant composition, but, due to the diversity of freshwaters, a range of compositions and recipes is required. Generic protocols are developed for preparing synthetic freshwaters of any desired composition. The major problems encountered in preparing hard and soft waters include dissolving sparingly soluble calcium carbonate, ensuring that the ionic components of each concentrated stock solution cannot form an insoluble salt and dealing with the supersaturation of calcium carbonate in many hard waters. For acidic waters the poor solubility of aluminium salts requires attention. These problems are overcome by preparing concentrated stock solutions according to carefully designed reaction paths that were tested using a combination of experiment and equilibrium modeling. These stock solutions must then be added in a prescribed order to prepare a final solution that is brought into equilibrium with the atmosphere. The example calculations for preparing hard, soft and acidic freshwater surrogates with major ion compositions the same as published analyses, are presented in a generalized fashion that should allow preparation of any synthetic freshwater according to its known analysis.

  14. Sex Chromosome Dosage Compensation in Heliconius Butterflies: Global yet Still Incomplete? (United States)

    Walters, James R; Hardcastle, Thomas J; Jiggins, Chris D


    The evolution of heterogametic sex chromosomes is often-but not always-accompanied by the evolution of dosage compensating mechanisms that mitigate the impact of sex-specific gene dosage on levels of gene expression. One emerging view of this process is that such mechanisms may only evolve in male-heterogametic (XY) species but not in female-heterogametic (ZW) species, which will consequently exhibit "incomplete" sex chromosome dosage compensation. However, recent results suggest that at least some Lepidoptera (moths and butterflies) may prove to be an exception to this prediction. Studies in bombycoid moths indicate the presence of a chromosome-wide epigenetic mechanism that effectively balances Z chromosome gene expression between the sexes by reducing Z-linked expression in males. In contrast, strong sex chromosome dosage effects without any reduction in male Z-linked expression were previously reported in a pyralid moth, suggesting a lack of any such dosage compensating mechanism. Here we report an analysis of sex chromosome dosage compensation in Heliconius butterflies, sampling multiple individuals for several different adult tissues (head, abdomen, leg, mouth, and antennae). Methodologically, we introduce a novel application of linear mixed-effects models to assess dosage compensation, offering a unified statistical framework that can estimate effects specific to chromosome, to sex, and their interactions (i.e., a dosage effect). Our results show substantially reduced Z-linked expression relative to autosomes in both sexes, as previously observed in bombycoid moths. This observation is consistent with an increasing body of evidence that some lepidopteran species possess an epigenetic dosage compensating mechanism that reduces Z chromosome expression in males to levels comparable with females. However, this mechanism appears to be imperfect in Heliconius, resulting in a modest dosage effect that produces an average 5-20% increase in male expression relative

  15. Influence of dosage form on the intravitreal pharmacokinetics of diclofenac. (United States)

    Durairaj, Chandrasekar; Kim, Stephen J; Edelhauser, Henry F; Shah, Jaymin C; Kompella, Uday B


    To prepare a suspension form of diclofenac and compare the influence of the injected form (suspension versus solution) on the intravitreal pharmacokinetics of diclofenac in Dutch belted pigmented rabbits. Diclofenac acid was prepared and characterized in a suspension formulation. Rabbit eyes were injected with either diclofenac sodium solution (0.3 mg) or diclofenac acid suspension (10 mg) prepared in 0.1 mL balanced salt solution. Rabbits were killed at regular time intervals, the eyes enucleated, and drug content quantified in the vitreous humor and retina-choroid tissue by high-performance liquid chromatography. Pharmacokinetic models were developed for both the dosage forms, and simulations were performed for different doses. Diclofenac acid with an approximate 5-mum particle size exhibited 3.5-fold lower solubility in vitreous humor, when compared with its sodium salt. The estimated settling velocity of the suspension in the vitreous humor was 3 cm/h. After diclofenac sodium salt solution injection, drug levels declined rapidly with no drug levels detectable after 24 hours in the vitreous humor and 4 hours in the RC. Throughout the assessed time course, drug levels were higher in the vitreous. However, sustained, high drug levels were observed in both the vitreous humor and the retina-choroid even on day 21 after diclofenac acid suspension injection, with retina-choroid drug levels being higher beginning at 0.25 hour. The elimination half-life of diclofenac suspension was 24 and 18 days in vitreous and retina-choroid, respectively, compared to 2.9 and 0.9 hours observed with diclofenac sodium. The pharmacokinetic models developed indicated a slow-release distribution or depot compartment for the diclofenac acid suspension in the posterior segment. Simulations indicated the inability of a 10-mg dose of diclofenac sodium solution to sustain drug levels in the vitreous beyond 11 days. By choosing a less soluble form of a drug such as diclofenac acid, vitreous

  16. Can Telescopes Help Leo Satellites Dodge Most Lethal Impacts? (United States)

    GUDIEL, ANDREA; Carroll, Joseph; Rowe, David


    Authors: Joseph Carroll and David RoweABSTRACT LEO objects are tracked by radar because it works day and night, in all weather. This fits military interest in potentially hostile objects. There is less interest in objects too small to be credible active threats. But accidental hypervelocity impact by even 5-10 mm objects can disable most LEO satellites. Such “cm-class” objects greatly outnumber objects of military interest, and will cause most accidental impact losses.Under good viewing conditions, a sunlit 5mm sphere with 0.15 albedo at 800 km altitude is a 19th magnitude object. A ground-based 0.5m telescope tracking it against a 20 mag/arcsec2 sky can see it in seconds, and provide population can be tracked frequently, accurately, and affordably enough to be avoided. The value of a conjunction warning service should scale with the number of lethal objects in its catalog. This should motivate a commercial service to find and catalog most lethal objects. There may already be >1 million such objects in LEO, nearly all debris fragments, mostly cm-class and at 600-1200 km altitude.Maintaining a ~million-item catalog requires a world-wide network of several dozen telescope sites with several telescopes at each site. Each telescope needs a mount capable of ~1,000,000 fast slews/year without wearing out.The paper discusses recent advances that make such a service far more feasible:1. Automated tasking and remote control of distributed telescope networks,2. Direct-drive mounts that can make millions of fast slews without wearing out,3. Telescope optics with low focal curvature that are in focus across large imagers,4. CMOS imagers with 95% peak QE and 1.5e- noise at 2E8 pix/sec readout rates,5. Methods for uncued detection of most lethal LEO debris (eg., >5 mm at 800 km),6. Initial orbit determination using 3 alt-az fixes made during the discovery pass,7. High-speed photometry to infer debris spin axis, to predict drag area changes,8. Better conjunction predictions

  17. Protease-sensitive synthetic prions.

    Directory of Open Access Journals (Sweden)

    David W Colby


    Full Text Available Prions arise when the cellular prion protein (PrP(C undergoes a self-propagating conformational change; the resulting infectious conformer is designated PrP(Sc. Frequently, PrP(Sc is protease-resistant but protease-sensitive (s prions have been isolated in humans and other animals. We report here that protease-sensitive, synthetic prions were generated in vitro during polymerization of recombinant (rec PrP into amyloid fibers. In 22 independent experiments, recPrP amyloid preparations, but not recPrP monomers or oligomers, transmitted disease to transgenic mice (n = 164, denoted Tg9949 mice, that overexpress N-terminally truncated PrP. Tg9949 control mice (n = 174 did not spontaneously generate prions although they were prone to late-onset spontaneous neurological dysfunction. When synthetic prion isolates from infected Tg9949 mice were serially transmitted in the same line of mice, they exhibited sPrP(Sc and caused neurodegeneration. Interestingly, these protease-sensitive prions did not shorten the life span of Tg9949 mice despite causing extensive neurodegeneration. We inoculated three synthetic prion isolates into Tg4053 mice that overexpress full-length PrP; Tg4053 mice are not prone to developing spontaneous neurological dysfunction. The synthetic prion isolates caused disease in 600-750 days in Tg4053 mice, which exhibited sPrP(Sc. These novel synthetic prions demonstrate that conformational changes in wild-type PrP can produce mouse prions composed exclusively of sPrP(Sc.

  18. Parental response to severe or lethal prenatal diagnosis

    DEFF Research Database (Denmark)

    Lou, Stina; Jensen, Lotte Groth; Petersen, Olav Bjørn


    . Prospective parents who continued the pregnancy wished to be acknowledged as parents, and engaged in planning to obtain a sense of meaning and control. Selective disclosure and concerns about negative responses were issues both for the parents who terminated and those who continued a pregnancy. Conclusion......Objective A severe or lethal prenatal diagnosis places great demands on prospective parents, who face choices of far-reaching consequences, such as continuing or terminating the pregnancy. How best to support these parents is a clinical challenge. This systematic review aimed to identify...... and synthesize the qualitative evidence regarding prospective parents’ responses to such prenatal diagnoses. Methods Following PRISMA guidelines, four databases were systematically searched and 28 studies met the inclusion criteria. Thematic analysis guided data extraction and synthesis of findings. The CERQual...

  19. Autotaxin overexpression causes embryonic lethality and vascular defects.

    Directory of Open Access Journals (Sweden)

    Hiroshi Yukiura

    Full Text Available Autotaxin (ATX is a secretory protein, which converts lysophospholipids to lysophosphatidic acid (LPA, and is essential for embryonic vascular formation. ATX is abundantly detected in various biological fluids and its level is elevated in some pathophysiological conditions. However, the roles of elevated ATX levels remain to be elucidated. In this study, we generated conditional transgenic (Tg mice overexpressing ATX and examined the effects of excess LPA signalling. We found that ATX overexpression in the embryonic period caused severe vascular defects and was lethal around E9.5. ATX was conditionally overexpressed in the neonatal period using the Cre/loxP system, which resulted in a marked increase in the plasma LPA level. This resulted in retinal vascular defects including abnormal vascular plexus and increased vascular regression. Our findings indicate that the ATX level must be carefully regulated to ensure coordinated vascular formation.

  20. Autotaxin Overexpression Causes Embryonic Lethality and Vascular Defects (United States)

    Yukiura, Hiroshi; Kano, Kuniyuki; Kise, Ryoji; Inoue, Asuka; Aoki, Junken


    Autotaxin (ATX) is a secretory protein, which converts lysophospholipids to lysophosphatidic acid (LPA), and is essential for embryonic vascular formation. ATX is abundantly detected in various biological fluids and its level is elevated in some pathophysiological conditions. However, the roles of elevated ATX levels remain to be elucidated. In this study, we generated conditional transgenic (Tg) mice overexpressing ATX and examined the effects of excess LPA signalling. We found that ATX overexpression in the embryonic period caused severe vascular defects and was lethal around E9.5. ATX was conditionally overexpressed in the neonatal period using the Cre/loxP system, which resulted in a marked increase in the plasma LPA level. This resulted in retinal vascular defects including abnormal vascular plexus and increased vascular regression. Our findings indicate that the ATX level must be carefully regulated to ensure coordinated vascular formation PMID:25992708

  1. In vitro cell culture lethal dose submitted to gamma radiation

    International Nuclear Information System (INIS)

    Moreno, Carolina S.; Rogero, Sizue O.; Rogero, Jose Roberto; Ikeda, Tamiko I.; Cruz, Aurea S.


    The present study was designed to evaluate the in vitro effect of gamma radiation in cell culture of mouse connective tissue exposed to different doses of gamma radiation and under several conditions. The cell viability was analyzed by neutral red uptake methodology. This assay was developed for establish a methodology to be used in the future in the study of resveratrol radioprotection. Resveratrol (3,4',5- trihydroxystilbene), a phenolic phytoalexin that occurs naturally in some spermatophytes, such as grapevines, in response to injury as fungal infections and exposure to ultraviolet light. In the wines this compound is found at high levels and is considered one of the highest antioxidant constituents. The intense antioxidant potential of resveratrol provides many pharmacological activities including cardioprotection, chemoprevention and anti-tumor effects. Our results demonstrated that 60 Co gamma radiation lethal dose (LD50) on NCTC clone 929 cells was about 340Gy. (author)

  2. Radiation-induced mutagenicity and lethality in Salmonella typhimurium

    International Nuclear Information System (INIS)

    Isildar, M.; Bakale, G.


    The mutagenic and lethal effects of ionizing radiation on histidine-deficient auxotrophs of Salmonella typhimurium were studied to improve the understanding of radiation damage to DNA. The auxotrophs were divided into two groups - one which is sensitive to base-pair substitutions and another sensitive to frameshifts. These groups were composed of parent-daughter pairs in which the chemical mutagenicity enhancing plasmid, pKM101, is absent in the parent strain and present in the daughter. Co-60 #betta#-radiation and 250 kV x-rays were used to irradiate the bacteria. Irradiation of the frameshift - sensitive strains which carry the pKm101 plasmid doubled the absolute number of induced revertants whereas irradiation of the base-pair substitution sensitive strain which also carries the pKm101 plasmid produced nearly no change in the number of induced revertants. A nearly negligible effect on the mutation rate was observed for all parent strains

  3. Gastrointestinal decontamination in healthy and lethally irradiated monkeys

    International Nuclear Information System (INIS)

    Hendriks, W.D.H.


    In periods of extreme immunosuppression, infections which are often life-threatening, frequently occur. In an attempt to prevent such infections in lethally irradiated rhesus monkeys, the animals were subjected to strict reverse isolation prior to irradiation and administrated orally with nonabsorbable antibiotics in order to eliminate their microflora. The antibiotic combination was selected on the basis of a sensitivity test and was added to the liquid food supply. To rapidly achieve a high bactericidal concentration in the intestine, the same antibiotics were additionally given orally for 5 days. The microflora was reduced rapidly; within a few days sterile cultures were obtained. Particularly after discontinuation of the administration of the additional antibiotics were colonizations found. In contrast to colonizations persisting from the first day of treatment on, the first were rather easy to suppress. (Auth.)

  4. Lethal intragroup aggression by adult male spider monkeys (Ateles geoffroyi). (United States)

    Campbell, Christina J


    I report three cases of coalitionary aggression by adult male black-handed spider monkeys (Ateles geoffroyi) against subadult males within their community on Barro Colorado Island (BCI), Panama. Two of these cases were followed by the disappearance and presumed death of the victim. Similar behavior was recently reported by Valero et al. [in press], who suggested that this behavior may be the result of intense male reproductive competition. Like the single instance they reported, the cases I report all occurred when the operational sex ratio was approximately 1:1, which suggests that intense competition among males for access to reproductively viable females may be a contributing factor. Additionally the very low density of spider monkeys on BCI may play a significant role in the occurrence of this lethal aggression. Large numbers of adult males are not necessary to protect a territorial boundary against neighboring groups, and additional males may act merely as mating competition. (c) 2006 Wiley-Liss, Inc.

  5. A novel poxvirus lethal to red squirrels (Sciurus vulgaris). (United States)

    Thomas, Kathryn; Tompkins, Daniel M; Sainsbury, Anthony W; Wood, Ann R; Dalziel, Robert; Nettleton, Peter F; McInnes, Colin J


    A parapoxvirus has been implicated in the decline of the red squirrel in the United Kingdom. Virus was isolated from an outbreak of lethal disease in red squirrels in the north-east of England. Experimental infection of captive-bred red squirrels confirmed that this virus was the cause of the severe skin lesions observed. Electron microscopic examination of the virus showed that it had a morphology typical of parapoxviruses whilst preliminary sequence data suggested a genomic G+C composition of approximately 66 %, again similar to that found in other parapoxviruses. However Southern hybridization analysis failed to detect three known parapoxvirus genes, two of which have been found so far only in the genus parapoxvirus. Comparative sequence analysis of two other genes, conserved across the eight recognized chordopoxvirus genera, suggests that the squirrel virus represents a previously unrecognized genus of the chordopoxvirus.

  6. Mechanisms of Lethal Cerebrovascular Accidents in Turner Syndrome. (United States)

    Byard, Roger W


    A case of intracerebral hemorrhage in Turner syndrome is reported with an analysis of possible causes of cerebrovascular accidents in this condition. A 42-year-old woman with known Turner syndrome died soon after hospital admission having been found unconscious at her home address. At autopsy, she showed typical features of Turner syndrome with short stature, webbing of the neck, underdeveloped breasts, and an increased carrying angle of the arm. Death was due to a large left-sided intracerebral hemorrhage extending from the left basal ganglia into the white matter of the frontal lobe and lateral ventricle. Cases of unexpected death in Turner syndrome may arise from occult cerebrovascular accidents which may be hemorrhagic or nonhemorrhagic. Associated features include hypertension, vascular malformations, accelerated atherogenesis, cystic medial necrosis, and moyamoya syndrome. The possibility of Turner syndrome should be considered in cases where there has been a lethal cerebrovascular event in a younger woman. © 2016 American Academy of Forensic Sciences.

  7. Evaluation of Lethal Giant Larvae as a Schistosomiasis Vaccine Candidate

    Directory of Open Access Journals (Sweden)

    Yufan Cao


    Full Text Available Schistosomiasis is a neglected tropical disease of humans, and it is considered to be the second most devastating parasitic disease after malaria. Eggs produced by normally developed female worms are important in the transmission of the parasite, and they responsible for the pathogenesis of schistosomiasis. The tumor suppressor gene lethal giant larvae (lgl has an essential function in establishing apical-basal cell polarity, cell proliferation, differentiation, and tissue organization. In our earlier study, downregulation of the lgl gene induced a significant reduction in the egg hatching rate of Schistosoma japonicum (Sj eggs. In this study, the Sjlgl gene was used as a vaccine candidate against schistosomiasis, and vaccination achieved and maintained a stable reduction of the egg hatching rate, which is consistent with previous studies, in addition to reducing the worm burden and liver egg burden in some trials.

  8. 76 FR 81806 - Ophthalmic and Topical Dosage Form New Animal Drugs; Ivermectin Topical Solution (United States)


    .... FDA-2011-N-0003] Ophthalmic and Topical Dosage Form New Animal Drugs; Ivermectin Topical Solution... solution of ivermectin. DATES: This rule is effective December 29, 2011. FOR FURTHER INFORMATION CONTACT... ANADA 200-318 for [[Page 81807

  9. Low-dosage helical CT applications for chest medical checkup and lung cancer screening

    International Nuclear Information System (INIS)

    Wang Ping; Cui Fa; Liang Huanqing; Zheng Minfei


    Objective: A discussion on low-dosage helical CT applications on chest medical checkup and lung cancer screening. Methods: On the 100 chest medical check up with three different of protocols, including standard-dosage (the tube current was 230 mAs) were compared with low-dose (tube current was 50 mAs or 30 mAs). Results: Low-dosage helical CT scan provides excellent images. In 100 chest medical checkup, 39 nodules or masses were revealed, enlarged lymph node was noted in 1 case; emphysema or bullae was demonstrated in 3 segments; thickening of bronchial wall was shown in 2 cases; and localized pleural thickening was found in 1 case. Conclusion: In chest checkup or lung cancer screening low-dosage helical CT (tube current 30 mAs) will not only guarantee image quality but also reduce the radiation dose during the examination. (authors)

  10. Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Proguanil Hydrochloride.

    NARCIS (Netherlands)

    Plöger, Gerlinde F; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D I R K W; Langguth, Peter; Mehta, Mehul U; Parr, Alan; Polli, James E; Shah, Vinod P; Tajiri, Tomokazu; Dressman, Jennifer B


    Literature data relevant to the decision to waive in vivo bioequivalence testing for the approval of generic immediate release solid oral dosage forms of proguanil hydrochloride are reviewed. To clarify the Biopharmaceutics Classification System (BCS) classification, experimental solubility and

  11. A study on the effects of ozone dosage on dissolved-ozone flotation (DOF) process performance. (United States)

    Jin, Xin; Jin, Pengkang; Wang, Xiaochang


    Dissolved-ozone flotation (DOF) is a tertiary wastewater treatment process, which combines ozonation and flotation. In this paper, a pilot-scale DOF system fed by secondary effluent from a wastewater treatment plant (WWTP) in China was used to study the effect of ozone dosage on the DOF process performance. The results show that an ozone dosage could affect the DOF performance to a large extent in terms of color and organic matter removal as well as disinfection performance. The optimal color and organic matter removal was achieved at an ozone dosage of 0.8 mg/l. For disinfection, significant improvement in performance could be achieved only when the organic matter removal was optimal. The optimal ozone dosage of at least 1.6 mg/l was put forward, in this case, in order to achieve the optimal color, turbidity, organic matter and disinfection performance.

  12. [Formal requirements and a cultural approach to the control of slow-release dosage forms]. (United States)

    Ciranni Signoretti, E


    Problems related with controlled release dosage forms are reported. The need for a standard criteria regarding both nomenclature and dissolution test is pointed out. The purpose is to permit a suitable control of the controlled release characteristics.

  13. Clinical criteria for medical staff exposure and reference dosage within the Galician health Service

    International Nuclear Information System (INIS)

    Garcia Comesana, J.


    The generalised use of ionising radiation tests is making these tests become the prime cause of exposure to artificial radiation, receiving one sixth of the dosage through background radiation. (Author)

  14. Evaluating the lethal and pre-lethal effects of a range of fungi against adult Anopheles stephensi mosquitoes

    Directory of Open Access Journals (Sweden)

    Blanford Simon


    Full Text Available Abstract Background Insecticide resistance is seriously undermining efforts to eliminate malaria. In response, research on alternatives to the use of chemical insecticides against adult mosquito vectors has been increasing. Fungal entomopathogens formulated as biopesticides have received much attention and have shown considerable potential. This research has necessarily focused on relatively few fungal isolates in order to ‘prove concept’. Further, most attention has been paid to examining fungal virulence (lethality and not the other properties of fungal infection that might also contribute to reducing transmission potential. Here, a range of fungal isolates were screened to examine variation in virulence and how this relates to additional pre-lethal reductions in feeding propensity. Methods The Asian malaria vector, Anopheles stephensi was exposed to 17 different isolates of entomopathogenic fungi belonging to species of Beauveria bassiana, Metarhizium anisopliae, Metarhizium acridum and Isaria farinosus. Each isolate was applied to a test substrate at a standard dose rate of 1×109 spores ml-1 and the mosquitoes exposed for six hours. Subsequently the insects were removed to mesh cages where survival was monitored over the next 14 days. During this incubation period the mosquitoes’ propensity to feed was assayed for each isolate by offering a feeding stimulant at the side of the cage and recording the number probing. Results and conclusions Fungal isolates showed a range of virulence to A. stephensi with some causing >80% mortality within 7 days, while others caused little increase in mortality relative to controls over the study period. Similarly, some isolates had a large impact on feeding propensity, causing >50% pre-lethal reductions in feeding rate, whereas other isolates had very little impact. There was clear correlation between fungal virulence and feeding reduction with virulence explaining nearly 70% of the variation in

  15. Pharmacokinetic and pharmacodynamic differences between two low dosages of aspirin may affect therapeutic outcomes. (United States)

    Cerletti, Chiara; Dell'Elba, Giuseppe; Manarini, Stefano; Pecce, Romina; Di Castelnuovo, Augusto; Scorpiglione, Nicola; Feliziani, Vincenzo; de Gaetano, Giovanni


    Meta-analyses of the prevention of major vascular events by aspirin suggest therapeutic equivalence of all dosages. However, the optimal dosage still remains problematic, and a recent trial found aspirin 160 mg/day to be more effective than 80 mg/day for secondary prevention of ischaemic stroke. To evaluate two low dosages of aspirin in terms of pharmacokinetics and pharmacodynamics (inhibition of platelet thromboxane generation and urinary excretion of thromboxane and prostacyclin metabolites). A randomised cross-over study was performed in 16 healthy volunteers (9 women and 7 men, 33.8 +/- 5.1 years old) given enteric-coated aspirin 80 or 160 mg/day for 7 days. Plasma concentrations of salicylate and aspirin were measured by high-performance liquid chromatography (HPLC) after both the first and the last dose (days 1 and 7). The usual pharmacokinetic parameters were then derived. Serum thromboxane B2 (TxB2) was measured by radioimmunoassay. The urinary excretion of 11-dehydro-TxB2 and 2,3-dinor-6-keto-prostaglandin F1alpha were measured on 8-hour urine samples by immunoassay after extraction and HPLC separation, both before and after 7 days of drug administration. With the 160 mg dosage, but not with the 80 mg dosage, higher concentrations of aspirin were found at day 7 compared with day 1. For aspirin 80 mg/day, 24-hour area under the concentration-time curve (AUC24) was similar on days 1 and 7 (569 +/- 339 vs 605 +/- 377 microg. h/L), but increased from 904 +/- 356 microg. h/L on day 1 to 1355 +/- 883 microg. h/L on day 7 with the higher dosage. Similarly, the AUC24 for salicylate was similar on days 1 and 7 with the lower dosage, but significantly increased from day 1 to day 7 after the higher dosage. This paralleled inhibition of serum TxB2 levels (99% vs 95% average inhibition by 160 and 80 mg/day) and of urinary excretion of thromboxane metabolite (77% vs 61% average inhibition by 160 and 80 mg/day), without altering the excretion of prostacyclin metabolite

  16. [Study on dosage rules of Aconitum herbs in oral prescriptions based on efficacy-toxicity relation]. (United States)

    Zhang, Xiao-Meng; Lin, Zhi-Jian; Li, Fan; Zhang, Bing; Guo, Xiao-Xin; Yang, Le


    Based on the relation of efficacy and toxicity, this study mined the dosage rules and characteristics of Aconitum herbs in oral prescriptions from 48 traditional ancient books from Eastern Han dynasty to Qing dynasty, to provide the basis for strengthening the clinical risk pharmacovigilance. In the 48 traditional ancient books, 4 521 prescriptions with clear daily oral dosage were included to establish a database. SPSS 20.0 software was used for statistics and analysis of the daily dosage characteristics with different kinds of herbs, indications, dose forms, processing, use in special population, and other aspects. The results showed that 67% prescriptions contained Aconitum carmichaeli(Fuzi), and 90% of them was less than 14.87 g·d⁻¹; The dosage of A. carmichaeli(Chuanwu) and A. kusnezoffii(Caowu) were less than 3.14 g·d⁻¹. In the prescriptions for treating typhoid, epidemic, edema and phlegm, the dosage of Aconitum was larger. There dosage in the decoction and vinum was significantly higher than that in the pill and powder. With the dynastic evolution, the dosage of Aconitum herbal medicines prescriptions and the application percentage of superposition drug also had decreased. For the special populations that with different metabolism process, such as old people, children, pregnant and lactating women, the application of Aconitum was not only with relatively small ratio, but also with lower dose. Therefore, based on the data-mining of ancient books, the dosage of Aconitum should not exceed the limit prescribed by the current China Pharmacopoeia, and also should be strictly controlled by considering various factors, which will ensure the balance of efficacy and toxicity. Copyright© by the Chinese Pharmaceutical Association.

  17. Methotrexate Dosage Reduction Upon Adalimumab Initiation: Clinical and Ultrasonographic Outcomes from the Randomized Noninferiority MUSICA Trial. (United States)

    Kaeley, Gurjit S; Evangelisto, Amy M; Nishio, Midori J; Goss, Sandra L; Liu, Shufang; Kalabic, Jasmina; Kupper, Hartmut


    To examine the clinical and ultrasonographic (US) outcomes of reducing methotrexate (MTX) dosage upon initiating adalimumab (ADA) in MTX-inadequate responders with moderately to severely active rheumatoid arthritis (RA). MUSICA (NCT01185288) was a double-blind, randomized, parallel-arm study of 309 patients with RA receiving MTX ≥ 15 mg/week for ≥ 12 weeks before screening. Patients were randomized to high dosage (20 mg/week) or low dosage (7.5 mg/week) MTX; all patients received 40 mg open-label ADA every other week for 24 weeks. The primary endpoint was Week 24 mean 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) to test for noninferiority of low-dosage MTX using a 15% margin. US images were scored using a 10-joint semiquantitative system incorporating OMERACT definitions for pathology, assessing synovial hypertrophy, vascularity, and bony erosions. Rapid improvement in clinical indices was observed in both groups after addition of ADA. The difference in mean DAS28-CRP (0.37, 95% CI 0.07-0.66) comparing low-dosage (4.12, 95% CI 3.88-4.34) versus high-dosage MTX (3.75, 95% CI 3.52-3.97) was statistically significant and non-inferiority was not met. Statistically significant differences were not detected for most clinical, functional, and US outcomes. Pharmacokinetic and safety profiles were similar. In MUSICA, Week 24 mean DAS28-CRP, the primary endpoint, did not meet non-inferiority for the low-dosage MTX group. Although the differences between the 2 MTX dosage groups were small, our study findings did not support routine MTX reduction in MTX inadequate responders initiating ADA.

  18. Efficiency of individual dosage of digoxin with calculated concentration

    Directory of Open Access Journals (Sweden)

    Zhao L


    digoxin and creatinine clearance, our results show that although there was a significant correlation between clearance of digoxin and creatinine clearance in the group overall, correlations were not evident within the different stages of renal function.Conclusion: The results of this study indicate that clearance of digoxin and the creatinine clearance rate cannot be explained by renal function alone and that the validity of the Konishi equation for individualizing the digoxin dosage in Chinese patients is limited, being applicable only in stage 3 renal disease. Further research in larger numbers of patients across all stages of renal function will be required in the future to verify the original Konishi model. Keywords: serum digoxin concentration, predicted concentration, renal insufficiency

  19. Evolution of Dosage Compensation in Anolis carolinensis, a Reptile with XX/XY Chromosomal Sex Determination (United States)

    Rupp, Shawn M.; Webster, Timothy H.; Olney, Kimberly C.; Hutchins, Elizabeth D.; Kusumi, Kenro


    In species with highly heteromorphic sex chromosomes, the degradation of one of the sex chromosomes will result in unequal gene expression between the sexes (e.g. between XX females and XY males) and between the sex chromosomes and the autosomes. Dosage compensation is a process whereby genes on the sex chromosomes achieve equal gene expression. We compared genome-wide levels of transcription between males and females, and between the X chromosome and the autosomes in the green anole, Anolis carolinensis. We present evidence for dosage compensation between the sexes, and between the sex chromosomes and the autosomes. When dividing the X chromosome into regions based on linkage groups, we discovered that genes in the first reported X-linked region, anole linkage group b (LGb), exhibit complete dosage compensation, although the rest of the X-linked genes exhibit incomplete dosage compensation. Our data further suggest that the mechanism of this dosage compensation is upregulation of the X chromosome in males. We report that approximately 10% of coding genes, most of which are on the autosomes, are differentially expressed between males and females. In addition, genes on the X chromosome exhibited higher ratios of nonsynonymous to synonymous substitution than autosomal genes, consistent with the fast-X effect. Our results from the green anole add an additional observation of dosage compensation in a species with XX/XY sex determination. PMID:28206607

  20. Synthetic LDL as targeted drug delivery vehicle (United States)

    Forte, Trudy M [Berkeley, CA; Nikanjam, Mina [Richmond, CA


    The present invention provides a synthetic LDL nanoparticle comprising a lipid moiety and a synthetic chimeric peptide so as to be capable of binding the LDL receptor. The synthetic LDL nanoparticle of the present invention is capable of incorporating and targeting therapeutics to cells expressing the LDL receptor for diseases associated with the expression of the LDL receptor such as central nervous system diseases. The invention further provides methods of using such synthetic LDL nanoparticles.

  1. Synthetic biology character and impact

    CERN Document Server

    Pade, Christian; Wigger, Henning; Gleich, Arnim


    Synthetic Biology is already an object of intensive debate. However, to a great extent the discussion to date has been concerned with fundamental ethical, religious and philosophical questions. By contrast, based on an investigation of the field’s scientific and technological character, this book focuses on new functionalities provided by synthetic biology and explores the associated opportunities and risks. Following an introduction to the subject and a discussion of the most central paradigms and methodologies, the book provides an overview of the structure of this field of science and technology. It informs the reader about the current stage of development, as well as topical problems and potential opportunities in important fields of application. But not only the science itself is in focus. In order to investigate its broader impact, ecological as well as ethical implications will be considered, paving the way for a discussion of responsibilities in the context of a field at a transitional crossroads be...

  2. Design Automation in Synthetic Biology. (United States)

    Appleton, Evan; Madsen, Curtis; Roehner, Nicholas; Densmore, Douglas


    Design automation refers to a category of software tools for designing systems that work together in a workflow for designing, building, testing, and analyzing systems with a target behavior. In synthetic biology, these tools are called bio-design automation (BDA) tools. In this review, we discuss the BDA tools areas-specify, design, build, test, and learn-and introduce the existing software tools designed to solve problems in these areas. We then detail the functionality of some of these tools and show how they can be used together to create the desired behavior of two types of modern synthetic genetic regulatory networks. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  3. Engineering Ecosystems and Synthetic Ecologies# (United States)

    Mee, Michael T; Wang, Harris H


    Microbial ecosystems play an important role in nature. Engineering these systems for industrial, medical, or biotechnological purposes are important pursuits for synthetic biologists and biological engineers moving forward. Here, we provide a review of recent progress in engineering natural and synthetic microbial ecosystems. We highlight important forward engineering design principles, theoretical and quantitative models, new experimental and manipulation tools, and possible applications of microbial ecosystem engineering. We argue that simply engineering individual microbes will lead to fragile homogenous populations that are difficult to sustain, especially in highly heterogeneous and unpredictable environments. Instead, engineered microbial ecosystems are likely to be more robust and able to achieve complex tasks at the spatial and temporal resolution needed for truly programmable biology. PMID:22722235

  4. Synthetic greenhouse gases under control

    International Nuclear Information System (INIS)

    Horisberger, B.; Karlaganis, G.


    This article discusses new Swiss regulations on the use of synthetic materials that posses a considerable greenhouse-warming potential. Synthetic materials such as hydro-chlorofluorocarbons HCFCs, perfluoride-hydrocarbons and sulphur hexafluoride have, in recent years, replaced chlorofluorocarbons CFCs, which were banned on account of their ozone depletion characteristics. The use of these persistent substances is now being limited to applications where more environment-friendly alternatives are not available. The measures decreed in the legislation, which include a general ban on HCFCs as of 2004 and a ban on the export of installations and equipment that use ozone-depleting refrigerants are described. Details on the legislation's effects on the Swiss refrigeration industry are listed and discussed

  5. Compounding in synthetic aperture imaging

    DEFF Research Database (Denmark)

    Hansen, J. M.; Jensen, J. A.


    from multiple spherical emissions to synthesize multiple transmit and receive apertures, corresponding to imaging the tissue from multiple directions. The many images are added incoherently, to produce a single compound image. Using a 192-element, 3.5-MHz, λ-pitch transducer, it is demonstrated from...... tissue-phantom measurements that the speckle is reduced and the contrast resolution improved when applying synthetic aperture compound imaging. At a depth of 4 cm, the size of the synthesized apertures is optimized for lesion detection based on the speckle information density. This is a performance...... measure for tissue contrast resolution which quantifies the tradeoff between resolution loss and speckle reduction. The speckle information density is improved by 25% when comparing synthetic aperture compounding to a similar setup for compounding using dynamic receive focusing. The cystic resolution...

  6. Characterization of Synthetic Peptides by Mass Spectrometry. (United States)

    Prabhala, Bala K; Mirza, Osman; Højrup, Peter; Hansen, Paul R


    Mass spectrometry (MS) is well suited for analysis of the identity and purity of synthetic peptides. The sequence of a synthetic peptide is most often known, so the analysis is mainly used to confirm the identity and purity of the peptide. Here, simple procedures are described for MALDI-TOF-MS and LC-MS of synthetic peptides.

  7. Synthetic thermoelectric materials comprising phononic crystals (United States)

    El-Kady, Ihab F; Olsson, Roy H; Hopkins, Patrick; Reinke, Charles; Kim, Bongsang


    Synthetic thermoelectric materials comprising phononic crystals can simultaneously have a large Seebeck coefficient, high electrical conductivity, and low thermal conductivity. Such synthetic thermoelectric materials can enable improved thermoelectric devices, such as thermoelectric generators and coolers, with improved performance. Such synthetic thermoelectric materials and devices can be fabricated using techniques that are compatible with standard microelectronics.

  8. Steel desulphurization with synthetic slag

    Energy Technology Data Exchange (ETDEWEB)

    Heput, T.; Ardelean, E.; Socalici, A.; Maksay, S.; Gavanescu, A.


    Generally speaking, sulfur is considered a harmful element for steel quality, reason why all the technological steps are being taken in order to eliminate it from the metal bath. This paper deals with the influence of the chemical composition, on the slag quantity and of the batch stirring condition upon the desulfurization process in the casting ladle by treatment with synthetic slag. The experiments were made at an open-hearth plant with the steel tapping in two ladles (the desulfurization was made with synthetic slag at one ladle while the other one was considered standard) and at the electric steel plant and for the synthetic slag formation a mix was used, made, according to several receipts, of : lime (50-75%), fluorine (0-17%); bauxite (0-32%) and aluminous slag (8-22%). The data were processed in the calculation programs EXCEL and MATLAB, which resulted in a series of correlations between the desulfurization degree and the chemical composition of the slag, respectively the slag quantity both for the charges bubbled with Argon and the un bubbled ones. (Author) 5 refs.

  9. Hydrogen speciation in synthetic quartz (United States)

    Aines, R.D.; Kirby, S.H.; Rossman, G.R.


    The dominant hydrogen impurity in synthetic quartz is molecular H2O. H-OH groups also occur, but there is no direct evidence for the hydrolysis of Si-O-Si bonds to yield Si-OH HO-Si groups. Molecular H2O concentrations in the synthetic quartz crystals studied range from less than 10 to 3,300 ppm (H/Si), and decrease smoothly by up to an order of magnitude with distance away from the seed. OH- concentrations range from 96 to 715 ppm, and rise smoothly with distance away from the seed by up to a factor of three. The observed OH- is probably all associated with cationic impurities, as in natural quartz. Molecular H2O is the dominant initial hydrogen impurity in weak quartz. The hydrolytic weakening of quartz may be caused by the transformation H2O + Si-O-Si ??? 2SiOH, but this may be a transitory change with the SiOH groups recombining to form H2O, and the average SiOH concentration remaining very low. Synthetic quartz is strengthened when the H2O is accumulated into fluid inclusions and cannot react with the quartz framework. ?? 1984 Springer-Verlag.

  10. An Internet Study of User's Experiences of the Synthetic Cathinone 4-Methylethcathinone (4-MEC). (United States)

    Van Hout, Marie Claire


    Abstract A synthetic cathinone called 4-methylethcathinone (4-MEC) emerged online in 2010, and was cyber-marketed to be a replacement for mephedrone. The study aimed to present user experiences of 4-MEC as reported on the Internet, with a focus on user profiles, sourcing and product characteristics, routes of administration, dosage, positive and undesirable effects, and comparisons to mephedrone. Twenty-three individual, anonymous trip reports of the sole use of 4-MEC, and 112 screenshots of general 4-MEC user discussion boards, were taken from a purposeful sample of public drug-related sites. A content textual analysis was conducted on extracted qualitative information and produced 41 categories compiled into five general themes: "Type of 4-MEC user"; "Sourcing, informed decision making, product characteristics, and quality assurance"; "Routes of administration, gauging of dosage, and consumption of other drugs"; "Time course effects and outcomes"; and "Comparisons with mephedrone." 4-MEC is sold as white beads, crystalline shards, or green balls. User motives centered on curiosity, pricing, and ease of web sourcing. Oral, nasal, injecting, eyeball, and rectal routes of administration were described. Testing for purity, "allergy testing," and gauging of dosage were common. Users described euphoric but short-lived effects, with little comedown. Continued research is vital to inform harm reduction.

  11. Crowd Behavior, Crowd Control, and the Use of Non-Lethal Weapons

    National Research Council Canada - National Science Library

    Kenny, John M; McPhail, Clark; Waddington, Peter; Heal, Sid; Ijames, Steve; Farrer, Donald N; Taylor, Jim; Odenthal, Dick


    .... This is a leading core capability sought by the Joint Non-lethal Weapons Program. The need to thoroughly examine crowd behavior grew out of the Panel's previous assessments of non-lethal weapons, which are being designed for crowd control...

  12. Acute-lethal toxicity (LC50) effect of Moringa oleifera (Lam.) Fresh ...

    African Journals Online (AJOL)


    aquaculture. This study assessed the acute-lethal toxicity (LC50) effect of Moringa oleifera fresh root-bark extract on fresh water fish, Oreochromis niloticus juveniles for 96-h under renewal toxicity exposure. Median. Lethal Concentration (LC50) for O. niloticus juvenile was 97.61 mgl-1 and high mortality was obtained at 200.

  13. Acute-lethal toxicity (LC 50 ) effect of Moringa oleifera (Lam.) Fresh ...

    African Journals Online (AJOL)

    Acute-lethal toxicity is a tool used in piscicide bio-safety assessment in fish farming prior to its proper application in sustainable aquaculture. Piscicides of plant origin are usually considered for bio-safety assessment because of their effects on non-target aquatic species in fish pond. Acute-lethal toxicity is an indication of ...

  14. Examining the Impact of Psychiatric Diagnosis and Comorbidity on the Medical Lethality of Adolescent "Suicide Attempts" (United States)

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


    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…

  15. 77 FR 6548 - Notice of Availability of Ballistic Survivability, Lethality and Vulnerability Analyses (United States)


    ... Department of the Army Notice of Availability of Ballistic Survivability, Lethality and Vulnerability... survivability, lethality and vulnerability (SLV) analyses. ARL/SLAD conducts SLV analyses, using the MUVES-S2 vulnerability model, to quantify system, subsystem and/or component level vulnerabilities of ground and air...

  16. Acute and sub-lethal response to mercury in Arctic and boreal calanoid copepods. (United States)

    Overjordet, Ida Beathe; Altin, Dag; Berg, Torunn; Jenssen, Bjørn Munro; Gabrielsen, Geir Wing; Hansen, Bjørn Henrik


    Acute lethal toxicity, expressed as LC50 values, is a widely used parameter in risk assessment of chemicals, and has been proposed as a tool to assess differences in species sensitivities to chemicals between climatic regions. Arctic Calanus glacialis and boreal Calanus finmarchicus were exposed to mercury (Hg(2+)) under natural environmental conditions including sea temperatures of 2° and 10°C, respectively. Acute lethal toxicity (96 h LC50) and sub-lethal molecular response (GST expression; in this article gene expression is used as a synonym of gene transcription, although it is acknowledged that gene expression is also regulated, e.g., at translation and protein stability level) were studied. The acute lethal toxicity was monitored for 96 h using seven different Hg concentrations. The sub-lethal experiment was set up on the basis of nominal LC50 values for each species using concentrations equivalent to 50, 5 and 0.5% of their 96 h LC50 value. No significant differences were found in acute lethal toxicity between the two species. The sub-lethal molecular response revealed large differences both in response time and the fold induction of GST, where the Arctic species responded both faster and with higher mRNA levels of GST after 48 h exposure. Under the natural exposure conditions applied in the present study, the Arctic species C. glacialis may potentially be more susceptible to mercury exposure on the sub-lethal level. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. The Danger Assessment: Validation of a Lethality Risk Assessment Instrument for Intimate Partner Femicide (United States)

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


    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…

  18. Foal with Overo lethal white syndrome born to a registered quarter horse mare


    Lightbody, Tamara


    A 16-hour-old white foal, born to a registered quarter horse mare, was examined for signs of colic. The foal had Overo lethal white syndrome, which causes ileocolonic agangliosis. This was confirmed by DNA testing. Since there is no treatment for Overo lethal white syndrome, the foal was euthanized.

  19. Foal with Overo lethal white syndrome born to a registered quarter horse mare. (United States)

    Lightbody, Tamara


    A 16-hour-old white foal, born to a registered quarter horse mare, was examined for signs of colic. The foal had Overo lethal white syndrome, which causes ileocolonic agangliosis. This was confirmed by DNA testing. Since there is no treatment for Overo lethal white syndrome, the foal was euthanized.

  20. Examining the impact of psychiatric diagnosis and comorbidity on the medical lethality of adolescent suicide attempts. (United States)

    McManama O'Brien, Kimberly H; Berzin, Stephanie C


    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 substance abuse. Regression results indicated having depression comorbid with any other diagnosis was not associated with medical lethality. However, having a substance abuse disorder was associated with higher suicide attempt lethality, highlighting the importance of substance abuse as a risk factor for lethal suicide attempts in adolescents. This finding stimulates critical thinking around the understanding of suicidal behavior in youth and the development and implementation of treatment strategies for suicidal adolescents with substance abuse disorders. © 2012 The American Association of Suicidology.

  1. Terrorist attacks escalate in frequency and fatalities preceding highly lethal attacks. (United States)

    Martens, Andy; Sainudiin, Raazesh; Sibley, Chris G; Schimel, Jeff; Webber, David


    Highly lethal terrorist attacks, which we define as those killing 21 or more people, account for 50% of the total number of people killed in all terrorist attacks combined, yet comprise only 3.5% of terrorist attacks. Given the disproportionate influence of these incidents, uncovering systematic patterns in attacks that precede and anticipate these highly lethal attacks may be of value for understanding attacks that exact a heavy toll on life. Here we examined whether the activity of terrorist groups escalates--both in the number of people killed per attack and in the frequency of attacks--leading up to highly lethal attacks. Analyses of terrorist attacks drawn from a state-of-the-art international terrorism database (The Global Terrorism Database) showed evidence for both types of escalation leading up to highly lethal attacks, though complexities to the patterns emerged as well. These patterns of escalation do not emerge among terrorist groups that never commit a highly lethal attack.

  2. Treatment of florfenicol of synthetic trout fish farm wastewater through nanofiltration and photocatalyst oxidation. (United States)

    Esmaili, Zakie; Cheshmberah, Fatemeh; Solaimany Nazar, Ali R; Farhadian, Mehrdad


    The aquaculture system is a potential significant source of antibacterial agents. The removal of florfenicol (Flo) antibiotic from synthetic aqueous wastewater is performed by applying a commercial thin film composite polyamide nanofilter (NF). For concentrated wastewater treatment, the advanced oxidation process (AOP) is applied. The effects of pH, pressure and Flo concentration on removal efficiency of NF and the effects of pH, Flo concentration and dosage of hydrogen peroxide and contact time on the AOP are assessed. In the nanofiltration system, it is found that an increase in pH enhances the removal efficiency up to 99%. In this membrane, an increase of pressure between 4 and 7 bar would increase the removal percentage, followed by a decrease from 7 to 10 bar. In AOP, it is observed that the degradation efficiency of Flo increases by both an increase in its initial concentration up to values above 50 ppm and contact time. The degradation efficiency of Flo is at its highest in the pH range of 7-10. With increasing H 2 O 2 dosage, from 0 to 500 ppm, the removal efficiency increases. The results of this study indicate that a combination of a polyamide nanofilteration together with an AOP introduces an effective manner of removing Flo antibiotic from synthetic trout fish farm wastewater.

  3. Recombinant thrombomodulin protects mice against histone-induced lethal thromboembolism.

    Directory of Open Access Journals (Sweden)

    Mayumi Nakahara

    Full Text Available INTRODUCTION: Recent studies have shown that histones, the chief protein component of chromatin, are released into the extracellular space during sepsis, trauma, and ischemia-reperfusion injury, and act as major mediators of the death of an organism. This study was designed to elucidate the cellular and molecular basis of histone-induced lethality and to assess the protective effects of recombinant thrombomodulin (rTM. rTM has been approved for the treatment of disseminated intravascular coagulation (DIC in Japan, and is currently undergoing a phase III clinical trial in the United States. METHODS: Histone H3 levels in plasma of healthy volunteers and patients with sepsis and DIC were measured using enzyme-linked immunosorbent assay. Male C57BL/6 mice were injected intravenously with purified histones, and pathological examinations were performed. The protective effects of rTM against histone toxicity were analyzed both in vitro and in mice. RESULTS: Histone H3 was not detectable in plasma of healthy volunteers, but significant levels were observed in patients with sepsis and DIC. These levels were higher in non-survivors than in survivors. Extracellular histones triggered platelet aggregation, leading to thrombotic occlusion of pulmonary capillaries and subsequent right-sided heart failure in mice. These mice displayed symptoms of DIC, including thrombocytopenia, prolonged prothrombin time, decreased fibrinogen, fibrin deposition in capillaries, and bleeding. Platelet depletion protected mice from histone-induced death in the first 30 minutes, suggesting that vessel occlusion by platelet-rich thrombi might be responsible for death during the early phase. Furthermore, rTM bound to extracellular histones, suppressed histone-induced platelet aggregation, thrombotic occlusion of pulmonary capillaries, and dilatation of the right ventricle, and rescued mice from lethal thromboembolism. CONCLUSIONS: Extracellular histones cause massive

  4. Importance of dosage standardization for interpreting transcriptomal signature profiles: Evidence from studies of xenoestrogens (United States)

    Shioda, Toshi; Chesnes, Jessica; Coser, Kathryn R.; Zou, Lihua; Hur, Jingyung; Dean, Kathleen L.; Sonnenschein, Carlos; Soto, Ana M.; Isselbacher, Kurt J.


    To obtain insights into similarities and differences in the biological actions of related drugs or toxic agents, their transcriptomal signature profiles (TSPs) have been examined in a large number of studies. However, many such reports did not provide proper justification for the dosage criteria of each agent. Using a well characterized cell culture model of estrogen-dependent proliferation of MCF7 human breast cancer cells, we demonstrate how different approaches to dosage standardization exert critical influences on TSPs, leading to different and even conflicting conclusions. Using quantitative cellular response (QCR)-based dosage criteria, TSPs were determined by Affymetrix microarray when cells were proliferating at comparable rates in the presence of various estrogens. We observed that TSPs of the xenoestrogens (e.g., genistein or bisphenol A) were clearly different from the TSP of 17β-estradiol; namely, the former strongly enhanced expression of genes involved in mitochondrial oxidative phosphorylation, whereas the latter showed minimal effects. In contrast, TSPs for genistein and 17β-estradiol were indistinguishable by using the marker gene expression-based dosage criteria, conditions in which there was comparable expression of the mRNA transcripts for the estrogen-inducible WISP2 gene. Our findings indicate that determination and interpretation of TSPs in pharmacogenomic and toxicogenomic studies that examine the transcriptomal actions of related agents by microarray require a clear rationale for the dosage standardization method to be used. We suggest that future studies involving TSP analyses use quantitative and objective dosage standardization methods, such as those with quantitative cellular response or marker gene expression-based dosage criteria. PMID:16882715

  5. Intrathecal baclofen in multiple sclerosis and spinal cord injury: complications and long-term dosage evolution. (United States)

    Draulans, Nathalie; Vermeersch, Kristof; Degraeuwe, Bart; Meurrens, Tom; Peers, Koen; Nuttin, Bart; Kiekens, Carlotte


    To investigate the long-term dosage evolution and complication rate of intrathecal baclofen use in multiple sclerosis and spinal cord injury patients, based on a large population with a long follow-up. Retrospective data analysis. Academic hospital. Patients with multiple sclerosis (n = 81) or spinal cord injury (n = 49) having an intrathecal baclofen pump implanted at the University Hospitals Leuven between 1988 and 2009. Medical records review of included patients in August 2010. Complications linked to intrathecal baclofen therapy. Daily baclofen dosage after 3 and 6 months, and yearly thereafter. Data on dosage evolution were analysed using a mixed-effect linear model. In 130 patients with a mean follow-up of 63 months, comprising 797 pump years, 104 complications were recorded. This corresponds to a complication rate of 0.011 per month, equally divided among both groups. Seventy-eight of these complications were catheter related. The mean dosage of baclofen stabilizes two years after implantation at 323 µg/day in the multiple sclerosis population. In spinal cord injury patients the daily dose only stabilizes after five years at a significantly higher dosage (504 µg/day). No significant increase in dosage is seen in the long term. In multiple sclerosis and spinal cord injury patients, intrathecal baclofen therapy has a complication rate of 1% per month. Complications are mainly due to catheter-related problems (74%). The intrathecal baclofen dosage stabilizes in the long term, indicating that long-term tolerance, defined as progressive diminution of the susceptibility to the effects of a drug, is not present.

  6. Semi-solid dosage form of clonazepam for rapid oral mucosal absorption. (United States)

    Sakata, Osamu; Machida, Yoshiharu; Onishi, Hiraku


    In order to obtain an alternative to the intravenous (i.v.) dosage form of clonazepam (CZ), an oral droplet formulation of CZ was developed previously; however, the droplet was physically unstable. Therefore, in the present study, it was attempted to develop an easily-handled dosage form, which was more physically stable and allowed rapid drug absorption from oral mucosa. A semi-solid dosage form, composed of polyethylene glycol 1500 (PEG), CZ, and oleic acid (OA) at 37/1/2 (w/w) and named PEG/CZ/OA, and a semi-solid dosage form containing PEG and CZ at 39/1 (w/w), called PEG/CZ, were prepared. Their physical stability in air at room temperature and oral mucosal absorption in rats were investigated. The semi-solid dosage forms were much more stable physically than the droplet, that is, no recrystallization of CZ was observed for at least 8 days. The effective concentration for humans and rats (20 ng/mL or more) was achieved within 30 min after buccal administration for both PEG/CZ/OA and PEG/CZ. The plasma concentration increased gradually and less varied at each time point for PEG/CZ/OA. PEG/CZ/OA was found to show more rapid and higher absorption of CZ in buccal administration than in sublingual administration. Buccal administration with the semi-solid dosage PEG/CZ with or without OA was suggested to be a possibly useful novel dosage form as an alternative to i.v. injection.

  7. Printability of Synthetic Papers by Electrophotography

    Directory of Open Access Journals (Sweden)

    Rozália Szentgyörgyvölgyi


    Full Text Available This paper deals with the printability of synthetic papers by the electrophotography technique. Prints of cmyk colour fields from 20% to 100% raster tone values were printed on three types of synthetic papers (one film synthetic paper and two fiber synthetic papers. The investigation of the appearance included densitometric measurement of the cmyk prints. The results have shown differences in the optical density and optical tone value between cmyk prints made on various synthetic papers. The highest optical density and the increase of the optical tone value were observed on the film synthetic paper, where cmyk prints were more saturated. The highest abrasion resistance of cmyk prints was obtained from the fibre synthetic paper.

  8. Synthetic biology: Emerging bioengineering in Indonesia (United States)

    Suhandono, Sony


    The development of synthetic biology will shape the new era of science and technology. It is an emerging bioengineering technique involving genetic engineering which can alter the phenotype and behavior of the cell or the new product. Synthetic biology may produce biomaterials, drugs, vaccines, biosensors, and even a recombinant secondary metabolite used in herbal and complementary medicine, such as artemisinin, a malaria drug which is usually extracted from the plant Artemisia annua. The power of synthetic biology has encouraged scientists in Indonesia, and is still in early development. This paper also covers some research from an Indonesian research institute in synthetic biology such as observing the production of bio surfactants and the enhanced production of artemisinin using a transient expression system. Synthetic biology development in Indonesia may also be related to the iGEM competition, a large synthetic biology research competition which was attended by several universities in Indonesia. The application of synthetic biology for drug discovery will be discussed.

  9. Lethal effect of glucose load on malignant cells

    International Nuclear Information System (INIS)

    Shmakova, N.L.; Yarmonenko, S.P.; Kozubek, S.


    Ehrlich ascites tumor (EAT) cells were treated with glucose load under anoxic conditions (for 15 or 60 min) and/or with γ radiation (20 Gy). The efficiency of the treatment was judged from the tumorigenic activity of EAT cell inocula. The markedly increased efficiency of the combined treatment of EAT cells using glucose load in anoxia and γ radiation is due to the additive action of both agents. The glucose load in anoxia leads to extensive desintegration of tumor cells. Further, the lethal effect of various pH values on EAT cells was investigated. Different pH values were obtained by means of both glucose load and phosphate buffers. The effect was investigated by determining the tumorigenic activity of EAT cells tested in vivo in mice and by determining the radiosensitivity of treated EAT cells. The results allowed us to conclude that the same values of pH lead to the same effect on EAT cells independently of the way by which the given pH value was reached. (author). 5 figs., 2 tabs., 12 refs

  10. Lethal Lullabies: A History of Opium Use in Infants. (United States)

    Obladen, Michael


    Poppy extract accompanied the human infant for more than 3 millenia. Motives for its use included excessive crying, suspected pain, and diarrhea. In antiquity, infantile sleeplessness was regarded as a disease. When treatment with opium was recommended by Galen, Rhazes, and Avicenna, baby sedation made its way into early medical treatises and pediatric instructions. Dabbing maternal nipples with bitter substances and drugging the infant with opium were used to hasten weaning. A freerider of gum lancing, opiates joined the treatment of difficult teething in the 17th century. Foundling hospitals and wet-nurses used them extensively. With industrialization, private use was rampant among the working class. In German-speaking countries, poppy extracts were administered in soups and pacifiers. In English-speaking countries, proprietary drugs containing opium were marketed under names such as soothers, nostrums, anodynes, cordials, preservatives, and specifics and sold at the doorstep or in grocery stores. Opium's toxicity for infants was common knowledge; thousands of cases of lethal intoxication had been reported from antiquity. What is remarkable is that the willingness to use it in infants persisted and that physicians continued to prescribe it for babies. Unregulated trade, and even that protected by governments, led to greatly increased private use of opiates during the 19th century. Intoxication became a significant factor in infant mortality. As late as 1912, the International Hague Convention forced governments to implement legislation that effectively curtailed access to opium and broke the dangerous habit of sedating infants. © The Author(s) 2015.

  11. Sticky foam as a less-than-lethal technology

    Energy Technology Data Exchange (ETDEWEB)

    Scott, S.H.


    Sandia National Labs (SNL) in 1994 completed a project funded by the National Institute of Justice (NIJ) to determine the applicability of sticky foam for correctional applications. Sticky foam is an extremely tacky, tenacious material used to block, entangle, and impair individuals. The NIJ project developed a gun capable of firing multiple shots of sticky foam, tested the gun and sticky foam effectiveness on SNL volunteers acting out prison and law enforcement scenarios, and had the gun and sticky foam evaluated by correctional representatives. Based on the NIJ project work, SNL supported the Marine Corps Mission, Operation United Shield, with sticky foam guns and supporting equipment to assist in the withdrawal of UN Peacekeepers from Somalia. Prior to the loan of the equipment, the Marines were given training in sticky foam characterization, toxicology, safety issues, cleanup and waste disposal, use limitations, use protocol and precautions, emergency facial clean-up, skin cleanup, gun filling, targeting and firing, and gun cleaning. The Marine Corps successfully used the sticky foam guns as part of that operation. This paper describes these recent developments of sticky foam for non-lethal uses and some of the lessons learned from scenario and application testing.

  12. Synthetic Biology Guides Biofuel Production

    Directory of Open Access Journals (Sweden)

    Michael R. Connor


    Full Text Available The advancement of microbial processes for the production of renewable liquid fuels has increased with concerns about the current fuel economy. The development of advanced biofuels in particular has risen to address some of the shortcomings of ethanol. These advanced fuels have chemical properties similar to petroleum-based liquid fuels, thus removing the need for engine modification or infrastructure redesign. While the productivity and titers of each of these processes remains to be improved, progress in synthetic biology has provided tools to guide the engineering of these processes through present and future challenges.

  13. Synthetic Fourier transform light scattering. (United States)

    Lee, Kyeoreh; Kim, Hyeon-Don; Kim, Kyoohyun; Kim, Youngchan; Hillman, Timothy R; Min, Bumki; Park, Yongkeun


    We present synthetic Fourier transform light scattering, a method for measuring extended angle-resolved light scattering (ARLS) from individual microscopic samples. By measuring the light fields scattered from the sample plane and numerically synthesizing them in Fourier space, the angle range of the ARLS patterns is extended up to twice the numerical aperture of the imaging system with unprecedented sensitivity and precision. Extended ARLS patterns of individual microscopic polystyrene beads, healthy human red blood cells (RBCs), and Plasmodium falciparum-parasitized RBCs are presented.

  14. Synthetic carbonaceous fuels and feedstocks (United States)

    Steinberg, Meyer


    This invention relates to the use of a three compartment electrolytic cell in the production of synthetic carbonaceous fuels and chemical feedstocks such as gasoline, methane and methanol by electrolyzing an aqueous sodium carbonate/bicarbonate solution, obtained from scrubbing atmospheric carbon dioxide with an aqueous sodium hydroxide solution, whereby the hydrogen generated at the cathode and the carbon dioxide liberated in the center compartment are combined thermocatalytically into methanol and gasoline blends. The oxygen generated at the anode is preferably vented into the atmosphere, and the regenerated sodium hydroxide produced at the cathode is reused for scrubbing the CO.sub.2 from the atmosphere.

  15. Synthetic Biology Guides Biofuel Production (United States)

    Connor, Michael R.; Atsumi, Shota


    The advancement of microbial processes for the production of renewable liquid fuels has increased with concerns about the current fuel economy. The development of advanced biofuels in particular has risen to address some of the shortcomings of ethanol. These advanced fuels have chemical properties similar to petroleum-based liquid fuels, thus removing the need for engine modification or infrastructure redesign. While the productivity and titers of each of these processes remains to be improved, progress in synthetic biology has provided tools to guide the engineering of these processes through present and future challenges. PMID:20827393

  16. Synthetic Aperture Vector Flow Imaging

    DEFF Research Database (Denmark)

    Villagómez Hoyos, Carlos Armando

    The main objective of this project was to continue the development of a synthetic aperture vector flow estimator. This type of estimator is capable of overcoming two of the major limitations in conventional ultrasound systems: 1) the inability to scan large region of interest with high temporal......, this thesis showed that novel information can be obtained with vector velocity methods providing quantitative estimates of blood flow and insight into the complexity of the hemodynamics dynamics. This could give the clinician a new tool in assessment and treatment of a broad range of diseases....

  17. Synthetic Aperture Vector Flow Imaging

    DEFF Research Database (Denmark)

    Oddershede, Niels


    of the thesis considers a method for estimating the two-dimensional velocity vector within the image plane. This method, called synthetic aperture vector flow imaging, is first shortly reviewed. The main contribution of this work is partly an analysis of the method with respect to focusing effects, motion...... estimation. The method can be used for increasing the frame rate of color flow maps or alternatively for a new imaging modality entitled quadroplex imaging, featuring a color flow map and two independent spectrograms at a high frame rate. The second is an alternative method for ultrasonic vector velocity...

  18. Protease-Sensitive Synthetic Prions


    Colby, David W.; Wain, Rachel; Baskakov, Ilia V.; Legname, Giuseppe; Palmer, Christina G.; Nguyen, Hoang-Oanh B.; Lemus, Azucena; Cohen, Fred E.; DeArmond, Stephen J.; Prusiner, Stanley B.


    Prions arise when the cellular prion protein (PrPC) undergoes a self-propagating conformational change; the resulting infectious conformer is designated PrPSc. Frequently, PrPSc is protease-resistant but protease-sensitive (s) prions have been isolated in humans and other animals. We report here that protease-sensitive, synthetic prions were generated in vitro during polymerization of recombinant (rec) PrP into amyloid fibers. In 22 independent experiments, recPrP amyloid preparations, but no...

  19. Hyperintense acute reperfusion marker is associated with higher contrast agent dosage in acute ischaemic stroke

    International Nuclear Information System (INIS)

    Ostwaldt, Ann-Christin; Schaefer, Tabea; Villringer, Kersten; Fiebach, Jochen B.; Rozanski, Michal; Ebinger, Martin; Jungehuelsing, Gerhard J.


    The hyperintense acute reperfusion marker (HARM) on fluid-attenuated inversion recovery (FLAIR) images is associated with blood-brain barrier (BBB) permeability changes. The aim of this study was to examine the influence of contrast agent dosage on HARM incidence in acute ischaemic stroke patients. We prospectively included 529 acute ischaemic stroke patients (204 females, median age 71 years). Patients underwent a first stroke-MRI within 24 hours from symptom onset and had a follow-up on day 2. The contrast agent Gadobutrol was administered to the patients for perfusion imaging or MR angiography. The total dosage was calculated as ml/kg body weight and ranged between 0.04 and 0.31 mmol/kg on the first examination. The incidence of HARM was evaluated on day 2 FLAIR images. HARM was detected in 97 patients (18.3 %). HARM incidence increased significantly with increasing dosages of Gadobutrol. Also, HARM positive patients were significantly older. HARM was not an independent predictor of worse clinical outcome, and we did not find an association with increase risk of haemorrhagic transformation. A higher dosage of Gadobutrol in acute stroke patients on initial MRI is associated with increased HARM incidence on follow-up. MRI studies on BBB should therefore standardize contrast agent dosages. (orig.)

  20. Effects of Web-Based Instruction on Nursing Students' Arithmetical and Drug Dosage Calculation Skills. (United States)

    Karabağ Aydin, Arzu; Dinç, Leyla


    Drug dosage calculation skill is critical for all nursing students to ensure patient safety, particularly during clinical practice. The study purpose was to evaluate the effectiveness of Web-based instruction on improving nursing students' arithmetical and drug dosage calculation skills using a pretest-posttest design. A total of 63 nursing students participated. Data were collected through the Demographic Information Form, and the Arithmetic Skill Test and Drug Dosage Calculation Skill Test were used as pre and posttests. The pretest was conducted in the classroom. A Web site was then constructed, which included audio presentations of lectures, quizzes, and online posttests. Students had Web-based training for 8 weeks and then they completed the posttest. Pretest and posttest scores were compared using the Wilcoxon test and correlation coefficients were used to identify the relationship between arithmetic and calculation skills scores. The results demonstrated that Web-based teaching improves students' arithmetic and drug dosage calculation skills. There was a positive correlation between the arithmetic skill and drug dosage calculation skill scores of students. Web-based teaching programs can be used to improve knowledge and skills at a cognitive level in nursing students.

  1. Effects of pharmaceutical processing on pepsin activity during the formulation of solid dosage forms. (United States)

    Kristó, Katalin; Pintye-Hódi, Klára


    The main aim of this study was to investigate the effects of pharmaceutical technological methods on pepsin activity during the formulation of solid dosage forms. The circumstances of direct compression and wet granulation were modeled. During direct compression, the heat and the compression force must be taken into consideration. The effects of these parameters were investigated in three materials (pure pepsin, and 1:1 (w/w) pepsin-tartaric acid and 1:1 (w/w) pepsin-citric acid powder mixtures). It was concluded that direct compression is appropriate for the formulation of solid dosage forms containing pepsin through application without acids or with acids at low compression force. The effects of wet granulation were investigated with a factorial design for the same three materials. The factors were time, temperature and moisture content. There was no significant effect of the factors when acids were not applied. Temperature was a significant factor when acids were applied. The negative effect was significantly higher for citric acid than for tartaric acid. It was found that wet granulation can be utilized for the processing of pepsin into solid dosage forms under well-controlled circumstances. The application of citric acid is not recommended during the formulation of solid dosage forms through wet granulation. A mathematically based optimization may be necessary for preformulation studies of the preparation of dosage forms containing sensitive enzymes.

  2. Dependence of surface smoothing, sputtering and etching phenomena on cluster ion dosage

    CERN Document Server

    Song, J H; Choi, W K


    The dependence of surface smoothing and sputtering phenomena of Si (1 0 0) solid surfaces irradiated by CO sub 2 cluster ions on cluster-ion dosage was investigated using an atomic force microscope. The flux and total ion dosage of impinging cluster ions at the acceleration voltage of 50 kV were fixed at 10 sup 9 ions/cm sup 2 s and were scanned from 5x10 sup 1 sup 0 to 5x10 sup 1 sup 3 ions/cm sup 2 , respectively. The density of hillocks induced by cluster ion impact was gradually increased with the dosage up to 5x10 sup 1 sup 1 ions/cm sup 2 , which caused that the irradiated surface became rough from 0.4 to 1.24 nm in root-mean-square roughness (sigma sub r sub m sub s). At the boundary of the ion dosage of 10 sup 1 sup 2 ions/cm sup 2 , the density of the induced hillocks was decreased and sigma sub r sub m sub s was about 1.21 nm, not being deteriorated further. At the dosage of 5x10 sup 1 sup 3 ions/cm sup 2 , the induced hillocks completely disappeared and the surface became very flat as much as sigma...

  3. Toxicity, dosage, and efficacy of vinorelbine (Navelbine) in dogs with spontaneous neoplasia. (United States)

    Poirier, Valerie J; Burgess, Kristine E; Adams, William M; Vail, David M


    The purpose of this study was to evaluate short-term adverse effects and determine a safe dosage for vinorelbine (Navelbine)--a new semisynthetic vinca alkaloid--in dogs with malignant tumors. Nineteen dogs were treated with vinorelbine as a 5-minute IV infusion every 7 days at starting dosages ranging from 10 to 20 mg/m2. The median number of treatments per dog was 7 (range, 1-11). The maximum tolerated dosage varied between 15 and 18 mg/m2, and a starting dosage of 15 mg/m2 is recommended. Neutropenia was the dose-limiting toxicity. Although efficacy was a secondary endpoint of this dosage-finding study, 2 dogs with metastatic bronchoalveolar carcinoma experienced a partial response for an overall response rate of 12.5% in 16 dogs with gross measurable disease. Three dogs with microscopic disease were treated (incompletely excised bronchoalveolar carcinoma or lymph node metastatic disease). Two died of pulmonary metastatic disease 113 and 196 days posttreatment, and 1 is still alive after at least 730 days. The well-tolerated toxicity profile and clinical activity observed in dogs with bronchoalveolar carcinoma warrants further investigation.

  4. Adrenal Insufficiency under Standard Dosage of Glucocorticoid Replacement after Unilateral Adrenalectomy for Cushing’s Syndrome

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    Kentaro Fujii


    Full Text Available Glucocorticoid replacement is needed for patients after adrenal surgery for Cushing’s syndrome; however, the adequate dosage is not easily determined. The patient was a 62-year-old woman who has had hypertension for 5 years and presented with heart failure due to hypertrophic cardiomyopathy. She consulted with us because of general fatigue, facial edema, and muscle weakness and was diagnosed with Cushing’s syndrome. A laparoscopic left adrenalectomy was performed, standard dosage of postoperative replacement was administered, and she was discharged with 30 mg/day of hydrocortisone (cortisol. However, she suffered from loss of appetite and was transferred to an emergency unit with the symptoms of adrenal insufficiency on postoperative day 15. After initial hydrocortisone replacement with 200 mg/day, the dosage was gradually decreased during hospitalization; however, reduction of hydrocortisone dosage lower than 60 mg/day was difficult because of nausea and fatigue. Her circadian cortisol profile after hydrocortisone administration showed delayed and lowered peaks, which suggested that hydrocortisone absorption in the intestine was impaired. Therefore, complicated heart failure may have led to the adrenal insufficiency in the patient. In such cases, we should consider postoperative administration of more than the standard dosage of hydrocortisone to avoid adrenal insufficiency after surgery for Cushing’s syndrome.

  5. Hyperintense acute reperfusion marker is associated with higher contrast agent dosage in acute ischaemic stroke

    Energy Technology Data Exchange (ETDEWEB)

    Ostwaldt, Ann-Christin; Schaefer, Tabea; Villringer, Kersten; Fiebach, Jochen B. [Charite Universitaetsmedizin Berlin, Academic Neuroradiology, Center for Stroke Research Berlin (CSB), Berlin (Germany); Rozanski, Michal; Ebinger, Martin [Charite Universitaetsmedizin Berlin, Academic Neuroradiology, Center for Stroke Research Berlin (CSB), Berlin (Germany); Charite Universitaetsmedizin, Department of Neurology, Berlin (Germany); Jungehuelsing, Gerhard J. [Stiftung des Buergerlichen Rechts, Juedisches Krankenhaus Berlin, Berlin (Germany)


    The hyperintense acute reperfusion marker (HARM) on fluid-attenuated inversion recovery (FLAIR) images is associated with blood-brain barrier (BBB) permeability changes. The aim of this study was to examine the influence of contrast agent dosage on HARM incidence in acute ischaemic stroke patients. We prospectively included 529 acute ischaemic stroke patients (204 females, median age 71 years). Patients underwent a first stroke-MRI within 24 hours from symptom onset and had a follow-up on day 2. The contrast agent Gadobutrol was administered to the patients for perfusion imaging or MR angiography. The total dosage was calculated as ml/kg body weight and ranged between 0.04 and 0.31 mmol/kg on the first examination. The incidence of HARM was evaluated on day 2 FLAIR images. HARM was detected in 97 patients (18.3 %). HARM incidence increased significantly with increasing dosages of Gadobutrol. Also, HARM positive patients were significantly older. HARM was not an independent predictor of worse clinical outcome, and we did not find an association with increase risk of haemorrhagic transformation. A higher dosage of Gadobutrol in acute stroke patients on initial MRI is associated with increased HARM incidence on follow-up. MRI studies on BBB should therefore standardize contrast agent dosages. (orig.)

  6. Declines in the lethality of suicide attempts explain the decline in suicide deaths in Australia.

    Directory of Open Access Journals (Sweden)

    Matthew J Spittal

    Full Text Available BACKGROUND: To investigate the epidemiology of a steep decrease in the incidence of suicide deaths in Australia. METHODS: National data on suicide deaths and deliberate self-harm for the period 1994-2007 were obtained from the Australian Institute of Health and Welfare. We calculated attempt and death rates for five major methods and the lethality of these methods. Negative binomial regression was used to estimate the size and significance of method-specific time-trends in attempts and lethality. RESULTS: Hanging, motor vehicle exhaust and firearms were the most lethal methods, and together accounted for 72% of all deaths. The lethality of motor vehicle exhaust attempts decreased sharply (RR = 0.94 per year, 95% CI 0.93-0.95 while the motor vehicle exhaust attempt rate changed little; this combination of motor vehicle exhaust trends explained nearly half of the overall decline in suicide deaths. Hanging lethality also decreased sharply (RR = 0.96 per year, 95% CI 0.956-0.965 but large increases in hanging attempts negated the effect on death rates. Firearm lethality changed little while attempts decreased. CONCLUSION: Declines in the lethality of suicide attempts-especially attempts by motor vehicle exhaust and hanging-explain the remarkable decline in deaths by suicide in Australia since 1997.

  7. Tracking the emergence of synthetic biology. (United States)

    Shapira, Philip; Kwon, Seokbeom; Youtie, Jan


    Synthetic biology is an emerging domain that combines biological and engineering concepts and which has seen rapid growth in research, innovation, and policy interest in recent years. This paper contributes to efforts to delineate this emerging domain by presenting a newly constructed bibliometric definition of synthetic biology. Our approach is dimensioned from a core set of papers in synthetic biology, using procedures to obtain benchmark synthetic biology publication records, extract keywords from these benchmark records, and refine the keywords, supplemented with articles published in dedicated synthetic biology journals. We compare our search strategy with other recent bibliometric approaches to define synthetic biology, using a common source of publication data for the period from 2000 to 2015. The paper details the rapid growth and international spread of research in synthetic biology in recent years, demonstrates that diverse research disciplines are contributing to the multidisciplinary development of synthetic biology research, and visualizes this by profiling synthetic biology research on the map of science. We further show the roles of a relatively concentrated set of research sponsors in funding the growth and trajectories of synthetic biology. In addition to discussing these analyses, the paper notes limitations and suggests lines for further work.

  8. Repurposing ribosomes for synthetic biology. (United States)

    Liu, Yi; Kim, Do Soon; Jewett, Michael C


    The translation system is the cell's factory for protein biosynthesis, stitching together hundreds to thousands of amino acids into proteins, which are required for the structure, function, and regulation of living systems. The extraordinary synthetic capability of this system, which includes the ribosome and its associated factors required for polymerization, has driven extensive efforts to harness it for societal use in areas as diverse as energy, materials, and medicine. A powerful example is recombinant protein production, which has impacted the lives of patients through the synthesis of biopharmaceuticals such as insulin. In nature, however, only limited sets of monomers are utilized, thereby resulting in limited sets of biopolymers (i.e., proteins). Expanding nature's repertoire of ribosomal monomers could yield new classes of enzymes, therapeutics, materials, and chemicals with diverse, genetically encoded chemistry. Here, we discuss recent progress towards engineering ribosomes both in vivo and in vitro. These fundamental and technical breakthroughs open doors for advanced applications in biotechnology and synthetic biology. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. DNA recognition by synthetic constructs. (United States)

    Pazos, Elena; Mosquera, Jesús; Vázquez, M Eugenio; Mascareñas, José L


    The interaction of transcription factors with specific DNA sites is key for the regulation of gene expression. Despite the availability of a large body of structural data on protein-DNA complexes, we are still far from fully understanding the molecular and biophysical bases underlying such interactions. Therefore, the development of non-natural agents that can reproduce the DNA-recognition properties of natural transcription factors remains a major and challenging goal in chemical biology. In this review we summarize the basics of double-stranded DNA recognition by transcription factors, and describe recent developments in the design and preparation of synthetic DNA binders. We mainly focus on synthetic peptides that have been designed by following the DNA interaction of natural proteins, and we discuss how the tools of organic synthesis can be used to make artificial constructs equipped with functionalities that introduce additional properties to the recognition process, such as sensing and controllability. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Towards developing algal synthetic biology. (United States)

    Scaife, Mark Aden; Smith, Alison Gail


    The genetic, physiological and metabolic diversity of microalgae has driven fundamental research into photosynthesis, flagella structure and function, and eukaryotic evolution. Within the last 10 years these organisms have also been investigated as potential biotechnology platforms, for example to produce high value compounds such as long chain polyunsaturated fatty acids, pigments and antioxidants, and for biodiesel precursors, in particular triacylglycerols (TAGs). Transformation protocols, molecular tools and genome sequences are available for a number of model species including the green alga Chlamydomonas reinhardtii and the diatom Phaeodactylum tricornutum, although for both species there are bottlenecks to be overcome to allow rapid and predictable genetic manipulation. One approach to do this would be to apply the principles of synthetic biology to microalgae, namely the cycle of Design-Build-Test, which requires more robust, predictable and high throughput methods. In this mini-review we highlight recent progress in the areas of improving transgene expression, genome editing, identification and design of standard genetic elements (parts), and the use of microfluidics to increase throughput. We suggest that combining these approaches will provide the means to establish algal synthetic biology, and that application of standard parts and workflows will avoid parallel development and capitalize on lessons learned from other systems. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  11. Shape analysis of synthetic diamond

    CERN Document Server

    Mullan, C


    Two-dimensional images of synthetic industrial diamond particles were obtained using a camera, framegrabber and PC-based image analysis software. Various methods for shape quantification were applied, including two-dimensional shape factors, Fourier series expansion of radius as a function of angle, boundary fractal analysis, polygonal harmonics, and comer counting methods. The shape parameter found to be the most relevant was axis ratio, defined as the ratio of the minor axis to the major axis of the ellipse with the same second moments of area as the particle. Axis ratio was used in an analysis of the sorting of synthetic diamonds on a vibrating table. A model was derived based on the probability that a particle of a given axis ratio would travel to a certain bin. The model described the sorting of bulk material accurately but it was found not to be applicable if the shape mix of the feed material changed dramatically. This was attributed to the fact that the particle-particle interference was not taken int...

  12. Photoreactivable sector of lethal damage in ultraviolet-irradiated Escherichia coli cells

    International Nuclear Information System (INIS)

    Balgavy, P.


    The photoreactivable sector of lethal damage in Escherichia coli Bsub(s-1), Escherichia coli B/r Hcr - and Escherichia coli B/r Hcr + cells after ultraviolet irradiation at 254 nm is 0.823 +- 0.004, 0.70 +- 0.01 and 0.53 +- 0.06, respectively, at 99% confidence limits. For the low values of the photoreactivable sector in the B/r Hcr - and B/r Hcr + strains are likely to be responsible dark repair processes which eliminate lethal damage, brought about by pyrimidine dimers, preferably in comparison with lethal damage caused by photoproducts of another type. (author)

  13. UV Spectrophotometric Method for the Estimation of Tadalafil in Bulk and Tablet Dosage form

    Directory of Open Access Journals (Sweden)

    Mohammad Yunoos


    Full Text Available A simple, sensitive, precise and highly accurate UV spectrophotometric method has been developed for the determination of tadalafil in bulk and tablet dosage form. Solution of tadalafil in methanol shows maximum absorbance at 284 nm. Beer’s law was obeyed in the concentration range of 2-20 mcg mL-1 with 1.65x104 mol-1 cm-1, the slope, intercept, correlation coefficient, detection and quantitation limits were also calculated. The proposed method has been applied successfully for the analysis of the drug in pure and in its tablets dosage forms. Result of percentage recovery and placebo interference shows that the method was not affected by the presence of common excipients. The method was validated by determining its sensitivity, accuracy and precision which proves suitability of the developed method for the routine estimation of tadalafil in bulk and solid dosage form.

  14. An evolutionary consequence of dosage compensation on Drosophila melanogaster female X-chromatin structure?

    Directory of Open Access Journals (Sweden)

    Oliver Brian


    Full Text Available Abstract Background X chromosomes are subject to dosage compensation in Drosophila males. Dosage compensation requires cis sequence features of the X chromosome that are present in both sexes by definition and trans acting factors that target chromatin modifying machinery to the X specifically in males. The evolution of this system could result in neutral X chromatin changes that will be apparent in females. Results We find that the general chromatin structure of female X chromosomes is distinct from autosomes. Additionally, specific histone marks associated with dosage compensation and active chromatin marks on the male X chromosome are also enriched on the X chromosomes of females, albeit to a lesser degree. Conclusions Our data indicate that X chromatin structure is fundamentally different from autosome structure in both sexes. We suggest that the differences between the X chromosomes and autosomes in females are a consequence of mechanisms that have evolved to ensure sufficient X chromosome expression in the soma of males.

  15. Large-scale population study of human cell lines indicates that dosage compensation is virtually complete.

    Directory of Open Access Journals (Sweden)

    Colette M Johnston


    Full Text Available X chromosome inactivation in female mammals results in dosage compensation of X-linked gene products between the sexes. In humans there is evidence that a substantial proportion of genes escape from silencing. We have carried out a large-scale analysis of gene expression in lymphoblastoid cell lines from four human populations to determine the extent to which escape from X chromosome inactivation disrupts dosage compensation. We conclude that dosage compensation is virtually complete. Overall expression from the X chromosome is only slightly higher in females and can largely be accounted for by elevated female expression of approximately 5% of X-linked genes. We suggest that the potential contribution of escape from X chromosome inactivation to phenotypic differences between the sexes is more limited than previously believed.

  16. [Summarize drug dosage forms in treatment of age-related macular degeneration disease]. (United States)

    Du, Mao-Bo; Liu, Shu-Zhi; Xu, Kai; Liang, Li-Na; He, Ai-Ping; Yao, Yao; Liu, Ya-Mei


    In this review, the authors summarized the drugs in treatment of the age-related macular degeneration (AMD or ARMD), including the pathogenesis of the age-related macular degeneration at home and abroad, dosage forms used in the treatment, and the drugs research and development directions in the future. AMD disease is the third largest blinding diseases all over the world, with an incidence of 6.62%. The dosage form of the traditional medicine is mostly oral formulations, playing a role in body, while the newly dosage form is topical drug delivery formulation. Traditional Chinese medicine (TCM) has certain advantages in the treatment of AMD disease and the development of topical drug delivery preparations with newly preparation technologies would have a very bright prospect in the future. Copyright© by the Chinese Pharmaceutical Association.

  17. Histomorphological study of submandibulary glands of rats submitted to low dosage of X-radiation

    International Nuclear Information System (INIS)

    Navarro, Claudia Maria; Onofre, Mirian Aparecida; Chan, Carolina; Cordeiro, Rita de Cassis Loiola; Raveli, Dirceu Barnabe


    The minimal dosage of X-ray that is likely to induce cellular alterations is unknown and there are just a few reports with low dosage in odontologic literature. The authors developed a histomorphological analysis of the submandibulary glands of rat that received low dosage of X radiation. The body of the animals was covered with a lead lamin leaving the cervical area uncovered. The submandibular glands were exposed to 1,80 Gy of X-radiation in a single dose. After 24, 48, 72 hours, 7, 14 and 21 days the glands were excised, fixed and prepared for analysis in light microscopy. Mild degenerative changes and nuclear pleomorfism, mainly on the first three experimental periods were observed. (author)

  18. Novo método de dosagem de soros antipeçonhentos em camundongos lactentes: I - dosagem do soro anticrotálico New method for dosage of antivenoms sera in baby mice: I-Anticrotalic serum's dosage

    Directory of Open Access Journals (Sweden)

    Bruno Soerensen


    Full Text Available A atividade biológica dos soros antipeçonhentos pode ser determinada "in vivo" em pombos, coelhos, cobaios e camundongos adultos, não existindo, entretanto, nenhum método que possa ser recomendado internacionalmente. Estudou-se comparativamente aos métodos tradicionais de dosagem de soros em pombos e camundongos adultos, a validade do uso de camundongos lactentes de 6 a 7 dias, pesando 4 a 5g, inoculados pela via subcutânea. Inicialmente foi determinada a toxidez do veneno de Crotalus durissus terríficus através do estudo da sintomatologia do envenenamento e da atividade letal. O estudo comparativo dos três métodos forneceu maior concordância de resultados em DE100 entre as dosagens realizadas com camundongos lactentes e adultos. A DE100 e DL50 determinadas em camundongos lactentes forneceu resultados mais constantes que os dos métodos de camundongos adultos e pombos. O uso deste novo método permite eliminar a dificuldade de obtenção do atual animal de prova; a utilização de um maior número de animais por ponto de avaliação biológica, possibilitando uma maior precisão e conseguindo-se uma uniformidade nas características exigidas neste tipo de dosagem como peso, idade e linhagem, visando a reprodução sistemática dos resultados.The biological activity of antiserum against venoms can be assessed by "in vivo" tests using pigeons, rabbits, guinea-pigs and adult mice although there is no International standardized reaction for it. The traditional methods using pigeons and adult mice were comparatively studied with those using mice of 4-5 g (6-7 days of age, inoculated by subcutaneous injection. The toxicity of the Crotalus durissus terrificus venom was initially determined by studying the symptomatology after administration of venom and lethal activity. The comparative study of these three methods showed that the best concordance in the results of the ED100 was obtained using adult and baby mice. The most homogeneous ED100

  19. Radiation rescue: mesenchymal stromal cells protect from lethal irradiation.

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    Claudia Lange

    Full Text Available BACKGROUND: Successful treatment of acute radiation syndromes relies on immediate supportive care. In patients with limited hematopoietic recovery potential, hematopoietic stem cell (HSC transplantation is the only curative treatment option. Because of time consuming donor search and uncertain outcome we propose MSC treatment as an alternative treatment for severely radiation-affected individuals. METHODS AND FINDINGS: Mouse mesenchymal stromal cells (mMSCs were expanded from bone marrow, retrovirally labeled with eGFP (bulk cultures and cloned. Bulk and five selected clonal mMSCs populations were characterized in vitro for their multilineage differentiation potential and phenotype showing no contamination with hematopoietic cells. Lethally irradiated recipients were i.v. transplanted with bulk or clonal mMSCs. We found a long-term survival of recipients with fast hematopoietic recovery after the transplantation of MSCs exclusively without support by HSCs. Quantitative PCR based chimerism analysis detected eGFP-positive donor cells in peripheral blood immediately after injection and in lungs within 24 hours. However, no donor cells in any investigated tissue remained long-term. Despite the rapidly disappearing donor cells, microarray and quantitative RT-PCR gene expression analysis in the bone marrow of MSC-transplanted animals displayed enhanced regenerative features characterized by (i decreased proinflammatory, ECM formation and adhesion properties and (ii boosted anti-inflammation, detoxification, cell cycle and anti-oxidative stress control as compared to HSC-transplanted animals. CONCLUSIONS: Our data revealed that systemically administered MSCs provoke a protective mechanism counteracting the inflammatory events and also supporting detoxification and stress management after radiation exposure. Further our results suggest that MSCs, their release of trophic factors and their HSC-niche modulating activity rescue endogenous hematopoiesis

  20. Analyzing temporal variation in the lethality of ETA

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    Sánchez-Cuenca, Ignacio


    Full Text Available This article analyzes time variation in the lethal violence of the terrorist organization ETA. Given the dynamic structure of the time series of fatalities, I look at the effect of a number of independent variables (the celebration of different types of elections, anti-ETA activity by extreme right-wing organizations and the GAL, police arrests, and other relevant events, such as the referendums on the Constitution and the Statute of Autonomy of Guernica. To do so, I have estimated several ARIMA models using the time series of fatalities between 1968 and 2007. Moreover, the results obtained are complemented by a historical-political analysis of the period of maximum violence, which took place during the Spanish transition to democracy.

    Este artículo analiza la variación temporal en la violencia letal de la organización terrorista ETA. Dada la estructura dinámica de la serie temporal de víctimas mortales, se estudia el efecto de una serie de variables independientes (celebración de distintos tipos de elecciones, actividad anti-ETA de la extrema derecha y del GAL, detenciones policiales y sucesos especiales como los referendos sobre la Constitución o el Estatuto de Autonomía de Guernica. Para ello, se estiman diversos modelos ARIMA con la serie trimestral de víctimas mortales entre 1968 y 2007. Además, se completan los resultados obtenidos con un análisis histórico-político del periodo de máxima violencia durante la transición a la democracia.

  1. Activated entomopathogenic nematode infective juveniles release lethal venom proteins.

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    Dihong Lu


    Full Text Available Entomopathogenic nematodes (EPNs are unique parasites due to their symbiosis with entomopathogenic bacteria and their ability to kill insect hosts quickly after infection. It is widely believed that EPNs rely on their bacterial partners for killing hosts. Here we disproved this theory by demonstrating that the in vitro activated infective juveniles (IJs of Steinernema carpocapsae (a well-studied EPN species release venom proteins that are lethal to several insects including Drosophila melanogaster. We confirmed that the in vitro activation is a good approximation of the in vivo process by comparing the transcriptomes of individual in vitro and in vivo activated IJs. We further analyzed the transcriptomes of non-activated and activated IJs and revealed a dramatic shift in gene expression during IJ activation. We also analyzed the venom proteome using mass spectrometry. Among the 472 venom proteins, proteases and protease inhibitors are especially abundant, and toxin-related proteins such as Shk domain-containing proteins and fatty acid- and retinol-binding proteins are also detected, which are potential candidates for suppressing the host immune system. Many of the venom proteins have conserved orthologs in vertebrate-parasitic nematodes and are differentially expressed during IJ activation, suggesting conserved functions in nematode parasitism. In summary, our findings strongly support a new model that S. carpocapsae and likely other Steinernema EPNs have a more active role in contributing to the pathogenicity of the nematode-bacterium complex than simply relying on their symbiotic bacteria. Furthermore, we propose that EPNs are a good model system for investigating vertebrate- and human-parasitic nematodes, especially regarding the function of excretory/secretory products.

  2. Subfunctionalization reduces the fitness cost of gene duplication in humans by buffering dosage imbalances

    Directory of Open Access Journals (Sweden)

    Fernández Ariel


    Full Text Available Abstract Background Driven essentially by random genetic drift, subfunctionalization has been identified as a possible non-adaptive mechanism for the retention of duplicate genes in small-population species, where widespread deleterious mutations are likely to cause complementary loss of subfunctions across gene copies. Through subfunctionalization, duplicates become indispensable to maintain the functional requirements of the ancestral locus. Yet, gene duplication produces a dosage imbalance in the encoded proteins and thus, as investigated in this paper, subfunctionalization must be subject to the selective forces arising from the fitness bottleneck introduced by the duplication event. Results We show that, while arising from random drift, subfunctionalization must be inescapably subject to selective forces, since the diversification of expression patterns across paralogs mitigates duplication-related dosage imbalances in the concentrations of encoded proteins. Dosage imbalance effects become paramount when proteins rely on obligatory associations to maintain their structural integrity, and are expected to be weaker when protein complexation is ephemeral or adventitious. To establish the buffering effect of subfunctionalization on selection pressure, we determine the packing quality of encoded proteins, an established indicator of dosage sensitivity, and correlate this parameter with the extent of paralog segregation in humans, using species with larger population -and more efficient selection- as controls. Conclusions Recognizing the role of subfunctionalization as a dosage-imbalance buffer in gene duplication events enabled us to reconcile its mechanistic nonadaptive origin with its adaptive role as an enabler of the evolution of genetic redundancy. This constructive role was established in this paper by proving the following assertion: If subfunctionalization is indeed adaptive, its effect on paralog segregation should scale with the dosage

  3. Levothyroxine Dosage Requirement During Pregnancy in Well-Controlled Hypothyroid Women: A Longitudinal Study. (United States)

    Kashi, Zahra; Bahar, Adele; Akha, Ozra; Hassanzade, Samane; Esmaeilisaraji, Leila; Hamzehgardeshi, Zeinab


    Untreated maternal hypothyroidism can have adverse effects on both the mother and fetus, but it can potentially be prevented by adequate levothyroxine replacement. This study was conducted to determine what percentage of hypothyroid pregnant women who were taking levothyroxine needed to adjust their medication dosage, and when and how much it should be increased. In this longitudinal study, 81 well-controlled hypothyroid women (TSH≤ 2.5 mIU/L) were monitored throughout pregnancy. Thyroid function tests were performed before conception, after the first missed menstrual period, in the second and third trimesters of pregnancy and one month after delivery. Levothyroxine dosage was adjusted according to TSH levels measured. Of the 81 pregnancies studied, the pregnancy outcomes were 74 full-term births, six abortions and one pre-term birth. The levothyroxine dosage needed to be increased in 84% (CI95%= 74-90) of the pregnancies (OR=5.2, CI95%= 2.9-9.4). Most levothyroxine dose adjustments were made in the first trimester of gestation. The levothyroxine requirement increased 50% (CI95%= 41-59) in the first trimester, 55% (CI95%= 45-64) in the second trimester and 62% (CI95%= 52-72) in the third trimester. Levothyroxine dosage was decreased for 6 cases (7.4%), and no adjustment was made for 7 women (8.6%). Increases in levothyroxine dosage administered in pregnancy appear to be indispensible in the majority of patients with well-controlled hypothyroidism, especially in the first trimester. However, this change was not universal and levothyroxine dosage decreased in a few cases and remained unchanged in others.

  4. Creating biological nanomaterials using synthetic biology. (United States)

    Rice, MaryJoe K; Ruder, Warren C


    Synthetic biology is a new discipline that combines science and engineering approaches to precisely control biological networks. These signaling networks are especially important in fields such as biomedicine and biochemical engineering. Additionally, biological networks can also be critical to the production of naturally occurring biological nanomaterials, and as a result, synthetic biology holds tremendous potential in creating new materials. This review introduces the field of synthetic biology, discusses how biological systems naturally produce materials, and then presents examples and strategies for incorporating synthetic biology approaches in the development of new materials. In particular, strategies for using synthetic biology to produce both organic and inorganic nanomaterials are discussed. Ultimately, synthetic biology holds the potential to dramatically impact biological materials science with significant potential applications in medical systems.

  5. Word selection affects perceptions of synthetic biology

    Directory of Open Access Journals (Sweden)

    Tonidandel Scott


    Full Text Available Abstract Members of the synthetic biology community have discussed the significance of word selection when describing synthetic biology to the general public. In particular, many leaders proposed the word "create" was laden with negative connotations. We found that word choice and framing does affect public perception of synthetic biology. In a controlled experiment, participants perceived synthetic biology more negatively when "create" was used to describe the field compared to "construct" (p = 0.008. Contrary to popular opinion among synthetic biologists, however, low religiosity individuals were more influenced negatively by the framing manipulation than high religiosity people. Our results suggest that synthetic biologists directly influence public perception of their field through avoidance of the word "create".

  6. Synthetic biology - the state of play. (United States)

    Kitney, Richard; Freemont, Paul


    Just over two years ago there was an article in Nature entitled "Five Hard Truths for Synthetic Biology". Since then, the field has moved on considerably. A number of economic commentators have shown that synthetic biology very significant industrial potential. This paper addresses key issues in relation to the state of play regarding synthetic biology. It first considers the current background to synthetic biology, whether it is a legitimate field and how it relates to foundational biological sciences. The fact that synthetic biology is a translational field is discussed and placed in the context of the industrial translation process. An important aspect of synthetic biology is platform technology, this topic is also discussed in some detail. Finally, examples of application areas are described. Copyright © 2012. Published by Elsevier B.V.

  7. Creating biological nanomaterials using synthetic biology

    International Nuclear Information System (INIS)

    Rice, MaryJoe K; Ruder, Warren C


    Synthetic biology is a new discipline that combines science and engineering approaches to precisely control biological networks. These signaling networks are especially important in fields such as biomedicine and biochemical engineering. Additionally, biological networks can also be critical to the production of naturally occurring biological nanomaterials, and as a result, synthetic biology holds tremendous potential in creating new materials. This review introduces the field of synthetic biology, discusses how biological systems naturally produce materials, and then presents examples and strategies for incorporating synthetic biology approaches in the development of new materials. In particular, strategies for using synthetic biology to produce both organic and inorganic nanomaterials are discussed. Ultimately, synthetic biology holds the potential to dramatically impact biological materials science with significant potential applications in medical systems. (review)

  8. Derivative spectrophotometric method for simultaneous determination of clindamycin phosphate and tretinoin in pharmaceutical dosage forms. (United States)

    Barazandeh Tehrani, Maliheh; Namadchian, Melika; Fadaye Vatan, Sedigheh; Souri, Effat


    A derivative spectrophotometric method was proposed for the simultaneous determination of clindamycin and tretinoin in pharmaceutical dosage forms. The measurement was achieved using the first and second derivative signals of clindamycin at (1D) 251 nm and (2D) 239 nm and tretinoin at (1D) 364 nm and (2D) 387 nm.The proposed method showed excellent linearity at both first and second derivative order in the range of 60-1200 and 1.25-25 μg/ml for clindamycin phosphate and tretinoin respectively. The within-day and between-day precision and accuracy was in acceptable range (CVpharmaceutical dosage form.

  9. UV Spectrophotometric Estimation of Acipimox inBulk and Capsule Dosage Form

    Directory of Open Access Journals (Sweden)

    A. Elphine Prabahar


    Full Text Available A new simple, rapid, accurate, sensitive and precise spectrophotometric method in ultra violet region has been developed for determination of acipimox (ACX in bulk and capsule dosage form. Acipimox exhibited maximum absorbance at 231 nm with apparent molar absorptivity of 1.5104 × 104 in distilled water. Beer’s law was found to be obeyed in the concentration range 1-10 μg mL-1. Correlation coefficient was found to be 0.9998. The developed method was validated respect to linearity, precision, accuracy. The proposed method is useful for the routine estimation of ACX in bulk and capsule dosage form.

  10. Short-time, high-dosage penicillin infusion therapy of syphilis

    DEFF Research Database (Denmark)

    Lomholt, Hans; Poulsen, Asmus; Brandrup, Flemming


    The optimal dosage and duration of penicillin treatment for the various stages of syphilis are not known. We present data on 20 patients with syphilis (primary, secondary or latent) treated with high-dose, short-time penicillin infusion therapy. Patients were given 10 MIU of penicillin G intraven......The optimal dosage and duration of penicillin treatment for the various stages of syphilis are not known. We present data on 20 patients with syphilis (primary, secondary or latent) treated with high-dose, short-time penicillin infusion therapy. Patients were given 10 MIU of penicillin G...

  11. CD4+ T cells targeting dominant and cryptic epitopes from Bacillus anthracis Lethal Factor

    Directory of Open Access Journals (Sweden)

    Stephanie eAscough


    Full Text Available 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 analysed 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 characterised epitopes that elicited a response following immunisation 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, 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 trangenics. 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

  12. Genome-Wide Dosage-Dependent and -Independent Regulation Contributes to Gene Expression and Evolutionary Novelty in Plant Polyploids. (United States)

    Shi, Xiaoli; Zhang, Changqing; Ko, Dae Kwan; Chen, Z Jeffrey


    Polyploidy provides evolutionary and morphological novelties in many plants and some animals. However, the role of genome dosage and composition in gene expression changes remains poorly understood. Here, we generated a series of resynthesized Arabidopsis tetraploids that contain 0-4 copies of Arabidopsis thaliana and Arabidopsis arenosa genomes and investigated ploidy and hybridity effects on gene expression. Allelic expression can be defined as dosage dependent (expression levels correlate with genome dosages) or otherwise as dosage independent. Here, we show that many dosage-dependent genes contribute to cell cycle, photosynthesis, and metabolism, whereas dosage-independent genes are enriched in biotic and abiotic stress responses. Interestingly, dosage-dependent genes tend to be preserved in ancient biochemical pathways present in both plant and nonplant species, whereas many dosage-independent genes belong to plant-specific pathways. This is confirmed by an independent analysis using Arabidopsis phylostratigraphic map. For A. thaliana loci, the dosage-dependent alleles are devoid of TEs and tend to correlate with H3K9ac, H3K4me3, and CG methylation, whereas the majority of dosage-independent alleles are enriched with TEs and correspond to H3K27me1, H3K27me3, and CHG (H = A, T, or C) methylation. Furthermore, there is a parent-of-origin effect on nonadditively expressed genes in the reciprocal allotetraploids especially when A. arenosa is used as the pollen donor, leading to metabolic and morphological changes. Thus, ploidy, epigenetic modifications, and cytoplasmic-nuclear interactions shape gene expression diversity in polyploids. Dosage-dependent expression can maintain growth and developmental stability, whereas dosage-independent expression can facilitate functional divergence between homeologs (subfunctionalization and/or neofunctionalization) during polyploid evolution. © The Author 2015. Published by Oxford University Press on behalf of the Society for

  13. A synthetic zero air standard (United States)

    Pearce, Ruth


    A Synthetic Zero Air Standard R. E. Hill-Pearce, K. V. Resner, D. R. Worton, P. J. Brewer The National Physical Laboratory Teddington, Middlesex TW11 0LW UK We present work towards providing traceability for measurements of high impact greenhouse gases identified by the World Meteorological Organisation (WMO) as critical for global monitoring. Standards for these components are required with challengingly low uncertainties to improve the quality assurance and control processes used for the global networks to better assess climate trends. Currently the WMO compatibility goals require reference standards with uncertainties of < 100 nmolmol-1 for CO2 (northern hemisphere) and < 2 nmolmol-1 for CH4 and CO. High purity zero gas is required for both the balance gas in the preparation of reference standards and for baseline calibrations of instrumentation. Quantification of the amount fraction of the target components in the zero gas is a significant contributor to the uncertainty and is challenging due to limited availability of reference standard at the amount fraction of the measurand and limited analytical techniques with sufficient detection limits. A novel dilutor was used to blend NPL Primary Reference Gas Mixtures containing CO2, CH4 and CO at atmospheric amount fractions with a zero gas under test. Several mixtures were generated with nominal dilution ratios ranging from 2000:1 to 350:1. The baseline of two cavity ring down spectrometers was calibrated using the zero gas under test after purification by oxidative removal of CO and hydrocarbons to < 1 nmolmol-1 (SAES PS15-GC50) followed by the removal of CO2 and water vapour to < 100 pmolmol-1 (SAES MC190). Using the standard addition method.[1] we have quantified the amount fraction of CO, CO2, and CH4 in scrubbed whole air (Scott Marrin) and NPL synthetic zero air. This is the first synthetic zero air standard with a matrix of N2, O2 and Ar closely matching ambient composition with gravimetrically assigned

  14. Geo synthetic-reinforced Pavement systems

    International Nuclear Information System (INIS)

    Zornberg, J. G.


    Geo synthetics have been used as reinforcement inclusions to improve pavement performance. while there are clear field evidence of the benefit of using geo synthetic reinforcements, the specific conditions or mechanisms that govern the reinforcement of pavements are, at best, unclear and have remained largely unmeasured. Significant research has been recently conducted with the objectives of: (i) determining the relevant properties of geo synthetics that contribute to the enhanced performance of pavement systems, (ii) developing appropriate analytical, laboratory and field methods capable of quantifying the pavement performance, and (iii) enabling the prediction of pavement performance as a function of the properties of the various types of geo synthetics. (Author)

  15. Veterans Affairs Suicide Prevention Synthetic Dataset (United States)

    Department of Veterans Affairs — The VA's Veteran Health Administration, in support of the Open Data Initiative, is providing the Veterans Affairs Suicide Prevention Synthetic Dataset (VASPSD). The...

  16. Characterization of Synthetic Peptides by Mass Spectrometry

    DEFF Research Database (Denmark)

    Prabhala, Bala K; Mirza, Osman; Højrup, Peter


    Mass spectrometry (MS) is well suited for analysis of the identity and purity of synthetic peptides. The sequence of a synthetic peptide is most often known, so the analysis is mainly used to confirm the identity and purity of the peptide. Here, simple procedures are described for MALDI-TOF-MS an......Mass spectrometry (MS) is well suited for analysis of the identity and purity of synthetic peptides. The sequence of a synthetic peptide is most often known, so the analysis is mainly used to confirm the identity and purity of the peptide. Here, simple procedures are described for MALDI...

  17. Synthetic biology assemblies for sustainable space exploration (United States)

    National Aeronautics and Space Administration — The work utilized synthetic biology to create sustainable food production processes by developing technology to efficiently convert inedible crop waste to...

  18. Crystal Structure of Protein Reveals Target for Drugs Against Lethal MERS Virus | FNLCR Staging (United States)

    A research team of scientists from the National Cancer Institute and the Frederick National Laboratory for Cancer Research recently identified the structure of a key protein of the virus that causes the highly lethal Middle East Respiratory Syndrome.

  19. Comparative influence of dose rate and radiation nature, on lethality after big mammals irradiation

    International Nuclear Information System (INIS)

    Destombe, C.; Le Fleche, Ph.; Grasseau, A.; Reynal, A.


    For the same dose and the 30 days lethality as biological criterion, the dose rate influence is more important than the radiation nature on the results of an big mammals total body irradiation. (authors)

  20. The Effects of Posture, Body Armor and Other Equipment on Rifleman Lethality

    National Research Council Canada - National Science Library

    Kramlich, Gary R., II


    ...? This study quantifies the effects of Soldier equipment on lethality through multi-factor logistic regression using data from range experiments with the 1st Brigade, 1st Infantry Division (Mechanized...

  1. CDC Vital Signs: Making Health Care Safer -- Stop Infections from Lethal CRE Germs Now (United States)

    ... Making Health Care Safer Stop Infections from Lethal CRE Germs Now Recommend on Facebook Tweet Share Compartir ... hospitals had at least one patient with a CRE (carbapenem-resistant Enterobacteriaceae) infection during the first half ...

  2. Lethal effects of Helianthemum lippii (L.) on Acanthamoeba castellanii cysts in vitro. (United States)

    Badria, F A; Hetta, M H; Sarhan, Rania M; Ezz El-Din, M H


    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.

  3. Synthetic biology: engineering molecular computers

    CERN Document Server

    CERN. Geneva


    Complicated systems cannot survive the rigors of a chaotic environment, without balancing mechanisms that sense, decide upon and counteract the exerted disturbances. Especially so with living organisms, forced by competition to incredible complexities, escalating also their self-controlling plight. Therefore, they compute. Can we harness biological mechanisms to create artificial computing systems? Biology offers several levels of design abstraction: molecular machines, cells, organisms... ranging from the more easily-defined to the more inherently complex. At the bottom of this stack we find the nucleic acids, RNA and DNA, with their digital structure and relatively precise interactions. They are central enablers of designing artificial biological systems, in the confluence of engineering and biology, that we call Synthetic biology. In the first part, let us follow their trail towards an overview of building computing machines with molecules -- and in the second part, take the case study of iGEM Greece 201...

  4. Preparation of synthetic standard minerals

    International Nuclear Information System (INIS)

    Herrick, C.C.; Bustamante, S.J.; Charls, R.W.; Cowan, R.E.; Hakkila, E.A.; Hull, D.E.; Olinger, B.W.; Roof, R.B.; Sheinberg, H.; Herrick, G.C.


    A number of techniques for synthetic mineral preparations have been examined. These techniques include hot-pressing in graphite dies at moderate pressures, high-pressure, high-temperature synthesis in a piston and cylinder apparatus, isostatic pressing under helium gas pressures, hydrous mineral preparations using water as the pressure medium, explosion-generated shock waves, and radiofrequency heating. Minerals suitable for equation-of-state studies (three-inch, high-density discs), for thermodynamic property determinations (low-density powders) and for microprobe standards (fusion-cast microbeads) have been prepared. Mechanical stress-strain calculations in the piston-cylinder apparatus have been initiated and their integration with thermal stress calculations is currently under investigation

  5. Synthetic biology of antimicrobial discovery (United States)

    Zakeri, Bijan; Lu, Timothy K.


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

  6. Synthetic aperture interferometry: error analysis

    Energy Technology Data Exchange (ETDEWEB)

    Biswas, Amiya; Coupland, Jeremy


    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.

  7. Synthetic aperture interferometry: error analysis

    International Nuclear Information System (INIS)

    Biswas, Amiya; Coupland, Jeremy


    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.

  8. Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells

    International Nuclear Information System (INIS)

    Kang, Jian; Sergio, C Marcelo; Sutherland, Robert L; Musgrove, Elizabeth A


    Although MYC is an attractive therapeutic target for breast cancer treatment, it has proven challenging to inhibit MYC directly, and clinically effective pharmaceutical agents targeting MYC are not yet available. An alternative approach is to identify genes that are synthetically lethal in MYC-dependent cancer. Recent studies have identified several cell cycle kinases as MYC synthetic-lethal genes. We therefore investigated the therapeutic potential of specific cyclin-dependent kinase (CDK) inhibition in MYC-driven breast cancer. Using small interfering RNA (siRNA), MYC expression was depleted in 26 human breast cancer cell lines and cell proliferation evaluated by BrdU incorporation. MYC-dependent and MYC-independent cell lines were classified based on their sensitivity to siRNA-mediated MYC knockdown. We then inhibited CDKs including CDK4/6, CDK2 and CDK1 individually using either RNAi or small molecule inhibitors, and compared sensitivity to CDK inhibition with MYC dependence in breast cancer cells. Breast cancer cells displayed a wide range of sensitivity to siRNA-mediated MYC knockdown. The sensitivity was correlated with MYC protein expression and MYC phosphorylation level. Sensitivity to siRNA-mediated MYC knockdown did not parallel sensitivity to the CDK4/6 inhibitor PD0332991; instead MYC-independent cell lines were generally sensitive to PD0332991. Cell cycle arrest induced by MYC knockdown was accompanied by a decrease in CDK2 activity, but inactivation of CDK2 did not selectively affect the viability of MYC-dependent breast cancer cells. In contrast, CDK1 inactivation significantly induced apoptosis and reduced viability of MYC-dependent cells but not MYC- independent cells. This selective induction of apoptosis by CDK1 inhibitors was associated with up-regulation of the pro-apoptotic molecule BIM and was p53-independent. Overall, these results suggest that further investigation of CDK1 inhibition as a potential therapy for MYC-dependent breast cancer

  9. Novel Chromatographic Methods for Simultaneous Quantification of Fish and Wheat Germ Oils Mixture in Pharmaceutical Dosage Forms. (United States)

    El-Yazbi, Amira F; El-Hawiet, Amr


    Two simple, direct and environment-friendly chromatographic methods, high-performance liquid chromatography (HPLC) and high-performance thin layer chromatographic (HPTLC), were developed for the determination of a binary mixture of fish oil (FO) and wheat germ oil (WGO), for the first time, in their pharmaceutical dosage forms with no need for any sample pretreatment. The HPLC separation was carried out using C-18 stationary phase with mobile phase of 15% formic acid (pH 6), methanol and acetonitrile through gradient-elution, 1.5 mL min-1 flow-rate and detection at 215 nm for FO and 280 nm for WGO. HPTLC separation was carried out on silica-coated plates using diethyl ether-petroleum ether (0.5:9.5, v/v) as mobile phase. Detection was at 215 nm for FO and 240 nm for WGO. Regression analysis showed good linear relationship with r > 0.999 in the concentration-ranges of 0.2-2 mg mL-1 and 2.5-20 μg band-1 for WGO by HPLC and HPTLC methods, respectively, and 0.4-10 mg mL-1 and 25-200 μg band-1 for FO by HPLC and HPTLC methods, respectively. The methods were validated, showed good analytical performance and were successfully applied for the analysis of pharmaceutical formulations and synthetic mixtures of the analytes with good recoveries. Therefore, the two methods could be conveniently adopted for routine analysis of similar products in quality control laboratories of pharmaceutical industries especially that simultaneous determination of FO-WGO mixture has not been reported previously. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email:

  10. Microorganism Utilization for Synthetic Milk (United States)

    Morford, Megan A.; Khodadad, Christina L.; Caro, Janicce I.; Spencer, LaShelle E.; Richards, Jeffery T.; Strayer, Richard F.; Birmele, Michele N.; Wheeler, Raymond M.


    A desired architecture for long duration spaceflight, like aboard the International Space Station or for future missions to Mars, is to provide a supply of fresh food crops for the astronauts. However, some crops can create a high proportion of inedible plant waste. The main goal of the Synthetic Biology project, Cow in a Column, was to produce the components of milk (sugar, lipid, protein) from inedible plant waste by utilizing microorganisms (fungi, yeast, bacteria). Of particular interest was utilizing the valuable polysaccharide, cellulose, found in plant waste, to naturally fuel-through microorganism cellular metabolism- the creation of sugar (glucose), lipid (milk fat), and protein (casein) in order to produce a synthetic edible food product. Environmental conditions such as pH, temperature, carbon source, aeration, and choice microorganisms were optimized in the laboratory and the desired end-products, sugars and lipids, were analyzed. Trichoderma reesei, a known cellulolytic fungus, was utilized to drive the production of glucose, with the intent that the produced glucose would serve as the carbon source for milk fat production and be a substitute for the milk sugar lactose. Lipid production would be carried out by Rhodosporidium toruloides, yeast known to accumulate those lipids that are typically found in milk fat. Results showed that glucose and total lipid content were below what was expected during this phase of experimentation. In addition, individual analysis of six fatty acids revealed that the percentage of each fatty acid was lower than naturally produced bovine milk. Overall, this research indicates that microorganisms could be utilized to breakdown inedible solid waste to produce useable products. For future work, the production of the casein protein for milk would require the development of a genetically modified organism, which was beyond the scope of the original project. Additional trials would be needed to further refine the required

  11. Modifier Genes for Mouse Phosphatidylinositol Transfer Protein alpha (vibrator) That Bypass Juvenile Lethality

    NARCIS (Netherlands)

    Concepcion, Dorothy; Johannes, Frank; Lo, Yuan Hung; Yao, Jay; Fong, Jerry; Hamilton, Bruce A.

    Phosphatidylinositol transfer proteins (PITPs) mediate lipid signaling and membrane trafficking in eukaryotic cells. Loss-of-function mutations of the gene encoding PITP alpha in mice result in a range of dosage-sensitive phenotypes, including neurological dysfunction, neurodegeneration, and

  12. Determination of the Median Lethal Dose and Electrophoretic Pattern of Hottentotta saulcyi (Scorpiones, Buthidae) Scorpion Venom


    Ya?mur, Ersen Ayd?n; ?zkan, ?zcan; Karaer, K Zafer


    Background: In this study, we investigated the lethal potency, electrophoretic protein pattern and in vivo effects of Hottentotta saulcyi scorpion venom in mice.Methods: Scorpions were collected at night, by using a UV lamp from Mardin Province, Turkey. Venom was obtained from mature H. saulcyi scorpions by electrical stimulation of the telson. The lethality of the venom was determined by i.v. injections using Swiss mice. In vivo effects of the venom were assessed by using the intraperitoneal...

  13. Lethal isotherms of cryoablation in a phantom study: effects of heat load, probe size, and number. (United States)

    Littrup, Peter J; Jallad, Bassel; Vorugu, Vinaya; Littrup, Gunnar; Currier, Brandt; George, Mikhail; Herring, Donald


    To assess the effects on the proportions of lethal ice (ie, colder than -30 degrees C) in phantoms with different heat loads created by varying the size and number of cryoprobes spaced 2 cm apart. Thermocouples at 0.5-, 1.0-, and 1.5-cm intervals from 1.7- or 2.4-mm-diameter cryoprobes were held by jigs accommodating a maximum of four cryoprobes. Agar phantoms (N = 24) used three sets of baseline temperatures: approximately 6 degrees C, 24 degrees C, and 39 degrees C. Temperatures during 15-minute freeze cycles were correlated with actual thermocouple locations seen within the ice by computed tomography (CT). Diameters and surface areas of the -30 degrees C lethal isotherm were assessed over time as percentages of the overall ice ball. The high-heat load phantom experiments (39 degrees C) showed the greatest impact on lethal zones by percentage for all probe configurations. At 15 minutes, single-, double-, triple-, and quadruple-probe arrangements of 2.4-mm cryoprobes had average lethal ice diameters of 1.2, 3.3, 4.1, and 4.9 cm, respectively, comprising 13%, 46%, 51%, and 56% surface areas of lethal ice, respectively. Surface areas and diameters of lethal ice made by 1.7-mm cryoprobes were 71% and 84% of those made by 2.4-mm cryoprobes, respectively. Lethal ice resides less than 1 cm behind the leading edge for nearly all probe configurations and heat loads. Single cryoprobes create very low percentages of lethal ice. Multiple cryoprobes overcome the high heat load of body temperature phantoms and help compensate for the lower freeze capacity of thinner cryoprobes.

  14. Flexible, Smart, and Lethal: Adapting US SEAD Doctrine to Changing Threats (United States)


    Summer 2016 | 65 Flexible , Smart, and Lethal Adapting US SEAD Doctrine to Changing Threats 2nd Lt Elliot M. Bucki, USAF* Disclaimer: The views and...difficult than in the past. Moreover, it specifically mentions how the mobility Summer 2016 | 67 Flexible , Smart, and Lethal of an IADS has made... flexibility is built into the targeting process and the ATO.4 Planning that incorporates decentralized execution is critical to any SEAD effort in an A2

  15. Recovery from UV-induced potentially lethal damage in systemic lupus erythematosus skin fibroblasts

    International Nuclear Information System (INIS)

    Zamansky, G.B.


    The repair of ultraviolet light-induced potentially lethal damage was investigated in density-inhibited skin fibroblast cell strains derived from patients with systemic lupus erythematosus. The effect of exposure to polychromatic ultraviolet light composed of environmentally relevant wavelengths or to the more commonly studied, short wavelength (254 nm) ultraviolet light was studied. Systemic lupus erythematosus cells, which are hypersensitive to ultraviolet light under growth promoting conditions, were able to repair potentially lethal damage as well as normal cells. (author)

  16. Scopolamine methylbromide mitigates radiation induced damage and lethality in zebrafish

    International Nuclear Information System (INIS)

    Shrivastava, Nitisha; Joshi, Jayadev; Ghosh, Subhajit; Dimri, Manali; Prem Kumar, Indracanti; Sehgal, Neeta


    In view of the strategic importance radiation countermeasures hold, the present study was undertaken to screen a collection of small molecule clinical compounds for possible radioprotective action using zebrafish as a model system. Preliminary screening in developing zebrafish embryos (24 hour post fertilization, (hpf)) using damage manifestations and survival as end point identified scopolamine methylbromide (SMB), a muscarinic receptor antagonist, as a potential radiomitigator. It was found to be optimal (60% survival advantage after 6 th post irradiation day) at a dose of 80 μM when added 3 h post 20 Gy exposure. Mechanistic studies suggested that SMB though exhibited no significant antioxidant potential, but was found to limit radiation induced apoptosis (pre G1 population) quantified through flow cytometry (6 and 5% reduction after 8 or 24 h after treatments) and annexin V staining (8% reduction). Further, quantitative analysis, using caspase 3 assay, revealed a 2.46 fold increase in apoptosis in irradiated group and treatment of irradiated zebrafish embryos with SMB led to a significant reduction in global apoptosis (1.7 fold; p<0.05) when compared to irradiated group. In silico studies based on structural and functional similarity with known radioprotectors suggested similarities with atropine, a known anti-inflammatory agent with muscarinic antagonism and radioprotective potential. In view of this SMB was tested, in silico, for possible anti-inflammatory action. Molecular docking studies revealed that SMB interacts (B.E-8.0 Kcal/mole) with cycloxygenase-2 (COX-2). In lieu of this, anti-inflammation activity was assessed through ChIN (chemically induced inflammation) method in 3 dpf (days post fertilization) embryos and SMB was found to significantly inhibit inflammation at all doses studied from 20-200 μM at 3 and 6 hpi (hours post inflammation). Overall the result suggests that scopolamine methylbromide mitigates radiation induced injury and lethality in

  17. Materials Applications for Non-Lethal: Aqueous Foams

    International Nuclear Information System (INIS)



    High expansion aqueous foam is an aggregation of bubbles that has the appearance of soap suds and is used to isolate individuals both visually and acoustically. It was developed in the 1920's in England to fight coal mine fires and has been widely used since for fire fighting and dust suppression. It was developed at Sandia National Laboratories (SNL) in the 1970's for nuclear safeguards and security applications. In the mid-1990s, the National Institute of Justice (NIJ), the research arm of the Department of Justice, began a project with SNL to determine the applicability of high expansion aqueous foam for correctional applications. NIJ funded the project as part of its search for new and better less-than-lethal weapons for responding to violent and dangerous individuals, where other means of force could lead to serious injuries. The phase one objectives of the project were to select a low-to-no toxicity foam concentrate (foaming agent) with physical characteristics suited for use in a single cell or large prison disturbances, and to determine if the selected foam concentrate could serve as a carrier for Oleoresin Capsicum (OC) irritant. The phase two objectives were to conduct an extensive toxicology review of the selected foam concentrate and OC irritant, and to conduct respiration simulation experiments in the selected high expansion aqueous foam. The phase three objectives were to build a prototype individual cell aqueous foam system and to study the feasibility of aqueous foams for large prison facility disturbances. The phase four and five objectives were to use the prototype system to do large scale foam physical characteristics testing of the selected foam concentrate, and to have the prototype single cell system further evaluated by correctional representatives. Prison rather than street scenarios were evaluated as the first and most likely place for using the aqueous foam since prisons have recurrent incidents where officers and inmates might be

  18. Materials Applications for Non-Lethal: Aqueous Foams

    Energy Technology Data Exchange (ETDEWEB)



    High expansion aqueous foam is an aggregation of bubbles that has the appearance of soap suds and is used to isolate individuals both visually and acoustically. It was developed in the 1920's in England to fight coal mine fires and has been widely used since for fire fighting and dust suppression. It was developed at Sandia National Laboratories (SNL) in the 1970's for nuclear safeguards and security applications. In the mid-1990s, the National Institute of Justice (NIJ), the research arm of the Department of Justice, began a project with SNL to determine the applicability of high expansion aqueous foam for correctional applications. NIJ funded the project as part of its search for new and better less-than-lethal weapons for responding to violent and dangerous individuals, where other means of force could lead to serious injuries. The phase one objectives of the project were to select a low-to-no toxicity foam concentrate (foaming agent) with physical characteristics suited for use in a single cell or large prison disturbances, and to determine if the selected foam concentrate could serve as a carrier for Oleoresin Capsicum (OC) irritant. The phase two objectives were to conduct an extensive toxicology review of the selected foam concentrate and OC irritant, and to conduct respiration simulation experiments in the selected high expansion aqueous foam. The phase three objectives were to build a prototype individual cell aqueous foam system and to study the feasibility of aqueous foams for large prison facility disturbances. The phase four and five objectives were to use the prototype system to do large scale foam physical characteristics testing of the selected foam concentrate, and to have the prototype single cell system further evaluated by correctional representatives. Prison rather than street scenarios were evaluated as the first and most likely place for using the aqueous foam since prisons have recurrent incidents where officers and inmates might

  19. Identification of a cryptic lethal mutation in the mouse t(w73) haplotype. (United States)

    Howell, Gareth R; Bergstrom, Rebecca A; Munroe, Robert J; Masse, Jessica; Schimenti, John C


    t haplotypes are naturally occurring, variant forms of the t complex on mouse chromosome 17, characterized by the presence of four inversions with respect to wild-type. They harbour mutations causing male sterility, male transmission ratio distortion (TRD) and embryonic lethality. Mice carrying t haplotypes have been found throughout the world, and genetic studies of the lethal mutations have identified at least 16 complementation groups. The embryonic lethal phenotypes of many t haplotypes have been characterized in detail, and are thought to be the consequence of homozygosity for single gene mutations. However, the existence of additional mutations in genes that function at later stages of development would be obscured. Here we investigated the possibility of multiple mutations in t haplotypes by screening the t(w73) haplotype for the presence of novel mutations. Since genetic analysis of t haplotype mutations is hindered by recombination suppression due to the inversions, deletion complexes covering the proximal two-thirds of the t complex were used to uncover the presence of any new lethal alleles. This analysis revealed a novel mutation between D17Jcs41 and D17Mit100, causing mice carrying both t(w73) and selected deletions to die at birth, prior to feeding. The finding of a new, cryptic lethal mutation in t haplotypes is an indication that these recombinationally isolated chromosomes, which already contain at least one lethal mutation that prevents homozygosity, may serve as sinks for the accumulation of additional recessive mutations.

  20. Reproductive-phase and interphase lethal cell damage after irradiation and treatment with cytostatics

    International Nuclear Information System (INIS)

    Hagemann, G.


    After X-ray irradiation of manual cells, two lethal fractions occur due to reproductive and interphase death under low and high radiation doses. The damage kinetics on which this fact is based is compared with hypothetical tumour frequencies and leucemia induction caused in experiments. The reproductive-lethal damage can be manifested by means of colony size spectrometry, with the median colony size class differences (MCD) serving as measure for the damage found. The simultaneous effects of the cytostatics BLEOMYCIN or ICRF 159 and X-rays on reproductive lethal and interphase-lethal damage are measured by means of MCD and survival fraction, and the additive and intensifying effect' is judged with the help of suitably defined terms. This shows that the clinically used ICRF 159 has an additive effect on interphase-lethal and a sub-additive effect on reproductive-lethal cell damage. Thus, favourable results may be expected for the electivity factor in fractionated irradiation and with regard to delayed damage in healthy tissue. (orig.) 891 MG/orig. 892 RDG [de

  1. Horizontal gene transfer and gene dosage drives adaptation to wood colonization in a tree pathogen

    NARCIS (Netherlands)

    Dhillon, Braham; Feau, Nicolas; Aerts, Andrea L; Beauseigle, Stéphanie; Bernier, Louis; Copeland, Alex; Foster, Adam; Gill, Navdeep; Henrissat, Bernard; Herath, Padmini; LaButti, Kurt M; Levasseur, Anthony; Lindquist, Erika A; Majoor, Eline; Ohm, Robin A; Pangilinan, Jasmyn L; Pribowo, Amadeus; Saddler, John N; Sakalidis, Monique L; de Vries, Ronald P; Grigoriev, Igor V; Goodwin, Stephen B; Tanguay, Philippe; Hamelin, Richard C


    Some of the most damaging tree pathogens can attack woody stems, causing lesions (cankers) that may be lethal. To identify the genomic determinants of wood colonization leading to canker formation, we sequenced the genomes of the poplar canker pathogen, Mycosphaerella populorum, and the closely

  2. 77 FR 4226 - Oral Dosage Form New Animal Drugs; Gentamicin Sulfate (United States)


    ... environment. Therefore, neither an environmental assessment nor an environmental impact statement is required... to the Center for Veterinary Medicine, 21 CFR part 520 is amended as follows: PART 520--ORAL DOSAGE.... Flynn, Acting Director, Center for Veterinary Medicine. BILLING CODE 4160-01-P ...

  3. The effect of different dosages of caffeine on endurance performance time

    NARCIS (Netherlands)

    Pasman, W.J.; Baak, M.A. van; Jeukendrup, A.E.; Haan, A. de


    The effect of different dosages of caffeine (0 - 5 - 9 - 13 mg · kg body weight-1) on endurance performance was examined. Nine well-trained cyclists participated in this study (VO2max 65.1 + 2.6 ml · kg-1 · min-1). Caffeine capsules were administered in random order and double-blind. One hour after

  4. 3D printing of high drug loaded dosage forms using thermoplastic polyurethanes. (United States)

    Verstraete, G; Samaro, A; Grymonpré, W; Vanhoorne, V; Van Snick, B; Boone, M N; Hellemans, T; Van Hoorebeke, L; Remon, J P; Vervaet, C


    It was the aim of this study to develop high drug loaded (>30%, w/w), thermoplastic polyurethane (TPU)-based dosage forms via fused deposition modelling (FDM). Model drugs with different particle size and aqueous solubility were pre-processed in combination with diverse TPU grades via hot melt extrusion (HME) into filaments with a diameter of 1.75 ± 0.05 mm. Subsequently, TPU-based filaments which featured acceptable quality attributes (i.e. consistent filament diameter, smooth surface morphology and good mechanical properties) were printed into tablets. The sustained release potential of the 3D printed dosage forms was tested in vitro. Moreover, the impact of printing parameters on the in vitro drug release was investigated. TPU-based filaments could be loaded with 60% (w/w) fine drug powder without observing severe shark skinning or inconsistent filament diameter. During 3D printing experiments, HME filaments based on hard TPU grades were successfully converted into personalized dosage forms containing a high concentration of crystalline drug (up to 60%, w/w). In vitro release kinetics were mainly affected by the matrix composition and tablet infill degree. Therefore, this study clearly demonstrated that TPU-based FDM feedstock material offers a lot of formulation freedom for the development of personalized dosage forms. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. [Development of signal aquisition and processing software in the preformulation tests of solid dosage forms]. (United States)

    Kelemen, András; Hódi, Klára; Eros, István


    The authors demonstrate the essence and possibility of the computer programming and its role in the pharmaceutical preformulation. The paper surveys its importance in the development of pharmaceutical dosage forms, in the determination of procedure parameters and in the quality assurance.

  6. Predictors of ovarian response in intrauterine insemination patients and development of a dosage nomogram

    DEFF Research Database (Denmark)

    Freiesleben, N L C; Lossl, K; Bogstad, J


    The objective of this prospective study was to identify predictors of ovarian response in ovulatory patients treated with low-dose recombinant FSH (rFSH), gonadotrophin-releasing hormone antagonist and intrauterine insemination (IUI), and to develop an rFSH dosage nomogram based on the findings...

  7. Review of global regulations concerning biowaivers for immediate release solid oral dosage forms.

    NARCIS (Netherlands)

    Gupta, E; Barends, D M; Yamashita, E; Lentz, K A; Harmsze, A M; Shah, V P; Dressman, J B; Lipper, R A


    The regulations with respect to biowaivers for immediate release (IR) solid oral dosage forms in the USA, the EU, Japan and from the World Health Organization (WHO) are summarized and compared. Two case studies are presented, one from our own files and one from the open literature, showing the

  8. Oxycodone/acetaminophen at low dosage: an alternative pain treatment for patients with rheumatoid arthritis. (United States)

    Raffaeli, William; Pari, Claudia; Corvetta, Angelo; Sarti, Donatella; Di Sabatino, Valentina; Biasi, Giovanni; Galeazzi, Maurizio


    To assess efficacy and safety of the association oxycodone/acetaminophen (oxycodone/acetaminophen) for pain treatment and disability improvement in patients with rheumatoid arthritis (RA). Patients with RA (n = 29), suffering from moderate to severe pain for more than 3 months, were included in the study, except those under RA therapy with biological drugs. The treatment started with oxycodone/acetaminophen at the dosage of 5 mg/325 mg, and then the dosage was titrated until the attainment of good pain relief. Antiemetic and laxative therapy was used for the prophylaxis of known opioid-related adverse events. Patients continued their RA therapy without changing the dosages, reported reduced pain intensity and disease activity, and improvement of disability. Forty-two percent of patients had a good clinical response to oxycodone/acetaminophen treatment, according to European League against Rheumatism (EULAR) assessment criteria, and 50 percent of patients reached the American College of Rheumatology 20 percent improvement criteria (ACR20). At the end of the study, the mean (+/- SD) daily effective oxycodone/acetaminophen dose was 13.8 (+/- 6.8) mg/720.4 (+/- 291.0) mg. No serious adverse event was observed. Nausea, vomiting, and stipsis of mild-moderate intensity were the most common adverse events. Oxycodone/acetaminophen at low dosages for the treatment of chronic pain in RA patients can be a good alternative to non-steroidal antiinflammatory drugs (NSAIDs), allowing the reduction of their consumption, while keeping RA therapy stable.

  9. In-vitro Characterization of Optimized Multi-Unit Dosage Forms of ...

    African Journals Online (AJOL)

    Michael Horsfall

    22: 2342–2343. Folloniner N and Doelker E. Biopharmaceutical comparison of oral multiple-unit and single unit sustained–release dosage forms .STP Pharma. Sciences. 1992; 2: 141-155. Vial–Bernasconi AC, Doelker E and Buri P (1988). Prolonged release Capsules; divided and monolithic forms. STP Pharma Sciences.

  10. Use of fluorescence spectroscopy to control ozone dosage in recirculating aquaculture systems

    DEFF Research Database (Denmark)

    Spiliotopoulou, Aikaterini; Martin, Richard; Pedersen, Lars-Flemming


    The aim of this study was to investigate the potential of fluorescence spectroscopy to be used as an ozone dosage determination tool in recirculating aquaculture systems (RASs), by studying the relationship between fluorescence intensities and dissolved organic matter (DOM) degradation by ozone...

  11. Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Amoxicillin Trihydrate.

    NARCIS (Netherlands)

    Thambavita, Dhanusha; Galappatthy, Priyadarshani; Mannapperuma, Uthpali; Jayakody, Lal; Cristofoletti, Rodrigo; Abrahamsson, Bertil; Groot, Dirk W; Langguth, Peter; Mehta, Mehul; Parr, Alan; Polli, James E; Shah, Vinod P; Dressman, Jennifer


    Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System

  12. Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Enalapril.

    NARCIS (Netherlands)

    Verbeeck, Roger K; Kanfer, Isadore; Löbenberg, Raimar; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Langguth, Peter; Polli, James E; Parr, Alan; Shah, Vinod P; Mehta, Mehul; Dressman, Jennifer B

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate-release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active

  13. Minimum effective dosages of anti-TNF in rheumatoid arthritis: a cross-sectional study. (United States)

    de la Torre, Inmaculada; Valor, Lara; Nieto, Juan Carlos; Montoro, María; Carreño, Luis


    To evaluate the modified dosages of anti-TNF in controlling disease activity in rheumatoid arthritis (RA) measured by DAS28-ESR. Cross-sectional study: RA patients treated with etanercept (ETN), adalimumab (ADA) or infliximab (IFX), at standard or modified doses. dosage, concomitant disease modifying drugs (DMARDs), DAS28-ESR. 195 RA patients included (79% women, mean age 58.1 years): ETN=81, ADA=56, IFX=58. Mean disease duration and time to first biological treatment was higher in IFX group (P=.01). Patients distribution by dosage: standard: ETN (72.8%), ADA (69.6%), IFX (27.6%); escalated: IFX (69%), ADA (5.4%), ETN (0%); reduced: ETN (27.1%), ADA (25%), IFX (3.4%). Concomitant DMARDs use was lower in ETN (58.2%) than ADA (66.07%) and IFX (79.31%). Higher proportion of responders (DAS28 ≤3.2) in ADA (65.3%) and ETN (61.7%) than IFX (48.3%). RA clinical control can be preserved with modified anti-TNF dosages. Controlled prospective studies should be performed to define when therapy can be tailored and for which patients. Copyright © 2013 Elsevier España, S.L. All rights reserved.


    Directory of Open Access Journals (Sweden)

    G. Babaee


    Full Text Available Evaluated under laboratory condition. The objective of the present study was to observe the effect of impregnated torn bednets on the number of bites by An. culicifacies A glass made tunnel test was designed to The effect of torn bednets treated with three dosages of cyfluthrin 5% EW, were induce hungry female mosquitoes to pass through holes cut in the pyrethroid treated nets. A guinea pig used as bait to attract mosquitoes through circular holes in the netting. With untreated netting, 72-87% of laboratory-reared females passed through the holes overnight, 64-92% blood-fed successfully and 0.3/9-4/3% died. When the netting was treated with cyfluthrin at doses of 25, 50 and 100 mg a.i./m2, the entry Index (the proportions that passed through the holes overnight were 43.37%, 42.82% and 24.72%; mortality rates were 66.31%, 81.45% and 95.99%; and the feeding rate were 45%, 27% and 3%. In conclusion it should be stressed that efficacy of pyrethroid impregnated bednets using “Tunnel Tests” showing acceptable protection rate both in lower and higher dosages as well as cause dead in the blood-fed mosquitoes. In addition, the higher dosages of these three dosages pyrethroid provided good levels of protection against An. culicifacies.

  15. Differentiation in the Amsterdam methadone dispensing circuit: determinants of methadone dosage and site of methadone prescription

    NARCIS (Netherlands)

    Langendam, M. W.; van Haastrecht, H. J.; van Brussel, G. H.; Reurs, H.; van den Hoek, A. A.; Coutinho, R. A.; van Ameijden, E. J.


    To evaluate the Methadone Dispensing Circuit in Amsterdam by identifying determinants of methadone dosage and client characteristics in the different types of methadone programmes. Four hundred and forty-four participants of a cohort study of drug users in Amsterdam who had consented to link data of

  16. 76 FR 40229 - Oral Dosage Form New Animal Drugs; Change of Sponsor (United States)


    ... HUMAN SERVICES Food and Drug Administration 21 CFR Part 520 Oral Dosage Form New Animal Drugs; Change of... Administration (FDA) is amending the animal drug regulations to reflect a change of sponsor for a new animal drug... informed FDA that it has transferred ownership of, and all rights and interest in, NADA 092-150 for Purina...

  17. Material Considerations for Fused-Filament Fabrication of Solid Dosage Forms. (United States)

    Fuenmayor, Evert; Forde, Martin; Healy, Andrew V; Devine, Declan M; Lyons, John G; McConville, Christopher; Major, Ian


    Material choice is a fundamental consideration when it comes to designing a solid dosage form. The matrix material will ultimately determine the rate of drug release since the physical properties (solubility, viscosity, and more) of the material control both fluid ingress and disintegration of the dosage form. The bulk properties (powder flow, concentration, and more) of the material should also be considered since these properties will influence the ability of the material to be successfully manufactured. Furthermore, there is a limited number of approved materials for the production of solid dosage forms. The present study details the complications that can arise when adopting pharmaceutical grade polymers for fused-filament fabrication in the production of oral tablets. The paper also presents ways to overcome each issue. Fused-filament fabrication is a hot-melt extrusion-based 3D printing process. The paper describes the problems encountered in fused-filament fabrication with Kollidon ® VA64, which is a material that has previously been utilized in direct compression and hot-melt extrusion processes. Formulation and melt-blending strategies were employed to increase the printability of the material. The paper defines for the first time the essential parameter profile required for successful 3D printing and lists several pre-screening tools that should be employed to guide future material formulation for the fused-filament fabrication of solid dosage forms.

  18. Should probenecid be used to reduce the dicloxacillin dosage in orthopaedic infections?

    DEFF Research Database (Denmark)

    Krogsgaard, M R; Hansen, B A; Slotsbjerg, T


    Reduction in the dosage of dicloxacillin from 500 mg to 250 mg 3 times a day would mean lowering of costs and less side-effects in orthopaedic infections. In this cross-over study, the serum concentrations of dicloxacillin were measured in 9 patients after administration of dicloxacillin 500 mg 3...

  19. 75 FR 26647 - Implantation or Injectable Dosage Form New Animal Drugs; Ivermectin (United States)


    ... CFR Part 522 [Docket No. FDA-2010-N-0002] Implantation or Injectable Dosage Form New Animal Drugs... Administration (FDA) is amending the animal drug regulations to reflect approval of an abbreviated new animal... parasites. DATES: This rule is effective May 12, 2010. FOR FURTHER INFORMATION CONTACT: John K. Harshman...

  20. 75 FR 54018 - Oral Dosage Form New Animal Drugs; Praziquantel and Pyrantel (United States)


    ... Administration 21 CFR Part 520 [Docket No. FDA-2010-N-0002] Oral Dosage Form New Animal Drugs; Praziquantel and... Administration (FDA) is amending the animal drug regulations to reflect approval of a supplemental new animal... parasites and for a revised kitten age and weight restriction. DATES: This rule is effective September 3...